{"entity": "journal", "iuid": "c85b59c4344e4484a7aefd5db75fe804", "timestamp": "2026-07-14T01:07:30.608Z", "links": {"self": {"href": "https://publications.scilifelab.se/journal/Am.%20J.%20Hum.%20Genet..json"}, "display": {"href": "https://publications.scilifelab.se/journal/Am.%20J.%20Hum.%20Genet."}}, "title": "Am. J. Hum. Genet.", "issn": "1537-6605", "issn-l": "0002-9297", "publications_count": 29, "publications": [{"entity": "publication", "iuid": "cb2dbb24ca8e445283868bfaa092da83", "links": {"self": {"href": "https://publications.scilifelab.se/publication/cb2dbb24ca8e445283868bfaa092da83.json"}, "display": {"href": "https://publications.scilifelab.se/publication/cb2dbb24ca8e445283868bfaa092da83"}}, "title": "Population history and admixture of the Fulani people from the Sahel.", "authors": [{"family": "Fortes-Lima", "given": "Cesar A", "initials": "CA"}, {"family": "Diallo", "given": "Mame Y", "initials": "MY"}, {"family": "Janou\u0161ek", "given": "V\u00e1clav", "initials": "V"}, {"family": "\u010cern\u00fd", "given": "Viktor", "initials": "V"}, {"family": "Schlebusch", "given": "Carina M", "initials": "CM"}], "type": "journal article", "published": "2025-02-06", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "volume": "112", "issue": "2", "pages": "261-275", "issn-l": "0002-9297"}, "abstract": "The Fulani people, one of the most important pastoralist groups in sub-Saharan Africa, are still largely underrepresented in population genomic research. They speak a Niger-Congo language called Fulfulde or Pulaar and live in scattered locations across the Sahel/Savannah belt, from the Atlantic Ocean to Lake Chad. According to historical records, their ancestors spread from Futa Toro in the Middle Senegal Valley to Futa-Jallon in Guinea and then eastward into the Sahel belt over the past 1,500 years. However, the earlier history of this traditionally pastoral population has not been well studied. To uncover the genetic structure and ancestry of this widespread population, we gathered genome-wide genotype data from 460 individuals across 18 local Fulani populations, along with comparative data from both modern and ancient worldwide populations. This represents a comprehensive geographically wide-scaled genome-wide study of the Fulani. We revealed a genetic component closely associated with all local Fulani populations, suggesting a shared ancestral component possibly linked to the beginning of African pastoralism in the Green Sahara. Comparison to ancient DNA results also identified the presence of an ancient Iberomaurusian-associated component across all Fulani groups, providing additional insights into their deep genetic history. Additionally, our genetic data indicate a later Fulani expansion from the western to the eastern Sahel, characterized by a clinal pattern and admixture with several other African populations north of the equator.", "doi": "10.1016/j.ajhg.2024.12.015", "pmid": "39919708", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11866953"}, {"db": "pii", "key": "S0002-9297(24)00457-9"}], "notes": [], "created": "2025-11-28T10:41:50.237Z", "modified": "2025-11-28T10:41:50.264Z"}, {"entity": "publication", "iuid": "fa7683a6a0ce40a48cda36eb39c141b3", "links": {"self": {"href": "https://publications.scilifelab.se/publication/fa7683a6a0ce40a48cda36eb39c141b3.json"}, "display": {"href": "https://publications.scilifelab.se/publication/fa7683a6a0ce40a48cda36eb39c141b3"}}, "title": "Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.", "authors": [{"family": "Wallenius", "given": "Joel", "initials": "J"}, {"family": "Kafantari", "given": "Efthymia", "initials": "E"}, {"family": "Jhaveri", "given": "Emma", "initials": "E"}, {"family": "Gorcenco", "given": "Sorina", "initials": "S"}, {"family": "Ameur", "given": "Adam", "initials": "A"}, {"family": "Karremo", "given": "Christin", "initials": "C"}, {"family": "Dobloug", "given": "Sigurd", "initials": "S"}, {"family": "Karrman", "given": "Kristina", "initials": "K"}, {"family": "de Koning", "given": "Tom", "initials": "T"}, {"family": "Ilinca", "given": "Andreea", "initials": "A"}, {"family": "Landqvist Wald\u00f6", "given": "Maria", "initials": "M"}, {"family": "Arvidsson", "given": "Andreas", "initials": "A"}, {"family": "Persson", "given": "Staffan", "initials": "S"}, {"family": "Englund", "given": "Elisabet", "initials": "E"}, {"family": "Ehrencrona", "given": "Hans", "initials": "H"}, {"family": "Puschmann", "given": "Andreas", "initials": "A", "orcid": "0000-0002-3201-8198", "researcher": {"href": "https://publications.scilifelab.se/researcher/c8144cd82c4944c28c45ecdfb822fa20.json"}}], "type": "journal article", "published": "2024-01-04", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "volume": "111", "issue": "1", "pages": "82-95", "issn-l": "0002-9297"}, "abstract": "Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 (ZFHX3) in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found ZFHX3 repeat expansions in three additional families, all from the region of Sk\u00e5ne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades. Anticipation was observed in all families and correlated with different repeat lengths determined through long-read sequencing in two family members. The most severely affected individuals had marked autonomic dysfunction, with severe orthostatism as the most disabling clinical feature. Neuropathology revealed p62-positive intracytoplasmic and intranuclear inclusions in neurons of the central and enteric nervous system, as well as alpha-synuclein positivity. ZFHX3 is located within the 16q22 locus, to which spinocerebellar ataxia type 4 (SCA4) repeatedly had been mapped; the clinical phenotype in our families corresponded well with the unique phenotype described in SCA4, and the original SCA4 kindred originated from Sweden. ZFHX3 has known functions in neuronal development and differentiation n both the central and peripheral nervous system. Our findings demonstrate that SCA4 is caused by repeat expansions in ZFHX3.", "doi": "10.1016/j.ajhg.2023.11.008", "pmid": "38035881", "labels": {"NGI Uppsala (Uppsala Genome Center)": "Collaborative", "NGI Long read": "Collaborative", "National Genomics Infrastructure": "Collaborative", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10806739"}, {"db": "pii", "key": "S0002-9297(23)00403-2"}], "notes": [], "created": "2023-11-30T10:31:15.712Z", "modified": "2025-02-28T14:11:20.301Z"}, {"entity": "publication", "iuid": "27c0209f98a942d8a70dc1cd46e9b1f9", "links": {"self": {"href": "https://publications.scilifelab.se/publication/27c0209f98a942d8a70dc1cd46e9b1f9.json"}, "display": {"href": "https://publications.scilifelab.se/publication/27c0209f98a942d8a70dc1cd46e9b1f9"}}, "title": "Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.", "authors": [{"family": "Rosenhahn", "given": "Erik", "initials": "E"}, {"family": "O'Brien", "given": "Thomas J", "initials": "TJ"}, {"family": "Zaki", "given": "Maha S", "initials": "MS"}, {"family": "Sorge", "given": "Ina", "initials": "I"}, {"family": "Wieczorek", "given": "Dagmar", "initials": "D"}, {"family": "Rostasy", "given": "Kevin", "initials": "K"}, {"family": "Vitobello", "given": "Antonio", "initials": "A"}, {"family": "Nambot", "given": "Sophie", "initials": "S"}, {"family": "Alkuraya", "given": "Fowzan S", "initials": "FS"}, {"family": "Hashem", "given": "Mais O", "initials": "MO"}, {"family": "Alhashem", "given": "Amal", "initials": "A"}, {"family": "Tabarki", "given": "Brahim", "initials": "B"}, {"family": "Alamri", "given": "Abdullah S", "initials": "AS"}, {"family": "Al Safar", "given": "Ayat H", "initials": "AH"}, {"family": "Bubshait", "given": "Dalal K", "initials": "DK"}, {"family": "Alahmady", "given": "Nada F", "initials": "NF"}, {"family": "Gleeson", "given": "Joseph G", "initials": "JG"}, {"family": "Abdel-Hamid", "given": "Mohamed S", "initials": "MS"}, {"family": "Lesko", "given": "Nicole", "initials": "N"}, {"family": "Ygberg", "given": "Sofia", "initials": "S"}, {"family": "Correia", "given": "Sandrina P", "initials": "SP"}, {"family": "Wredenberg", "given": "Anna", "initials": "A"}, {"family": "Alavi", "given": "Shahryar", "initials": "S"}, {"family": "Seyedhassani", "given": "Seyed M", "initials": "SM"}, {"family": "Ebrahimi Nasab", "given": "Mahya", "initials": "M"}, {"family": "Hussien", "given": "Haytham", "initials": "H"}, {"family": "Omar", "given": "Tarek E I", "initials": "TEI"}, {"family": "Harzallah", "given": "Ines", "initials": "I"}, {"family": "Touraine", "given": "Renaud", "initials": "R"}, {"family": "Tajsharghi", "given": "Homa", "initials": "H"}, {"family": "Morsy", "given": "Heba", "initials": "H"}, {"family": "Houlden", "given": "Henry", "initials": "H"}, {"family": "Shahrooei", "given": "Mohammad", "initials": "M"}, {"family": "Ghavideldarestani", "given": "Maryam", "initials": "M"}, {"family": "Abdel-Salam", "given": "Ghada M H", "initials": "GMH"}, {"family": "Torella", "given": "Annalaura", "initials": "A"}, {"family": "Zanobio", "given": "Mariateresa", "initials": "M"}, {"family": "Terrone", "given": "Gaetano", "initials": "G"}, {"family": "Brunetti-Pierri", "given": "Nicola", "initials": "N"}, {"family": "Omrani", "given": "Abdolmajid", "initials": "A"}, {"family": "Hentschel", "given": "Julia", "initials": "J"}, {"family": "Lemke", "given": "Johannes R", "initials": "JR"}, {"family": "Sticht", "given": "Heinrich", "initials": "H"}, {"family": "Abou Jamra", "given": "Rami", "initials": "R"}, {"family": "Brown", "given": "Andre E X", "initials": "AEX"}, {"family": "Maroofian", "given": "Reza", "initials": "R"}, {"family": "Platzer", "given": "Konrad", "initials": "K"}], "type": "journal article", "published": "2022-08-04", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "volume": "109", "issue": "8", "pages": "1421-1435", "issn-l": "0002-9297"}, "abstract": "PPFIBP1 encodes for the liprin-\u03b21 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.", "doi": "10.1016/j.ajhg.2022.06.008", "pmid": "35830857", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9388382"}, {"db": "pii", "key": "S0002-9297(22)00261-0"}], "notes": [], "created": "2022-11-25T14:08:21.171Z", "modified": "2022-11-25T14:08:21.174Z"}, {"entity": "publication", "iuid": "290244e1fc43467897f79ecf0ffdbcb8", "links": {"self": {"href": "https://publications.scilifelab.se/publication/290244e1fc43467897f79ecf0ffdbcb8.json"}, "display": {"href": "https://publications.scilifelab.se/publication/290244e1fc43467897f79ecf0ffdbcb8"}}, "title": "Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.", "authors": [{"family": "Trpchevska", "given": "Natalia", "initials": "N"}, {"family": "Freidin", "given": "Maxim B", "initials": "MB"}, {"family": "Broer", "given": "Linda", "initials": "L"}, {"family": "Oosterloo", "given": "Berthe C", "initials": "BC"}, {"family": "Yao", "given": "Shuyang", "initials": "S"}, {"family": "Zhou", "given": "Yitian", "initials": "Y"}, {"family": "Vona", "given": "Barbara", "initials": "B"}, {"family": "Bishop", "given": "Charles", "initials": "C"}, {"family": "Bizaki-Vallaskangas", "given": "Argyro", "initials": "A"}, {"family": "Canlon", "given": "Barbara", "initials": "B"}, {"family": "Castellana", "given": "Fabio", "initials": "F"}, {"family": "Chasman", "given": "Daniel I", "initials": "DI"}, {"family": "Cherny", "given": "Stacey", "initials": "S"}, {"family": "Christensen", "given": "Kaare", "initials": "K"}, {"family": "Concas", "given": "Maria Pina", "initials": "MP"}, {"family": "Correa", "given": "Adolfo", "initials": "A"}, {"family": "Elkon", "given": "Ran", "initials": "R"}, {"family": "Estonian Biobank Research Team", "given": "", "initials": ""}, {"family": "Mengel-From", "given": "Jonas", "initials": "J"}, {"family": "Gao", "given": "Yan", "initials": "Y"}, {"family": "Giersch", "given": "Anne B S", "initials": "ABS"}, {"family": "Girotto", "given": "Giorgia", "initials": "G"}, {"family": "Gudjonsson", "given": "Alexander", "initials": "A"}, {"family": "Gudnason", "given": "Vilmundur", "initials": "V"}, {"family": "Heard-Costa", "given": "Nancy L", "initials": "NL"}, {"family": "Hertzano", "given": "Ronna", "initials": "R"}, {"family": "Hjelmborg", "given": "Jacob V B", "initials": "JVB"}, {"family": "Hjerling-Leffler", "given": "Jens", "initials": "J"}, {"family": "Hoffman", "given": "Howard J", "initials": "HJ"}, {"family": "Kaprio", "given": "Jaakko", "initials": "J"}, {"family": "Kettunen", "given": "Johannes", "initials": "J"}, {"family": "Krebs", "given": "Kristi", "initials": "K"}, {"family": "K\u00e4hler", "given": "Anna K", "initials": "AK"}, {"family": "Lallemend", "given": "Francois", "initials": "F"}, {"family": "Launer", "given": "Lenore J", "initials": "LJ"}, {"family": "Lee", "given": "I-Min", "initials": "I"}, {"family": "Leonard", "given": "Hampton", "initials": "H"}, {"family": "Li", "given": "Chuan-Ming", "initials": "C"}, {"family": "Lowenheim", "given": "Hubert", "initials": "H"}, {"family": "Magnusson", "given": "Patrik K E", "initials": "PKE"}, {"family": "van Meurs", "given": "Joyce", "initials": "J"}, {"family": "Milani", "given": "Lili", "initials": "L"}, {"family": "Morton", "given": "Cynthia C", "initials": "CC"}, {"family": "M\u00e4kitie", "given": "Antti", "initials": "A"}, {"family": "Nalls", "given": "Mike A", "initials": "MA"}, {"family": "Nardone", "given": "Giuseppe Giovanni", "initials": "GG"}, {"family": "Nygaard", "given": "Marianne", "initials": "M"}, {"family": "Palviainen", "given": "Teemu", "initials": "T"}, {"family": "Pratt", "given": "Sheila", "initials": "S"}, {"family": "Quaranta", "given": "Nicola", "initials": "N"}, {"family": "R\u00e4m\u00f6", "given": "Joel", "initials": "J"}, {"family": "Saarentaus", "given": "Elmo", "initials": "E"}, {"family": "Sardone", "given": "Rodolfo", "initials": "R"}, {"family": "Satizabal Barrera", "given": "Claudia L", "initials": "CL"}, {"family": "Schweinfurth", "given": "John M", "initials": "JM"}, {"family": "Seshadri", "given": "Sudha", "initials": "S"}, {"family": "Shiroma", "given": "Eric", "initials": "E"}, {"family": "Shulman", "given": "Eldad", "initials": "E"}, {"family": "Simonsick", "given": "Eleanor", "initials": "E"}, {"family": "Spankovich", "given": "Christopher", "initials": "C"}, {"family": "Tropitzsch", "given": "Anke", "initials": "A"}, {"family": "Lauschke", "given": "Volker M", "initials": "VM"}, {"family": "Sullivan", "given": "Patrick F", "initials": "PF"}, {"family": "Goedegebure", "given": "Andre", "initials": "A"}, {"family": "Cederroth", "given": "Christopher R", "initials": "CR"}, {"family": "Williams", "given": "Frances M K", "initials": "FMK"}, {"family": "Nagtegaal", "given": "Andries Paul", "initials": "AP"}], "type": "journal article", "published": "2022-05-12", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "issn-l": "0002-9297", "volume": "109", "issue": "6", "pages": "1077-1091"}, "abstract": "Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.", "doi": "10.1016/j.ajhg.2022.04.010", "pmid": "35580588", "labels": {"National Genomics Infrastructure": "Service", "NGI SNP genotyping": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(22)00158-6"}], "notes": [], "created": "2022-05-23T13:59:36.677Z", "modified": "2022-11-29T12:04:55.870Z"}, {"entity": "publication", "iuid": "56a4fca99c23457cbffab26350b351f1", "links": {"self": {"href": "https://publications.scilifelab.se/publication/56a4fca99c23457cbffab26350b351f1.json"}, "display": {"href": "https://publications.scilifelab.se/publication/56a4fca99c23457cbffab26350b351f1"}}, "title": "Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy.", "authors": [{"family": "Fatima", "given": "Ambrin", "initials": "A"}, {"family": "Hoeber", "given": "Jan", "initials": "J"}, {"family": "Schuster", "given": "Jens", "initials": "J"}, {"family": "Koshimizu", "given": "Eriko", "initials": "E"}, {"family": "Maya-Gonzalez", "given": "Carolina", "initials": "C"}, {"family": "Keren", "given": "Boris", "initials": "B"}, {"family": "Mignot", "given": "Cyril", "initials": "C"}, {"family": "Akram", "given": "Talia", "initials": "T"}, {"family": "Ali", "given": "Zafar", "initials": "Z"}, {"family": "Miyatake", "given": "Satoko", "initials": "S"}, {"family": "Tanigawa", "given": "Junpei", "initials": "J"}, {"family": "Koike", "given": "Takayoshi", "initials": "T"}, {"family": "Kato", "given": "Mitsuhiro", "initials": "M"}, {"family": "Murakami", "given": "Yoshiko", "initials": "Y"}, {"family": "Abdullah", "given": "Uzma", "initials": "U"}, {"family": "Ali", "given": "Muhammad Akhtar", "initials": "MA"}, {"family": "Fadoul", "given": "Rein", "initials": "R"}, {"family": "Laan", "given": "Loora", "initials": "L"}, {"family": "Castillejo-L\u00f3pez", "given": "Casimiro", "initials": "C"}, {"family": "Liik", "given": "Maarika", "initials": "M"}, {"family": "Jin", "given": "Zhe", "initials": "Z"}, {"family": "Birnir", "given": "Bryndis", "initials": "B"}, {"family": "Matsumoto", "given": "Naomichi", "initials": "N"}, {"family": "Baig", "given": "Shahid M", "initials": "SM"}, {"family": "Klar", "given": "Joakim", "initials": "J"}, {"family": "Dahl", "given": "Niklas", "initials": "N"}], "type": "journal article", "published": "2021-04-01", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "volume": "108", "issue": "4", "pages": "739-748", "issn-l": "0002-9297"}, "abstract": "Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.", "doi": "10.1016/j.ajhg.2021.02.015", "pmid": "33711248", "labels": {"NGI Uppsala (Uppsala Genome Center)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(21)00057-4"}, {"db": "pmc", "key": "PMC8059333"}], "notes": [], "created": "2021-04-09T17:52:14.286Z", "modified": "2024-01-16T13:48:40.133Z"}, {"entity": "publication", "iuid": "a5ffc222ff2f4848955dbd9ffdb38a85", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a5ffc222ff2f4848955dbd9ffdb38a85.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a5ffc222ff2f4848955dbd9ffdb38a85"}}, "title": "Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.", "authors": [{"family": "Li", "given": "Chen", "initials": "C"}, {"family": "Stoma", "given": "Svetlana", "initials": "S"}, {"family": "Lotta", "given": "Luca A", "initials": "LA"}, {"family": "Warner", "given": "Sophie", "initials": "S"}, {"family": "Albrecht", "given": "Eva", "initials": "E"}, {"family": "Allione", "given": "Alessandra", "initials": "A"}, {"family": "Arp", "given": "Pascal P", "initials": "PP"}, {"family": "Broer", "given": "Linda", "initials": "L"}, {"family": "Buxton", "given": "Jessica L", "initials": "JL"}, {"family": "Da Silva Couto Alves", "given": "Alexessander", "initials": "A"}, {"family": "Deelen", "given": "Joris", "initials": "J"}, {"family": "Fedko", "given": "Iryna O", "initials": "IO"}, {"family": "Gordon", "given": "Scott D", "initials": "SD"}, {"family": "Jiang", "given": "Tao", "initials": "T"}, {"family": "Karlsson", "given": "Robert", "initials": "R"}, {"family": "Kerrison", "given": "Nicola", "initials": "N"}, {"family": "Loe", "given": "Taylor K", "initials": "TK"}, {"family": "Mangino", "given": "Massimo", "initials": "M"}, {"family": "Milaneschi", "given": "Yuri", "initials": "Y"}, {"family": "Miraglio", "given": "Benjamin", "initials": "B"}, {"family": "Pervjakova", "given": "Natalia", "initials": "N"}, {"family": "Russo", "given": "Alessia", "initials": "A"}, {"family": "Surakka", "given": "Ida", "initials": "I"}, {"family": "van der Spek", "given": "Ashley", "initials": "A"}, {"family": "Verhoeven", "given": "Josine E", "initials": "JE"}, {"family": "Amin", "given": "Najaf", "initials": "N"}, {"family": "Beekman", "given": "Marian", "initials": "M"}, {"family": "Blakemore", "given": "Alexandra I", "initials": "AI"}, {"family": "Canzian", "given": "Federico", "initials": "F"}, {"family": "Hamby", "given": "Stephen E", "initials": "SE"}, {"family": "Hottenga", "given": "Jouke-Jan", "initials": "JJ"}, {"family": "Jones", "given": "Peter D", "initials": "PD"}, {"family": "Jousilahti", "given": "Pekka", "initials": "P"}, {"family": "M\u00e4gi", "given": "Reedik", "initials": "R"}, {"family": "Medland", "given": "Sarah E", "initials": "SE"}, {"family": "Montgomery", "given": "Grant W", "initials": "GW"}, {"family": "Nyholt", "given": "Dale R", "initials": "DR"}, {"family": "Perola", "given": "Markus", "initials": "M"}, {"family": "Pietil\u00e4inen", "given": "Kirsi H", "initials": "KH"}, {"family": "Salomaa", "given": "Veikko", "initials": "V"}, {"family": "Sillanp\u00e4\u00e4", "given": "Elina", "initials": "E"}, {"family": "Suchiman", "given": "H Eka", "initials": "HE"}, {"family": "van Heemst", "given": "Diana", "initials": "D"}, {"family": "Willemsen", "given": "Gonneke", "initials": "G"}, {"family": "Agudo", "given": "Antonio", "initials": "A"}, {"family": "Boeing", "given": "Heiner", "initials": "H"}, {"family": "Boomsma", "given": "Dorret I", "initials": "DI"}, {"family": "Chirlaque", "given": "Maria-Dolores", "initials": "MD"}, {"family": "Fagherazzi", "given": "Guy", "initials": "G"}, {"family": "Ferrari", "given": "Pietro", "initials": "P"}, {"family": "Franks", "given": "Paul", "initials": "P"}, {"family": "Gieger", "given": "Christian", "initials": "C"}, {"family": "Eriksson", "given": "Johan Gunnar", "initials": "JG"}, {"family": "Gunter", "given": "Marc", "initials": "M"}, {"family": "H\u00e4gg", "given": "Sara", "initials": "S"}, {"family": "Hovatta", "given": "Iiris", "initials": "I"}, {"family": "Imaz", "given": "Liher", "initials": "L"}, {"family": "Kaprio", "given": "Jaakko", "initials": "J"}, {"family": "Kaaks", "given": "Rudolf", "initials": "R"}, {"family": "Key", "given": "Timothy", "initials": "T"}, {"family": "Krogh", "given": "Vittorio", "initials": "V"}, {"family": "Martin", "given": "Nicholas G", "initials": "NG"}, {"family": "Melander", "given": "Olle", "initials": "O"}, {"family": "Metspalu", "given": "Andres", "initials": "A"}, {"family": "Moreno", "given": "Concha", "initials": "C"}, {"family": "Onland-Moret", "given": "N Charlotte", "initials": "NC"}, {"family": "Nilsson", "given": "Peter", "initials": "P", "orcid": "0000-0002-4657-8532", "researcher": {"href": "https://publications.scilifelab.se/researcher/799bcf1cf8cf451296f4535dd4ca9dc0.json"}}, {"family": "Ong", "given": "Ken K", "initials": "KK"}, {"family": "Overvad", "given": "Kim", "initials": "K"}, {"family": "Palli", "given": "Domenico", "initials": "D"}, {"family": "Panico", "given": "Salvatore", "initials": "S"}, {"family": "Pedersen", "given": "Nancy L", "initials": "NL"}, {"family": "Penninx", "given": "Brenda W J H", "initials": "BWJH"}, {"family": "Quir\u00f3s", "given": "J Ram\u00f3n", "initials": "JR"}, {"family": "Jarvelin", "given": "Marjo Riitta", "initials": "MR"}, {"family": "Rodr\u00edguez-Barranco", "given": "Miguel", "initials": "M"}, {"family": "Scott", "given": "Robert A", "initials": "RA"}, {"family": "Severi", "given": "Gianluca", "initials": "G"}, {"family": "Slagboom", "given": "P Eline", "initials": "PE"}, {"family": "Spector", "given": "Tim D", "initials": "TD"}, {"family": "Tjonneland", "given": "Anne", "initials": "A"}, {"family": "Trichopoulou", "given": "Antonia", "initials": "A"}, {"family": "Tumino", "given": "Rosario", "initials": "R"}, {"family": "Uitterlinden", "given": "Andr\u00e9 G", "initials": "AG"}, {"family": "van der Schouw", "given": "Yvonne T", "initials": "YT"}, {"family": "van Duijn", "given": "Cornelia M", "initials": "CM"}, {"family": "Weiderpass", "given": "Elisabete", "initials": "E"}, {"family": "Denchi", "given": "Eros Lazzerini", "initials": "EL"}, {"family": "Matullo", "given": "Giuseppe", "initials": "G"}, {"family": "Butterworth", "given": "Adam S", "initials": "AS"}, {"family": "Danesh", "given": "John", "initials": "J"}, {"family": "Samani", "given": "Nilesh J", "initials": "NJ"}, {"family": "Wareham", "given": "Nicholas J", "initials": "NJ"}, {"family": "Nelson", "given": "Christopher P", "initials": "CP"}, {"family": "Langenberg", "given": "Claudia", "initials": "C"}, {"family": "Codd", "given": "Veryan", "initials": "V"}], "type": "journal article", "published": "2020-03-05", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "volume": "106", "issue": "3", "pages": "389-404", "issn-l": "0002-9297"}, "abstract": "Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.", "doi": "10.1016/j.ajhg.2020.02.006", "pmid": "32109421", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(20)30048-3"}, {"db": "pmc", "key": "PMC7058826"}], "notes": [], "created": "2020-03-03T12:57:27.050Z", "modified": "2021-11-10T12:53:17.953Z"}, {"entity": "publication", "iuid": "4678681995a049ef9f7b56ce8b425c73", "links": {"self": {"href": "https://publications.scilifelab.se/publication/4678681995a049ef9f7b56ce8b425c73.json"}, "display": {"href": "https://publications.scilifelab.se/publication/4678681995a049ef9f7b56ce8b425c73"}}, "title": "Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.", "authors": [{"family": "Ferreira", "given": "Manuel A R", "initials": "MAR"}, {"family": "Mathur", "given": "Riddhima", "initials": "R"}, {"family": "Vonk", "given": "Judith M", "initials": "JM"}, {"family": "Szwajda", "given": "Agnieszka", "initials": "A"}, {"family": "Brumpton", "given": "Ben", "initials": "B"}, {"family": "Granell", "given": "Raquel", "initials": "R"}, {"family": "Brew", "given": "Bronwyn K", "initials": "BK"}, {"family": "Ullemar", "given": "Vilhelmina", "initials": "V"}, {"family": "Lu", "given": "Yi", "initials": "Y"}, {"family": "Jiang", "given": "Yunxuan", "initials": "Y"}, {"family": "23andMe Research Team", "given": "", "initials": ""}, {"family": "eQTLGen Consortium", "given": "", "initials": ""}, {"family": "BIOS Consortium", "given": "", "initials": ""}, {"family": "Magnusson", "given": "Patrik K E", "initials": "PKE"}, {"family": "Karlsson", "given": "Robert", "initials": "R"}, {"family": "Hinds", "given": "David A", "initials": "DA"}, {"family": "Paternoster", "given": "Lavinia", "initials": "L"}, {"family": "Koppelman", "given": "Gerard H", "initials": "GH"}, {"family": "Almqvist", "given": "Catarina", "initials": "C"}], "type": "journal article", "published": "2019-04-04", "journal": {"volume": "104", "issn": "1537-6605", "issue": "4", "pages": "665-684", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h 2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.", "doi": "10.1016/j.ajhg.2019.02.022", "pmid": "30929738", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(19)30067-9"}, {"db": "pmc", "key": "PMC6451732"}], "notes": [], "created": "2019-04-12T14:00:38.338Z", "modified": "2021-06-21T12:08:57.171Z"}, {"entity": "publication", "iuid": "6a246daa9ede49238c93e12475dc2a73", "links": {"self": {"href": "https://publications.scilifelab.se/publication/6a246daa9ede49238c93e12475dc2a73.json"}, "display": {"href": "https://publications.scilifelab.se/publication/6a246daa9ede49238c93e12475dc2a73"}}, "title": "A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.", "authors": [{"family": "Ferreira", "given": "Carlos R", "initials": "CR"}, {"family": "Xia", "given": "Zhi-Jie", "initials": "ZJ"}, {"family": "Cl\u00e9ment", "given": "Aur\u00e9lie", "initials": "A"}, {"family": "Parry", "given": "David A", "initials": "DA"}, {"family": "Davids", "given": "Mariska", "initials": "M"}, {"family": "Taylan", "given": "Fulya", "initials": "F"}, {"family": "Sharma", "given": "Prashant", "initials": "P"}, {"family": "Turgeon", "given": "Coleman T", "initials": "CT"}, {"family": "Blanco-S\u00e1nchez", "given": "Bernardo", "initials": "B"}, {"family": "Ng", "given": "Bobby G", "initials": "BG"}, {"family": "Logan", "given": "Clare V", "initials": "CV"}, {"family": "Wolfe", "given": "Lynne A", "initials": "LA"}, {"family": "Solomon", "given": "Benjamin D", "initials": "BD"}, {"family": "Cho", "given": "Megan T", "initials": "MT"}, {"family": "Douglas", "given": "Ganka", "initials": "G"}, {"family": "Carvalho", "given": "Daniel R", "initials": "DR"}, {"family": "Bratke", "given": "Heiko", "initials": "H"}, {"family": "Haug", "given": "Marte Gj\u00f8l", "initials": "MG"}, {"family": "Phillips", "given": "Jennifer B", "initials": "JB"}, {"family": "Wegner", "given": "Jeremy", "initials": "J"}, {"family": "Tiemeyer", "given": "Michael", "initials": "M"}, {"family": "Aoki", "given": "Kazuhiro", "initials": "K"}, {"family": "Undiagnosed Diseases Network", "given": "", "initials": ""}, {"family": "Scottish Genome Partnership", "given": "", "initials": ""}, {"family": "Nordgren", "given": "Ann", "initials": "A"}, {"family": "Hammarsj\u00f6", "given": "Anna", "initials": "A"}, {"family": "Duker", "given": "Angela L", "initials": "AL"}, {"family": "Rohena", "given": "Luis", "initials": "L"}, {"family": "Hove", "given": "Hanne Buciek", "initials": "HB"}, {"family": "Ek", "given": "Jakob", "initials": "J"}, {"family": "Adams", "given": "David", "initials": "D"}, {"family": "Tifft", "given": "Cynthia J", "initials": "CJ"}, {"family": "Onyekweli", "given": "Tito", "initials": "T"}, {"family": "Weixel", "given": "Tara", "initials": "T"}, {"family": "Macnamara", "given": "Ellen", "initials": "E"}, {"family": "Radtke", "given": "Kelly", "initials": "K"}, {"family": "Powis", "given": "Z\u00f6e", "initials": "Z"}, {"family": "Earl", "given": "Dawn", "initials": "D"}, {"family": "Gabriel", "given": "Melissa", "initials": "M"}, {"family": "Russi", "given": "Alvaro H Serrano", "initials": "AHS"}, {"family": "Brick", "given": "Lauren", "initials": "L"}, {"family": "Kozenko", "given": "Mariya", "initials": "M"}, {"family": "Tham", "given": "Emma", "initials": "E"}, {"family": "Raymond", "given": "Kimiyo M", "initials": "KM"}, {"family": "Phillips", "given": "John A", "initials": "JA"}, {"family": "Tiller", "given": "George E", "initials": "GE"}, {"family": "Wilson", "given": "William G", "initials": "WG"}, {"family": "Hamid", "given": "Rizwan", "initials": "R"}, {"family": "Malicdan", "given": "May C V", "initials": "MCV"}, {"family": "Nishimura", "given": "Gen", "initials": "G"}, {"family": "Grigelioniene", "given": "Giedre", "initials": "G"}, {"family": "Jackson", "given": "Andrew", "initials": "A"}, {"family": "Westerfield", "given": "Monte", "initials": "M"}, {"family": "Bober", "given": "Michael B", "initials": "MB"}, {"family": "Gahl", "given": "William A", "initials": "WA"}, {"family": "Freeze", "given": "Hudson H", "initials": "HH"}], "type": "journal article", "published": "2018-10-04", "journal": {"volume": "103", "issn": "1537-6605", "issue": "4", "pages": "553-567", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.", "doi": "10.1016/j.ajhg.2018.09.003", "pmid": "30290151", "labels": {"Clinical Genomics Stockholm": "Service", "Bioinformatics Support for Computational Resources": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(18)30314-8"}, {"db": "pmc", "key": "PMC6174323"}], "notes": [], "created": "2018-10-29T09:07:37.591Z", "modified": "2024-01-16T13:48:45.389Z"}, {"entity": "publication", "iuid": "1dd273f849134fb5844f129cd7b822d9", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1dd273f849134fb5844f129cd7b822d9.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1dd273f849134fb5844f129cd7b822d9"}}, "title": "A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.", "authors": [{"family": "Sung", "given": "Yun J", "initials": "YJ"}, {"family": "Winkler", "given": "Thomas W", "initials": "TW"}, {"family": "de Las Fuentes", "given": "Lisa", "initials": "L"}, {"family": "Bentley", "given": "Amy R", "initials": "AR"}, {"family": "Brown", "given": "Michael R", "initials": "MR"}, {"family": "Kraja", "given": "Aldi T", "initials": "AT"}, {"family": "Schwander", "given": "Karen", "initials": "K"}, {"family": "Ntalla", "given": "Ioanna", "initials": "I"}, {"family": "Guo", "given": "Xiuqing", "initials": "X"}, {"family": "Franceschini", "given": "Nora", "initials": "N"}, {"family": "Lu", "given": "Yingchang", "initials": "Y"}, {"family": "Cheng", "given": "Ching-Yu", "initials": "CY"}, {"family": "Sim", "given": "Xueling", "initials": "X"}, {"family": "Vojinovic", "given": "Dina", "initials": "D"}, {"family": "Marten", "given": "Jonathan", "initials": "J"}, {"family": "Musani", "given": "Solomon K", "initials": "SK"}, {"family": "Li", "given": "Changwei", "initials": "C"}, {"family": "Feitosa", "given": "Mary F", "initials": "MF"}, {"family": "Kilpel\u00e4inen", "given": "Tuomas O", "initials": "TO"}, {"family": "Richard", "given": "Melissa A", "initials": "MA"}, {"family": "Noordam", "given": "Raymond", "initials": "R"}, {"family": "Aslibekyan", "given": "Stella", "initials": "S"}, {"family": "Aschard", "given": "Hugues", "initials": "H"}, {"family": "Bartz", "given": "Traci M", "initials": "TM"}, {"family": "Dorajoo", "given": "Rajkumar", "initials": "R"}, {"family": "Liu", "given": "Yongmei", "initials": "Y"}, {"family": "Manning", "given": "Alisa K", "initials": "AK"}, {"family": "Rankinen", "given": "Tuomo", "initials": "T"}, {"family": "Smith", "given": "Albert Vernon", "initials": "AV"}, {"family": "Tajuddin", "given": "Salman M", "initials": "SM"}, {"family": "Tayo", "given": "Bamidele O", "initials": "BO"}, {"family": "Warren", "given": "Helen R", "initials": "HR"}, {"family": "Zhao", "given": "Wei", "initials": 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{"family": "Rotimi", "given": "Charles N", "initials": "CN"}, {"family": "Province", "given": "Michael A", "initials": "MA"}, {"family": "van Duijn", "given": "Cornelia M", "initials": "CM"}, {"family": "Tai", "given": "E Shyong", "initials": "ES"}, {"family": "Wong", "given": "Tien Yin", "initials": "TY"}, {"family": "Loos", "given": "Ruth J F", "initials": "RJF"}, {"family": "Reiner", "given": "Alex P", "initials": "AP"}, {"family": "Rotter", "given": "Jerome I", "initials": "JI"}, {"family": "Zhu", "given": "Xiaofeng", "initials": "X"}, {"family": "Bierut", "given": "Laura J", "initials": "LJ"}, {"family": "Gauderman", "given": "W James", "initials": "WJ"}, {"family": "Caulfield", "given": "Mark J", "initials": "MJ"}, {"family": "Elliott", "given": "Paul", "initials": "P"}, {"family": "Rice", "given": "Kenneth", "initials": "K"}, {"family": "Munroe", "given": "Patricia B", "initials": "PB"}, {"family": "Morrison", "given": "Alanna C", "initials": "AC"}, {"family": "Cupples", "given": "L Adrienne", "initials": "LA"}, {"family": "Rao", "given": "Dabeeru C", "initials": "DC"}, {"family": "Chasman", "given": "Daniel I", "initials": "DI"}], "type": "journal article", "published": "2018-03-01", "journal": {"volume": "102", "issn": "1537-6605", "issue": "3", "pages": "375-400", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined \u223c18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5\u00a0\u00d7 10", "doi": "10.1016/j.ajhg.2018.01.015", "pmid": "29455858", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(18)30017-X"}], "notes": [], "created": "2018-05-25T13:25:54.630Z", "modified": "2024-01-16T13:48:46.822Z"}, {"entity": "publication", "iuid": "8d30f96d3ed34e76b303cfeab798e8e9", "links": {"self": {"href": "https://publications.scilifelab.se/publication/8d30f96d3ed34e76b303cfeab798e8e9.json"}, "display": {"href": "https://publications.scilifelab.se/publication/8d30f96d3ed34e76b303cfeab798e8e9"}}, "title": "Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression.", "authors": [{"family": "Hauberg", "given": "Mads Engel", "initials": "ME"}, {"family": "Zhang", "given": "Wen", "initials": "W"}, {"family": "Giambartolomei", "given": "Claudia", "initials": "C"}, {"family": "Franz\u00e9n", "given": "Oscar", "initials": "O"}, {"family": "Morris", "given": "David L", "initials": "DL"}, {"family": "Vyse", "given": "Timothy J", "initials": "TJ"}, {"family": "Ruusalepp", "given": "Arno", "initials": "A"}, {"family": "CommonMind Consortium", "given": "", "initials": ""}, {"family": "Sklar", "given": "Pamela", "initials": "P"}, {"family": "Schadt", "given": "Eric E", "initials": "EE"}, {"family": "Bj\u00f6rkegren", "given": "Johan L M", "initials": "JLM"}, {"family": "Roussos", "given": "Panos", "initials": "P"}], "type": "journal article", "published": "2017-06-01", "journal": {"volume": "100", "issn": "1537-6605", "issue": "6", "pages": "885-894", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate < 0.05. These genes were often not closest to the genetic variant and were primarily identified in eQTLs derived from pathophysiologically relevant tissues. For instance, genes with expression changes associated with lipid traits were mostly identified in the liver, and those associated with cardiovascular disease were identified in arterial tissue. The affected genes additionally point to biological processes implicated in the interrogated traits, such as the interleukin-27 pathway in rheumatoid arthritis. Further, comparing trait-associated gene expression changes across traits suggests that pleiotropy is a widespread phenomenon and points to specific instances of both agonistic and antagonistic pleiotropy. For instance, expression of SNX19 and ABCB9 is positively correlated with both the risk of schizophrenia and educational attainment. To facilitate interpretation, we provide this lexicon of how common trait-associated genetic variants alter gene expression in various tissues as the online database GWAS2Genes.", "doi": "10.1016/j.ajhg.2017.04.016", "pmid": "28552197", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(17)30161-1"}, {"db": "pmc", "key": "PMC5474225"}], "notes": [], "created": "2017-10-27T06:59:34.187Z", "modified": "2021-06-21T15:36:46.748Z"}, {"entity": "publication", "iuid": "e9b423853fda43e58cf0a1af977d5fea", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e9b423853fda43e58cf0a1af977d5fea.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e9b423853fda43e58cf0a1af977d5fea"}}, "title": "Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.", "authors": [{"family": "Kapferer-Seebacher", "given": "Ines", "initials": "I"}, {"family": "Pepin", "given": "Melanie", "initials": "M"}, {"family": "Werner", "given": "Roland", "initials": "R"}, {"family": "Aitman", "given": "Timothy J", "initials": "TJ"}, {"family": "Nordgren", "given": "Ann", "initials": "A"}, {"family": "Stoiber", "given": "Heribert", "initials": "H"}, {"family": "Thielens", "given": "Nicole", "initials": "N"}, {"family": "Gaboriaud", "given": "Christine", "initials": "C"}, {"family": "Amberger", "given": "Albert", "initials": "A"}, {"family": "Schossig", "given": "Anna", "initials": "A"}, {"family": "Gruber", "given": "Robert", "initials": "R"}, {"family": "Giunta", "given": "Cecilia", "initials": "C"}, {"family": "Bamshad", "given": "Michael", "initials": "M"}, {"family": "Bj\u00f6rck", "given": "Erik", "initials": "E"}, {"family": "Chen", "given": "Christina", "initials": "C"}, {"family": "Chitayat", "given": "David", "initials": "D"}, {"family": "Dorschner", "given": "Michael", "initials": "M"}, {"family": "Schmitt-Egenolf", "given": "Marcus", "initials": "M"}, {"family": "Hale", "given": "Christopher J", "initials": "CJ"}, {"family": "Hanna", "given": "David", "initials": "D"}, {"family": "Hennies", "given": "Hans Christian", "initials": "HC"}, {"family": "Heiss-Kisielewsky", "given": "Irene", "initials": "I"}, {"family": "Lindstrand", "given": "Anna", "initials": "A"}, {"family": "Lundberg", "given": "Pernilla", "initials": "P"}, {"family": "Mitchell", "given": "Anna L", "initials": "AL"}, {"family": "Nickerson", "given": "Deborah A", "initials": "DA"}, {"family": "Reinstein", "given": "Eyal", "initials": "E"}, {"family": "Rohrbach", "given": "Marianne", "initials": "M"}, {"family": "Romani", "given": "Nikolaus", "initials": "N"}, {"family": "Schmuth", "given": "Matthias", "initials": "M"}, {"family": "Silver", "given": "Rachel", "initials": "R"}, {"family": "Taylan", "given": "Fulya", "initials": "F"}, {"family": "Vandersteen", "given": "Anthony", "initials": "A"}, {"family": "Vandrovcova", "given": "Jana", "initials": "J"}, {"family": "Weerakkody", "given": "Ruwan", "initials": "R"}, {"family": "Yang", "given": "Margaret", "initials": "M"}, {"family": "Pope", "given": "F Michael", "initials": "FM"}, {"family": "Molecular Basis of Periodontal EDS Consortium", "given": null, "initials": null}, {"family": "Byers", "given": "Peter H", "initials": "PH"}, {"family": "Zschocke", "given": "Johannes", "initials": "J"}], "type": "journal article", "published": "2016-11-03", "journal": {"volume": "99", "issn": "1537-6605", "issue": "5", "pages": "1005-1014", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.", "doi": "10.1016/j.ajhg.2016.08.019", "pmid": "27745832", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(16)30376-7"}, {"db": "pmc", "key": "PMC5097948"}], "notes": [], "created": "2017-05-03T13:02:20.000Z", "modified": "2017-09-06T11:51:11.984Z"}, {"entity": "publication", "iuid": "41ae0a76968243e097a7cb4c95df969c", "links": {"self": {"href": "https://publications.scilifelab.se/publication/41ae0a76968243e097a7cb4c95df969c.json"}, "display": {"href": "https://publications.scilifelab.se/publication/41ae0a76968243e097a7cb4c95df969c"}}, "title": "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.", "authors": [{"family": "Haack", "given": "Tobias B", "initials": "TB"}, {"family": "Ignatius", "given": "Erika", "initials": "E"}, {"family": "Calvo-Garrido", "given": "Javier", "initials": "J"}, {"family": "Iuso", "given": "Arcangela", "initials": "A"}, {"family": "Isohanni", "given": "Pirjo", "initials": "P"}, {"family": "Maffezzini", "given": "Camilla", "initials": "C"}, {"family": "L\u00f6nnqvist", "given": "Tuula", "initials": "T"}, {"family": "Suomalainen", "given": "Anu", "initials": "A"}, {"family": "Gorza", "given": "Matteo", "initials": "M"}, {"family": "Kremer", "given": "Laura S", "initials": "LS"}, {"family": "Graf", "given": "Elisabeth", "initials": "E"}, {"family": "Hartig", "given": "Monika", "initials": "M"}, {"family": "Berutti", "given": "Riccardo", "initials": "R"}, {"family": "Paucar", "given": "Martin", "initials": "M"}, {"family": "Svenningsson", "given": "Per", "initials": "P"}, {"family": "Stranneheim", "given": "Henrik", "initials": "H"}, {"family": "Brandberg", "given": "G\u00f6ran", "initials": "G"}, {"family": "Wedell", "given": "Anna", "initials": "A"}, {"family": "Kurian", "given": "Manju A", "initials": "MA"}, {"family": "Hayflick", "given": "Susan A", "initials": "SA"}, {"family": "Venco", "given": "Paola", "initials": "P"}, {"family": "Tiranti", "given": "Valeria", "initials": "V"}, {"family": "Strom", "given": "Tim M", "initials": "TM"}, {"family": "Dichgans", "given": "Martin", "initials": "M"}, {"family": "Horvath", "given": "Rita", "initials": "R"}, {"family": "Holinski-Feder", "given": "Elke", "initials": "E"}, {"family": "Freyer", "given": "Christoph", "initials": "C"}, {"family": "Meitinger", "given": "Thomas", "initials": "T"}, {"family": "Prokisch", "given": "Holger", "initials": "H"}, {"family": "Senderek", "given": "Jan", "initials": "J"}, {"family": "Wredenberg", "given": "Anna", "initials": "A"}, {"family": "Carroll", "given": "Christopher J", "initials": "CJ"}, {"family": "Klopstock", "given": "Thomas", "initials": "T"}], "type": "journal article", "published": "2016-09-01", "journal": {"volume": "99", "issn": "1537-6605", "issue": "3", "pages": "735-743", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.", "doi": "10.1016/j.ajhg.2016.06.026", "pmid": "27545679", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(16)30230-0"}, {"db": "pmc", "key": "PMC5010644"}], "notes": [], "created": "2017-05-03T12:58:57.260Z", "modified": "2020-01-21T13:56:01.857Z"}, {"entity": "publication", "iuid": "c7d8ad7c96384e25968a3f5f183a9235", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c7d8ad7c96384e25968a3f5f183a9235.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c7d8ad7c96384e25968a3f5f183a9235"}}, "title": "Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.", "authors": [{"family": "Mahajan", "given": "Anubha", "initials": "A"}, {"family": "Rodan", "given": "Aylin R", "initials": "AR"}, {"family": "Le", "given": "Thu H", "initials": "TH"}, {"family": "Gaulton", "given": "Kyle J", "initials": "KJ"}, {"family": "Haessler", "given": "Jeffrey", "initials": "J"}, {"family": "Stilp", "given": "Adrienne M", "initials": "AM"}, {"family": "Kamatani", "given": "Yoichiro", "initials": "Y"}, {"family": "Zhu", "given": "Gu", "initials": "G"}, {"family": "Sofer", "given": "Tamar", "initials": "T"}, {"family": "Puri", "given": "Sanjana", "initials": "S"}, {"family": "Schellinger", "given": "Jeffrey N", "initials": "JN"}, {"family": "Chu", "given": "Pei-Lun", "initials": "PL"}, {"family": "Cechova", "given": "Sylvia", "initials": "S"}, {"family": "van Zuydam", "given": "Natalie", "initials": "N"}, {"family": "SUMMIT Consortium", "given": null, "initials": null}, {"family": "BioBank Japan Project", "given": null, "initials": null}, {"family": "Arnlov", "given": "Johan", "initials": "J"}, {"family": "Flessner", "given": "Michael F", "initials": "MF"}, {"family": "Giedraitis", "given": "Vilmantas", "initials": "V"}, {"family": "Heath", "given": "Andrew C", "initials": "AC"}, {"family": "Kubo", "given": "Michiaki", "initials": "M"}, {"family": "Larsson", "given": "Anders", "initials": "A"}, {"family": "Lindgren", "given": "Cecilia M", "initials": "CM"}, {"family": "Madden", "given": "Pamela A F", "initials": "PA"}, {"family": "Montgomery", "given": "Grant W", "initials": "GW"}, {"family": "Papanicolaou", "given": "George J", "initials": "GJ"}, {"family": "Reiner", "given": "Alex P", "initials": "AP"}, {"family": "Sundstr\u00f6m", "given": "Johan", "initials": "J"}, {"family": "Thornton", "given": "Timothy A", "initials": "TA"}, {"family": "Lind", "given": "Lars", "initials": "L"}, {"family": "Ingelsson", "given": "Erik", "initials": "E"}, {"family": "Cai", "given": "Jianwen", "initials": "J"}, {"family": "Martin", "given": "Nicholas G", "initials": "NG"}, {"family": "Kooperberg", "given": "Charles", "initials": "C"}, {"family": "Matsuda", "given": "Koichi", "initials": "K"}, {"family": "Whitfield", "given": "John B", "initials": "JB"}, {"family": "Okada", "given": "Yukinori", "initials": "Y"}, {"family": "Laurie", "given": "Cathy C", "initials": "CC"}, {"family": "Morris", "given": "Andrew P", "initials": "AP"}, {"family": "Franceschini", "given": "Nora", "initials": "N"}], "type": "journal article", "published": "2016-09-01", "journal": {"volume": "99", "issn": "1537-6605", "issue": "3", "pages": "636-646", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5\u00a0\u00d7 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of \"credible sets\" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.", "doi": "10.1016/j.ajhg.2016.07.012", "pmid": "27588450", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(16)30286-5"}, {"db": "pmc", "key": "PMC5011075"}], "notes": [], "created": "2017-05-03T12:59:48.729Z", "modified": "2024-01-16T13:48:49.545Z"}, {"entity": "publication", "iuid": "3b59fe7e32bd4963b4c2eee0f068a70f", "links": {"self": {"href": "https://publications.scilifelab.se/publication/3b59fe7e32bd4963b4c2eee0f068a70f.json"}, "display": {"href": "https://publications.scilifelab.se/publication/3b59fe7e32bd4963b4c2eee0f068a70f"}}, "title": "Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.", "authors": [{"family": "Stessman", "given": "Holly A F", "initials": "HA"}, {"family": "Willemsen", "given": "Marjolein H", "initials": "MH"}, {"family": "Fenckova", "given": "Michaela", "initials": "M"}, {"family": "Penn", "given": "Osnat", "initials": "O"}, {"family": "Hoischen", "given": "Alexander", "initials": "A"}, {"family": "Xiong", "given": "Bo", "initials": "B"}, {"family": "Wang", "given": "Tianyun", "initials": "T"}, {"family": "Hoekzema", "given": "Kendra", "initials": "K"}, {"family": "Vives", "given": "Laura", "initials": "L"}, {"family": "Vogel", "given": "Ida", "initials": "I"}, {"family": "Brunner", "given": "Han G", "initials": "HG"}, {"family": "van der Burgt", "given": "Ineke", "initials": "I"}, {"family": "Ockeloen", "given": "Charlotte W", "initials": "CW"}, {"family": "Schuurs-Hoeijmakers", "given": "Janneke H", "initials": "JH"}, {"family": "Klein Wassink-Ruiter", "given": "Jolien S", "initials": "JS"}, {"family": "Stumpel", "given": "Connie", "initials": "C"}, {"family": "Stevens", "given": "Servi J C", "initials": "SJ"}, {"family": "Vles", "given": "Hans S", "initials": "HS"}, {"family": "Marcelis", "given": "Carlo M", "initials": "CM"}, {"family": "van Bokhoven", "given": "Hans", "initials": "H"}, {"family": "Cantagrel", "given": "Vincent", "initials": "V"}, {"family": "Colleaux", "given": "Laurence", "initials": "L"}, {"family": "Nicouleau", "given": "Michael", "initials": "M"}, {"family": "Lyonnet", "given": "Stanislas", "initials": "S"}, {"family": "Bernier", "given": "Raphael A", "initials": "RA"}, {"family": "Gerdts", "given": "Jennifer", "initials": "J"}, {"family": "Coe", "given": "Bradley P", "initials": "BP"}, {"family": "Romano", "given": "Corrado", "initials": "C"}, {"family": "Alberti", "given": "Antonino", "initials": "A"}, {"family": "Grillo", "given": "Lucia", "initials": "L"}, {"family": "Scuderi", "given": "Carmela", "initials": "C"}, {"family": "Nordenskj\u00f6ld", "given": "Magnus", "initials": "M"}, {"family": "Kvarnung", "given": "Malin", "initials": "M"}, {"family": "Guo", "given": "Hui", "initials": "H"}, {"family": "Xia", "given": "Kun", "initials": "K"}, {"family": "Piton", "given": "Am\u00e9lie", "initials": "A"}, {"family": "Gerard", "given": "B\u00e9n\u00e9dicte", "initials": "B"}, {"family": "Genevieve", "given": "David", "initials": "D"}, {"family": "Delobel", "given": "Bruno", "initials": "B"}, {"family": "Lehalle", "given": "Daphne", "initials": "D"}, {"family": "Perrin", "given": "Laurence", "initials": "L"}, {"family": "Prieur", "given": "Fabienne", "initials": "F"}, {"family": "Thevenon", "given": "Julien", "initials": "J"}, {"family": "Gecz", "given": "Jozef", "initials": "J"}, {"family": "Shaw", "given": "Marie", "initials": "M"}, {"family": "Pfundt", "given": "Rolph", "initials": "R"}, {"family": "Keren", "given": "Boris", "initials": "B"}, {"family": "Jacquette", "given": "Aurelia", "initials": "A"}, {"family": "Schenck", "given": "Annette", "initials": "A"}, {"family": "Eichler", "given": "Evan E", "initials": "EE"}, {"family": "Kleefstra", "given": "Tjitske", "initials": "T"}], "type": "journal article", "published": "2016-03-03", "journal": {"volume": "98", "issn": "1537-6605", "issue": "3", "pages": "541-552", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 \u00d7 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.", "doi": "10.1016/j.ajhg.2016.02.004", "pmid": "26942287", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(16)00055-0"}, {"db": "pmc", "key": "PMC4890241"}], "notes": [], "created": "2017-05-08T07:59:37.034Z", "modified": "2017-09-06T11:51:11.826Z"}, {"entity": "publication", "iuid": "1689bf73e1454cd39f7bf4f6c2468232", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1689bf73e1454cd39f7bf4f6c2468232.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1689bf73e1454cd39f7bf4f6c2468232"}}, "title": "Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models.", "authors": [{"family": "Chen", "given": "Xu", "initials": "X"}, {"family": "Kuja-Halkola", "given": "Ralf", "initials": "R"}, {"family": "Rahman", "given": "Iffat", "initials": "I"}, {"family": "Arpeg\u00e5rd", "given": "Johannes", "initials": "J"}, {"family": "Viktorin", "given": "Alexander", "initials": "A"}, {"family": "Karlsson", "given": "Robert", "initials": "R"}, {"family": "H\u00e4gg", "given": "Sara", "initials": "S"}, {"family": "Svensson", "given": "Per", "initials": "P"}, {"family": "Pedersen", "given": "Nancy L", "initials": "NL"}, {"family": "Magnusson", "given": "Patrik K E", "initials": "PK"}], "type": "comparative study", "published": "2015-11-05", "journal": {"volume": "97", "issn": "1537-6605", "issue": "5", "pages": "708-714", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "In order to further illuminate the potential role of dominant genetic variation in the \"missing heritability\" debate, we investigated the additive (narrow-sense heritability, h(2)) and dominant (\u03b4(2)) genetic variance for 18 human complex traits. Within the same study base (10,682 Swedish twins), we calculated and compared the estimates from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood [GREML(d)] method. Contributions of \u03b4(2) were evident for 14 traits in twin models (average \u03b4(2)twin = 0.25, range 0.14-0.49), two of which also displayed significant \u03b4(2) in the GREMLd analyses (triglycerides \u03b4(2)SNP = 0.28 and waist circumference \u03b4(2)SNP = 0.19). On average, the proportion of h(2)SNP/h(2)twin was 70% for ADE-fitted traits (for which the best-fitting model included additive and dominant genetic and unique environmental components) and 31% for AE-fitted traits (for which the best-fitting model included additive genetic and unique environmental components). Independent evidence for contribution from shared environment, also in ADE-fitted traits, was obtained from self-reported within-pair contact frequency and age at separation. We conclude that despite the fact that additive genetics appear to constitute the bulk of genetic influences for most complex traits, dominant genetic variation might often be masked by shared environment in twin and family studies and might therefore have a more prominent role than what family-based estimates often suggest. The risk of erroneously attributing all inherited genetic influences (additive and dominant) to the h(2) in too-small twin studies might also lead to exaggerated \"missing heritability\" (the proportion of h(2) that remains unexplained by SNPs).", "doi": "10.1016/j.ajhg.2015.10.004", "pmid": "26544805", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (SNP&SEQ Technology Platform)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(15)00406-1"}, {"db": "pmc", "key": "PMC4667127"}], "notes": [], "created": "2017-05-02T12:56:45.275Z", "modified": "2020-01-21T13:56:00.885Z"}, {"entity": "publication", "iuid": "1988d3d3ea4940688583a3c7799c7ea6", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1988d3d3ea4940688583a3c7799c7ea6.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1988d3d3ea4940688583a3c7799c7ea6"}}, "title": "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26.", "authors": [{"family": "Kishita", "given": "Yoshihito", "initials": "Y"}, {"family": "Pajak", "given": "Aleksandra", "initials": "A"}, {"family": "Bolar", "given": "Nikhita Ajit", "initials": "NA"}, {"family": "Marobbio", "given": "Carlo M T", "initials": "CM"}, {"family": "Maffezzini", "given": "Camilla", "initials": "C"}, {"family": "Miniero", "given": "Daniela V", "initials": "DV"}, {"family": "Monn\u00e9", "given": "Magnus", "initials": "M"}, {"family": "Kohda", "given": "Masakazu", "initials": "M"}, {"family": "Stranneheim", "given": "Henrik", "initials": "H"}, {"family": "Murayama", "given": "Kei", "initials": "K"}, {"family": "Naess", "given": "Karin", "initials": "K"}, {"family": "Lesko", "given": "Nicole", "initials": "N"}, {"family": "Bruhn", "given": "Helene", "initials": "H"}, {"family": "Mourier", "given": "Arnaud", "initials": "A"}, {"family": "Wibom", "given": "Rolf", "initials": "R"}, {"family": "Nennesmo", "given": "Inger", "initials": "I"}, {"family": "Jespers", "given": "Ann", "initials": "A"}, {"family": "Govaert", "given": "Paul", "initials": "P"}, {"family": "Ohtake", "given": "Akira", "initials": "A"}, {"family": "Van Laer", "given": "Lut", "initials": "L"}, {"family": "Loeys", "given": "Bart L", "initials": "BL"}, {"family": "Freyer", "given": "Christoph", "initials": "C"}, {"family": "Palmieri", "given": "Ferdinando", "initials": "F"}, {"family": "Wredenberg", "given": "Anna", "initials": "A"}, {"family": "Okazaki", "given": "Yasushi", "initials": "Y"}, {"family": "Wedell", "given": "Anna", "initials": "A"}], "type": "journal article", "published": "2015-11-05", "journal": {"volume": "97", "issn": "1537-6605", "issue": "5", "pages": "761-768", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.", "doi": "10.1016/j.ajhg.2015.09.013", "pmid": "26522469", "labels": {"National Genomics Infrastructure": null, "NGI Stockholm (Genomics Applications)": null, "NGI Stockholm (Genomics Production)": null, "Clinical Genomics Stockholm": null, "Clinical Genomics": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(15)00402-4"}, {"db": "pmc", "key": "PMC4667130"}], "notes": [], "created": "2017-05-02T12:57:36.953Z", "modified": "2020-01-21T13:56:00.921Z"}, {"entity": "publication", "iuid": "4051a33efa10422bb0709e3c4de124d2", "links": {"self": {"href": "https://publications.scilifelab.se/publication/4051a33efa10422bb0709e3c4de124d2.json"}, "display": {"href": "https://publications.scilifelab.se/publication/4051a33efa10422bb0709e3c4de124d2"}}, "title": "Defects of CRB2 cause steroid-resistant nephrotic syndrome.", "authors": [{"family": "Ebarasi", "given": "Lwaki", "initials": "L"}, {"family": "Ashraf", "given": "Shazia", "initials": "S"}, {"family": "Bierzynska", "given": "Agnieszka", "initials": "A"}, {"family": "Gee", "given": "Heon Yung", "initials": "HY"}, {"family": "McCarthy", "given": "Hugh J", "initials": "HJ"}, {"family": "Lovric", "given": "Svjetlana", "initials": "S"}, {"family": "Sadowski", "given": "Carolin E", "initials": "CE"}, {"family": "Pabst", "given": "Werner", "initials": "W"}, {"family": "Vega-Warner", "given": "Virginia", "initials": "V"}, {"family": "Fang", "given": "Humphrey", "initials": "H"}, {"family": "Koziell", "given": "Ania", "initials": "A"}, {"family": "Simpson", "given": "Michael A", "initials": "MA"}, {"family": "Dursun", "given": "Ismail", "initials": "I"}, {"family": "Serdaroglu", "given": "Erkin", "initials": "E"}, {"family": "Levy", "given": "Shawn", "initials": "S"}, {"family": "Saleem", "given": "Moin A", "initials": "MA"}, {"family": "Hildebrandt", "given": "Friedhelm", "initials": "F"}, {"family": "Majumdar", "given": "Arindam", "initials": "A"}], "type": "journal article", "published": "2015-01-08", "journal": {"volume": "96", "issn": "1537-6605", "issue": "1", "pages": "153-161", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.", "doi": "10.1016/j.ajhg.2014.11.014", "pmid": "25557779", "labels": {"Genome Engineering Zebrafish": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(14)00480-7"}, {"db": "pmc", "key": "PMC4289689"}], "notes": [], "created": "2017-05-02T12:56:54.032Z", "modified": "2017-09-06T11:49:54.968Z"}, {"entity": "publication", "iuid": "f230ea784e1a485b885429b851c34bf2", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f230ea784e1a485b885429b851c34bf2.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f230ea784e1a485b885429b851c34bf2"}}, "title": "Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.", "authors": [{"family": "Acuna-Hidalgo", "given": "Rocio", "initials": "R"}, {"family": "Schanze", "given": "Denny", "initials": "D"}, {"family": "Kariminejad", "given": "Ariana", "initials": "A"}, {"family": "Nordgren", "given": "Ann", "initials": "A"}, {"family": "Kariminejad", "given": "Mohamad Hasan", "initials": "MH"}, {"family": "Conner", "given": "Peter", "initials": "P"}, {"family": "Grigelioniene", "given": "Giedre", "initials": "G"}, {"family": "Nilsson", "given": "Daniel", "initials": "D"}, {"family": "Nordenskj\u00f6ld", "given": "Magnus", "initials": "M"}, {"family": "Wedell", "given": "Anna", "initials": "A"}, {"family": "Freyer", "given": "Christoph", "initials": "C"}, {"family": "Wredenberg", "given": "Anna", "initials": "A"}, {"family": "Wieczorek", "given": "Dagmar", "initials": "D"}, {"family": "Gillessen-Kaesbach", "given": "Gabriele", "initials": "G"}, {"family": "Kayserili", "given": "H\u00fclya", "initials": "H"}, {"family": "Elcioglu", "given": "Nursel", "initials": "N"}, {"family": "Ghaderi-Sohi", "given": "Siavash", "initials": "S"}, {"family": "Goodarzi", "given": "Payman", "initials": "P"}, {"family": "Setayesh", "given": "Hamidreza", "initials": "H"}, {"family": "van de Vorst", "given": "Maartje", "initials": "M"}, {"family": "Steehouwer", "given": "Marloes", "initials": "M"}, {"family": "Pfundt", "given": "Rolph", "initials": "R"}, {"family": "Krabichler", "given": "Birgit", "initials": "B"}, {"family": "Curry", "given": "Cynthia", "initials": "C"}, {"family": "MacKenzie", "given": "Malcolm G", "initials": "MG"}, {"family": "Boycott", "given": "Kym M", "initials": "KM"}, {"family": "Gilissen", "given": "Christian", "initials": "C"}, {"family": "Janecke", "given": "Andreas R", "initials": "AR"}, {"family": "Hoischen", "given": "Alexander", "initials": "A"}, {"family": "Zenker", "given": "Martin", "initials": "M"}], "type": "journal article", "published": "2014-09-04", "journal": {"volume": "95", "issn": "1537-6605", "issue": "3", "pages": "285-293", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.", "doi": "10.1016/j.ajhg.2014.07.012", "pmid": "25152457", "labels": {"National Genomics Infrastructure": null, "NGI Stockholm (Genomics Applications)": null, "NGI Stockholm (Genomics Production)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(14)00321-8"}, {"db": "pmc", "key": "PMC4157144"}], "notes": [], "created": "2017-05-04T14:58:19.929Z", "modified": "2020-01-21T13:56:06.251Z"}, {"entity": "publication", "iuid": "699cbce661ea4664b72a5dbb7460d1c9", "links": {"self": {"href": "https://publications.scilifelab.se/publication/699cbce661ea4664b72a5dbb7460d1c9.json"}, "display": {"href": "https://publications.scilifelab.se/publication/699cbce661ea4664b72a5dbb7460d1c9"}}, "title": "Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity.", "authors": [{"family": "Han", "given": "Buhm", "initials": "B"}, {"family": "Diogo", "given": "Doroth\u00e9e", "initials": "D"}, {"family": "Eyre", "given": "Steve", "initials": "S"}, {"family": "Kallberg", "given": "Henrik", "initials": "H"}, {"family": "Zhernakova", "given": "Alexandra", "initials": "A"}, {"family": "Bowes", "given": "John", "initials": "J"}, {"family": "Padyukov", "given": "Leonid", "initials": "L"}, {"family": "Okada", "given": "Yukinori", "initials": "Y"}, {"family": "Gonz\u00e1lez-Gay", "given": "Miguel A", "initials": "MA"}, {"family": "Rantap\u00e4\u00e4-Dahlqvist", "given": "Solbritt", "initials": "S"}, {"family": "Martin", "given": "Javier", "initials": "J"}, {"family": "Huizinga", "given": "Tom W J", "initials": "TW"}, {"family": "Plenge", "given": "Robert M", "initials": "RM"}, {"family": "Worthington", "given": "Jane", "initials": "J"}, {"family": "Gregersen", "given": "Peter K", "initials": "PK"}, {"family": "Klareskog", "given": "Lars", "initials": "L"}, {"family": "de Bakker", "given": "Paul I W", "initials": "PI"}, {"family": "Raychaudhuri", "given": "Soumya", "initials": "S"}], "type": "journal article", "published": "2014-04-03", "journal": {"volume": "94", "issn": "1537-6605", "issue": "4", "pages": "522-532", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DR\u03b21 (p = 1.4 \u00d7 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 \u00d7 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1(\u2217)03 (encoding serine at 11) and HLA-B(\u2217)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR\u03b21 Ser11+Leu11: p = 5.8 \u00d7 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 \u00d7 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR\u03b21 position 11 were distinct (p < 2.9 \u00d7 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 \u00d7 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.", "doi": "10.1016/j.ajhg.2014.02.013", "pmid": "24656864", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(14)00071-8"}, {"db": "pmc", "key": "PMC3980428"}], "notes": [], "created": "2017-10-30T13:30:53.705Z", "modified": "2020-01-21T13:56:08.331Z"}, {"entity": "publication", "iuid": "145871fa182441639d4baf2c9c647cf0", "links": {"self": {"href": "https://publications.scilifelab.se/publication/145871fa182441639d4baf2c9c647cf0.json"}, "display": {"href": "https://publications.scilifelab.se/publication/145871fa182441639d4baf2c9c647cf0"}}, "title": "Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development.", "authors": [{"family": "Peyrard-Janvid", "given": "Myriam", "initials": "M"}, {"family": "Leslie", "given": "Elizabeth J", "initials": "EJ"}, {"family": "Kousa", "given": "Youssef A", "initials": "YA"}, {"family": "Smith", "given": "Tiffany L", "initials": "TL"}, {"family": "Dunnwald", "given": "Martine", "initials": "M"}, {"family": "Magnusson", "given": "M\u00e5ns", "initials": "M"}, {"family": "Lentz", "given": "Brian A", "initials": "BA"}, {"family": "Unneberg", "given": "Per", "initials": "P"}, {"family": "Fransson", "given": "Ingegerd", "initials": "I"}, {"family": "Koillinen", "given": "Hannele K", "initials": "HK"}, {"family": "Rautio", "given": "Jorma", "initials": "J"}, {"family": "Pegelow", "given": "Marie", "initials": "M"}, {"family": "Karsten", "given": "Agneta", "initials": "A"}, {"family": "Basel-Vanagaite", "given": "Lina", "initials": "L"}, {"family": "Gordon", "given": "William", "initials": "W"}, {"family": "Andersen", "given": "Bogi", "initials": "B"}, {"family": "Svensson", "given": "Thomas", "initials": "T", "orcid": "0000-0002-9190-2979", "researcher": {"href": "https://publications.scilifelab.se/researcher/dc636683ece84dc4ac3e4d10df0c7a49.json"}}, {"family": "Murray", "given": "Jeffrey C", "initials": "JC"}, {"family": "Cornell", "given": "Robert A", "initials": "RA"}, {"family": "Kere", "given": "Juha", "initials": "J"}, {"family": "Schutte", "given": "Brian C", "initials": "BC"}], "type": "journal article", "published": "2014-01-02", "journal": {"volume": "94", "issn": "1537-6605", "issue": "1", "pages": "23-32", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Mutations in interferon regulatory factor 6 (IRF6) account for \u223c70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.", "doi": "10.1016/j.ajhg.2013.11.009", "pmid": "24360809", "labels": {"Mutation Analysis Facility (MAF)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(13)00524-7"}, {"db": "pmc", "key": "PMC3882735"}], "notes": [], "created": "2017-05-04T15:03:39.288Z", "modified": "2021-07-05T13:07:20.923Z"}, {"entity": "publication", "iuid": "f5d0e962ca7849b3aab152e12b610925", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f5d0e962ca7849b3aab152e12b610925.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f5d0e962ca7849b3aab152e12b610925"}}, "title": "Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs.", "authors": [{"family": "Hemani", "given": "Gibran", "initials": "G"}, {"family": "Yang", "given": "Jian", "initials": "J"}, {"family": "Vinkhuyzen", "given": "Anna", "initials": "A"}, {"family": "Powell", "given": "Joseph E", "initials": "JE"}, {"family": "Willemsen", "given": "Gonneke", "initials": "G"}, {"family": "Hottenga", "given": "Jouke-Jan", "initials": "J"}, {"family": "Abdellaoui", "given": "Abdel", "initials": "A"}, {"family": "Mangino", "given": "Massimo", "initials": "M"}, {"family": "Valdes", "given": "Ana M", "initials": "AM"}, {"family": "Medland", "given": "Sarah E", "initials": "SE"}, {"family": "Madden", "given": "Pamela A", "initials": "PA"}, {"family": "Heath", "given": "Andrew C", "initials": "AC"}, {"family": "Henders", "given": "Anjali K", "initials": "AK"}, {"family": "Nyholt", "given": "Dale R", "initials": "DR"}, {"family": "de Geus", "given": "Eco J C", "initials": "EJC"}, {"family": "Magnusson", "given": "Patrik K E", "initials": "PKE"}, {"family": "Ingelsson", "given": "Erik", "initials": "E"}, {"family": "Montgomery", "given": "Grant W", "initials": "GW"}, {"family": "Spector", "given": "Timothy D", "initials": "TD"}, {"family": "Boomsma", "given": "Dorret I", "initials": "DI"}, {"family": "Pedersen", "given": "Nancy L", "initials": "NL"}, {"family": "Martin", "given": "Nicholas G", "initials": "NG"}, {"family": "Visscher", "given": "Peter M", "initials": "PM"}], "type": "journal article", "published": "2013-11-07", "journal": {"volume": "93", "issn": "1537-6605", "issue": "5", "pages": "865-875", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6\u00a0\u00d7 10(-)(7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2\u00a0\u00d7 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.", "doi": "10.1016/j.ajhg.2013.10.005", "pmid": "24183453", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(13)00462-X"}, {"db": "pmc", "key": "PMC3965855"}], "notes": [], "created": "2017-05-04T14:57:47.556Z", "modified": "2020-01-21T13:56:08.575Z"}, {"entity": "publication", "iuid": "2a6d5589972f48ed8e8c7b2523aeba35", "links": {"self": {"href": "https://publications.scilifelab.se/publication/2a6d5589972f48ed8e8c7b2523aeba35.json"}, "display": {"href": "https://publications.scilifelab.se/publication/2a6d5589972f48ed8e8c7b2523aeba35"}}, "title": "Meta-analysis of gene-level associations for rare variants based on single-variant statistics.", "authors": [{"family": "Hu", "given": "Yi-Juan", "initials": "Y"}, {"family": "Berndt", "given": "Sonja I", "initials": "SI"}, {"family": "Gustafsson", "given": "Stefan", "initials": "S"}, {"family": "Ganna", "given": "Andrea", "initials": "A"}, {"family": "Genetic Investigation of ANthropometric Traits (GIANT) Consortium", "given": "None", "initials": "N"}, {"family": "Hirschhorn", "given": "Joel", "initials": "J"}, {"family": "North", "given": "Kari E", "initials": "KE"}, {"family": "Ingelsson", "given": "Erik", "initials": "E"}, {"family": "Lin", "given": "Dan-Yu", "initials": "D"}], "type": "journal article", "published": "2013-08-08", "journal": {"volume": "93", "issn": "1537-6605", "issue": "2", "pages": "236-248", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying \"causal\" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.", "doi": "10.1016/j.ajhg.2013.06.011", "pmid": "23891470", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "S0002-9297(13)00280-2"}, {"db": "pmc", "key": "PMC3738834"}], "notes": [], "created": "2017-05-04T14:57:47.877Z", "modified": "2020-01-21T13:56:08.583Z"}, {"entity": "publication", "iuid": "77b8c1e7b0a14bd4940ea15e8f8ed19a", "links": {"self": {"href": "https://publications.scilifelab.se/publication/77b8c1e7b0a14bd4940ea15e8f8ed19a.json"}, "display": {"href": "https://publications.scilifelab.se/publication/77b8c1e7b0a14bd4940ea15e8f8ed19a"}}, "title": "Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids.", "authors": [{"family": "Ameur", "given": "Adam", "initials": "A", "orcid": "0000-0001-6085-6749", "researcher": {"href": "https://publications.scilifelab.se/researcher/e960811513664a78b2804a00ee70f7c3.json"}}, {"family": "Enroth", "given": "Stefan", "initials": "S"}, {"family": "Johansson", "given": "Asa", "initials": "A"}, {"family": "Zaboli", "given": "Ghazal", "initials": "G"}, {"family": "Igl", "given": "Wilmar", "initials": "W"}, {"family": "Johansson", "given": "Anna C V", "initials": "AC"}, {"family": "Rivas", "given": "Manuel A", "initials": "MA"}, {"family": "Daly", "given": "Mark J", "initials": "MJ"}, {"family": "Schmitz", "given": "Gerd", "initials": "G"}, {"family": "Hicks", "given": "Andrew A", "initials": "AA"}, {"family": "Meitinger", "given": "Thomas", "initials": "T"}, {"family": "Feuk", "given": "Lars", "initials": "L", "orcid": "0000-0003-2355-2919", "researcher": {"href": "https://publications.scilifelab.se/researcher/3eb2f826b3554d4b9971bf0766b275c4.json"}}, {"family": "van Duijn", "given": "Cornelia", "initials": "C"}, {"family": "Oostra", "given": "Ben", "initials": "B"}, {"family": "Pramstaller", "given": "Peter P", "initials": "PP"}, {"family": "Rudan", "given": "Igor", "initials": "I"}, {"family": "Wright", "given": "Alan F", "initials": "AF"}, {"family": "Wilson", "given": "James F", "initials": "JF"}, {"family": "Campbell", "given": "Harry", "initials": "H"}, {"family": "Gyllensten", "given": "Ulf", "initials": "U"}], "type": "journal article", "published": "2012-05-04", "journal": {"volume": "90", "issn": "1537-6605", "issue": "5", "pages": "809-820", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.", "doi": "10.1016/j.ajhg.2012.03.014", "pmid": "22503634", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (Uppsala Genome Center)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(12)00158-9"}, {"db": "pmc", "key": "PMC3376635"}], "notes": [], "created": "2017-05-04T14:57:28.310Z", "modified": "2021-07-07T14:37:06.520Z"}, {"entity": "publication", "iuid": "586f6b11de1d47dba7ce229c441380b4", "links": {"self": {"href": "https://publications.scilifelab.se/publication/586f6b11de1d47dba7ce229c441380b4.json"}, "display": {"href": "https://publications.scilifelab.se/publication/586f6b11de1d47dba7ce229c441380b4"}}, "title": "Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2.", "authors": [{"family": "Spiegel", "given": "Ronen", "initials": "R"}, {"family": "Pines", "given": "Ophry", "initials": "O"}, {"family": "Ta-Shma", "given": "Asaf", "initials": "A"}, {"family": "Burak", "given": "Efrat", "initials": "E"}, {"family": "Shaag", "given": "Avraham", "initials": "A"}, {"family": "Halvardson", "given": "Jonatan", "initials": "J"}, {"family": "Edvardson", "given": "Shimon", "initials": "S"}, {"family": "Mahajna", "given": "Muhammad", "initials": "M"}, {"family": "Zenvirt", "given": "Shamir", "initials": "S"}, {"family": "Saada", "given": "Ann", "initials": "A"}, {"family": "Shalev", "given": "Stavit", "initials": "S"}, {"family": "Feuk", "given": "Lars", "initials": "L", "orcid": "0000-0003-2355-2919", "researcher": {"href": "https://publications.scilifelab.se/researcher/3eb2f826b3554d4b9971bf0766b275c4.json"}}, {"family": "Elpeleg", "given": "Orly", "initials": "O"}], "type": "journal article", "published": "2012-03-09", "journal": {"volume": "90", "issn": "1537-6605", "issue": "3", "pages": "518-523", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.", "doi": "10.1016/j.ajhg.2012.01.009", "pmid": "22405087", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (Uppsala Genome Center)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(12)00043-2"}, {"db": "pmc", "key": "PMC3309186"}], "notes": [], "created": "2017-05-04T14:57:28.614Z", "modified": "2021-07-07T14:15:07.577Z"}, {"entity": "publication", "iuid": "7175ee02a0724c8ebeeb6f7ba3ac27f0", "links": {"self": {"href": "https://publications.scilifelab.se/publication/7175ee02a0724c8ebeeb6f7ba3ac27f0.json"}, "display": {"href": "https://publications.scilifelab.se/publication/7175ee02a0724c8ebeeb6f7ba3ac27f0"}}, "title": "Age-related somatic structural changes in the nuclear genome of human blood cells.", "authors": [{"family": "Forsberg", "given": "Lars A", "initials": "LA"}, {"family": "Rasi", "given": "Chiara", "initials": "C"}, {"family": "Razzaghian", "given": "Hamid R", "initials": "HR"}, {"family": "Pakalapati", "given": "Geeta", "initials": "G"}, {"family": "Waite", "given": "Lindsay", "initials": "L"}, {"family": "Thilbeault", "given": "Krista Stanton", "initials": "KS"}, {"family": "Ronowicz", "given": "Anna", "initials": "A"}, {"family": "Wineinger", "given": "Nathan E", "initials": "NE"}, {"family": "Tiwari", "given": "Hemant K", "initials": "HK"}, {"family": "Boomsma", "given": "Dorret", "initials": "D"}, {"family": "Westerman", "given": "Maxwell P", "initials": "MP"}, {"family": "Harris", "given": "Jennifer R", "initials": "JR"}, {"family": "Lyle", "given": "Robert", "initials": "R"}, {"family": "Essand", "given": "Magnus", "initials": "M"}, {"family": "Eriksson", "given": "Fredrik", "initials": "F"}, {"family": "Assimes", "given": "Themistocles L", "initials": "TL"}, {"family": "Iribarren", "given": "Carlos", "initials": "C"}, {"family": "Strachan", "given": "Eric", "initials": "E"}, {"family": "O'Hanlon", "given": "Terrance P", "initials": "TP"}, {"family": "Rider", "given": "Lisa G", "initials": "LG"}, {"family": "Miller", "given": "Frederick W", "initials": "FW"}, {"family": "Giedraitis", "given": "Vilmantas", "initials": "V"}, {"family": "Lannfelt", "given": "Lars", "initials": "L"}, {"family": "Ingelsson", "given": "Martin", "initials": "M"}, {"family": "Piotrowski", "given": "Arkadiusz", "initials": "A"}, {"family": "Pedersen", "given": "Nancy L", "initials": "NL"}, {"family": "Absher", "given": "Devin", "initials": "D"}, {"family": "Dumanski", "given": "Jan P", "initials": "JP"}], "type": "journal article", "published": "2012-02-10", "journal": {"volume": "90", "issn": "1537-6605", "issue": "2", "pages": "217-228", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects \u226560 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were \u226455 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.", "doi": "10.1016/j.ajhg.2011.12.009", "pmid": "22305530", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (SNP&SEQ Technology Platform)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(11)00544-1"}, {"db": "pmc", "key": "PMC3276669"}], "notes": [], "created": "2017-05-04T15:00:52.563Z", "modified": "2020-01-21T13:56:02.985Z"}, {"entity": "publication", "iuid": "5aebe6334bed4654b7be912fbaa50694", "links": {"self": {"href": "https://publications.scilifelab.se/publication/5aebe6334bed4654b7be912fbaa50694.json"}, "display": {"href": "https://publications.scilifelab.se/publication/5aebe6334bed4654b7be912fbaa50694"}}, "title": "Blood pressure loci identified with a gene-centric array.", "authors": [{"family": "Johnson", "given": "Toby", "initials": "T"}, {"family": "Gaunt", "given": "Tom R", "initials": "TR"}, {"family": "Newhouse", "given": "Stephen J", "initials": "SJ"}, {"family": "Padmanabhan", "given": "Sandosh", "initials": "S"}, {"family": "Tomaszewski", "given": "Maciej", "initials": "M"}, {"family": "Kumari", "given": "Meena", "initials": "M"}, {"family": "Morris", "given": "Richard W", "initials": "RW"}, {"family": "Tzoulaki", "given": "Ioanna", "initials": "I"}, {"family": "O'Brien", "given": "Eoin T", "initials": "ET"}, {"family": "Poulter", "given": "Neil R", "initials": "NR"}, {"family": "Sever", "given": "Peter", "initials": "P"}, {"family": "Shields", "given": "Denis C", "initials": "DC"}, {"family": "Thom", "given": "Simon", "initials": "S"}, {"family": "Wannamethee", "given": "Sasiwarang G", "initials": "SG"}, {"family": "Whincup", "given": "Peter H", "initials": "PH"}, {"family": "Brown", "given": "Morris J", "initials": "MJ"}, {"family": "Connell", "given": "John M", "initials": "JM"}, {"family": "Dobson", "given": "Richard J", "initials": "RJ"}, {"family": "Howard", "given": "Philip J", "initials": "PJ"}, {"family": "Mein", "given": "Charles A", "initials": "CA"}, {"family": "Onipinla", "given": "Abiodun", "initials": "A"}, {"family": "Shaw-Hawkins", "given": "Sue", "initials": "S"}, {"family": "Zhang", "given": "Yun", "initials": "Y"}, {"family": "Davey Smith", "given": "George", "initials": "G"}, {"family": "Day", "given": "Ian N M", "initials": "IN"}, {"family": "Lawlor", "given": "Debbie A", "initials": "DA"}, {"family": "Goodall", "given": "Alison H", "initials": "AH"}, {"family": "Cardiogenics Consortium", "given": null, "initials": null}, {"family": "Fowkes", "given": "F Gerald", "initials": "FG"}, {"family": "Abecasis", "given": "Gon\u00e7alo R", "initials": "GR"}, {"family": "Elliott", "given": "Paul", "initials": "P"}, {"family": "Gateva", "given": "Vesela", "initials": "V"}, {"family": "Global BPgen Consortium", "given": null, "initials": null}, {"family": "Braund", "given": "Peter S", "initials": "PS"}, {"family": "Burton", "given": "Paul R", "initials": "PR"}, {"family": "Nelson", "given": "Christopher P", "initials": "CP"}, {"family": "Tobin", "given": "Martin D", "initials": "MD"}, {"family": "van der Harst", "given": "Pim", "initials": "P"}, {"family": "Glorioso", "given": "Nicola", "initials": "N"}, {"family": "Neuvrith", "given": "Hani", "initials": "H"}, {"family": "Salvi", "given": "Erika", "initials": "E"}, {"family": "Staessen", "given": "Jan A", "initials": "JA"}, {"family": "Stucchi", "given": "Andrea", "initials": "A"}, {"family": "Devos", "given": "Nabila", "initials": "N"}, {"family": "Jeunemaitre", "given": "Xavier", "initials": "X"}, {"family": "Plouin", "given": "Pierre-Fran\u00e7ois", "initials": "PF"}, {"family": "Tichet", "given": "Jean", "initials": "J"}, {"family": "Juhanson", "given": "Peeter", "initials": "P"}, {"family": "Org", "given": "Elin", "initials": "E"}, {"family": "Putku", "given": "Margus", "initials": "M"}, {"family": "S\u00f5ber", "given": "Siim", "initials": "S"}, {"family": "Veldre", "given": "Gudrun", "initials": "G"}, {"family": "Viigimaa", "given": "Margus", "initials": "M"}, {"family": "Levinsson", "given": "Anna", "initials": "A"}, {"family": "Rosengren", "given": "Annika", "initials": "A"}, {"family": "Thelle", "given": "Dag S", "initials": "DS"}, {"family": "Hastie", "given": "Claire E", "initials": "CE"}, {"family": "Hedner", "given": "Thomas", "initials": "T"}, {"family": "Lee", "given": "Wai K", "initials": "WK"}, {"family": "Melander", "given": "Olle", "initials": "O"}, {"family": "Wahlstrand", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Hardy", "given": "Rebecca", "initials": "R"}, {"family": "Wong", "given": "Andrew", "initials": "A"}, {"family": "Cooper", "given": "Jackie A", "initials": "JA"}, {"family": "Palmen", "given": "Jutta", "initials": "J"}, {"family": "Chen", "given": "Li", "initials": "L"}, {"family": "Stewart", "given": "Alexandre F R", "initials": "AF"}, {"family": "Wells", "given": "George A", "initials": "GA"}, {"family": "Westra", "given": "Harm-Jan", "initials": "HJ"}, {"family": "Wolfs", "given": "Marcel G M", "initials": "MG"}, {"family": "Clarke", "given": "Robert", "initials": "R"}, {"family": "Franzosi", "given": "Maria Grazia", "initials": "MG"}, {"family": "Goel", "given": "Anuj", "initials": "A"}, {"family": "Hamsten", "given": "Anders", "initials": "A"}, {"family": "Lathrop", "given": "Mark", "initials": "M"}, {"family": "Peden", "given": "John F", "initials": "JF"}, {"family": "Seedorf", "given": "Udo", "initials": "U"}, {"family": "Watkins", "given": "Hugh", "initials": "H"}, {"family": "Ouwehand", "given": "Willem H", "initials": "WH"}, {"family": "Sambrook", "given": "Jennifer", "initials": "J"}, {"family": "Stephens", "given": "Jonathan", "initials": "J"}, {"family": "Casas", "given": "Juan-Pablo", "initials": "JP"}, {"family": "Drenos", "given": "Fotios", "initials": "F"}, {"family": "Holmes", "given": "Michael V", "initials": "MV"}, {"family": "Kivimaki", "given": "Mika", "initials": "M"}, {"family": "Shah", "given": "Sonia", "initials": "S"}, {"family": "Shah", "given": "Tina", "initials": "T"}, {"family": "Talmud", "given": "Philippa J", "initials": "PJ"}, {"family": "Whittaker", "given": "John", "initials": "J"}, {"family": "Wallace", "given": "Chris", "initials": "C"}, {"family": "Delles", "given": "Christian", "initials": "C"}, {"family": "Laan", "given": "Maris", "initials": "M"}, {"family": "Kuh", "given": "Diana", "initials": "D"}, {"family": "Humphries", "given": "Steve E", "initials": "SE"}, {"family": "Nyberg", "given": "Fredrik", "initials": "F"}, {"family": "Cusi", "given": "Daniele", "initials": "D"}, {"family": "Roberts", "given": "Robert", "initials": "R"}, {"family": "Newton-Cheh", "given": "Christopher", "initials": "C"}, {"family": "Franke", "given": "Lude", "initials": "L"}, {"family": "Stanton", "given": "Alice V", "initials": "AV"}, {"family": "Dominiczak", "given": "Anna F", "initials": "AF"}, {"family": "Farrall", "given": "Martin", "initials": "M"}, {"family": "Hingorani", "given": "Aroon D", "initials": "AD"}, {"family": "Samani", "given": "Nilesh J", "initials": "NJ"}, {"family": "Caulfield", "given": "Mark J", "initials": "MJ"}, {"family": "Munroe", "given": "Patricia B", "initials": "PB"}], "type": "journal article", "published": "2011-12-09", "journal": {"volume": "89", "issn": "1537-6605", "issue": "6", "pages": "688-700", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56\u00a0\u00d7 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56\u00a0\u00d7 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.", "doi": "10.1016/j.ajhg.2011.10.013", "pmid": "22100073", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (SNP&SEQ Technology Platform)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(11)00447-2"}, {"db": "pmc", "key": "PMC3234370"}], "notes": [], "created": "2017-05-04T15:00:39.882Z", "modified": "2020-01-21T13:56:02.489Z"}, {"entity": "publication", "iuid": "a6b88208359d498db34ce8a14fa0d829", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a6b88208359d498db34ce8a14fa0d829.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a6b88208359d498db34ce8a14fa0d829"}}, "title": "Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.", "authors": [{"family": "Bown", "given": "Matthew J", "initials": "MJ"}, {"family": "Jones", "given": "Gregory T", "initials": "GT"}, {"family": "Harrison", "given": "Seamus C", "initials": "SC"}, {"family": "Wright", "given": "Benjamin J", "initials": "BJ"}, {"family": "Bumpstead", "given": "Suzannah", "initials": "S"}, {"family": "Baas", "given": "Annette F", "initials": "AF"}, {"family": "Gretarsdottir", "given": "Solveig", "initials": "S"}, {"family": "Badger", "given": "Stephen A", "initials": "SA"}, {"family": "Bradley", "given": "Declan T", "initials": "DT"}, {"family": "Burnand", "given": "Kevin", "initials": "K"}, {"family": "Child", "given": "Anne H", "initials": "AH"}, {"family": "Clough", "given": "Rachel E", "initials": "RE"}, {"family": "Cockerill", "given": "Gillian", "initials": "G"}, {"family": "Hafez", "given": "Hany", "initials": "H"}, {"family": "Scott", "given": "D Julian A", "initials": "DJ"}, {"family": "Futers", "given": "Simon", "initials": "S"}, {"family": "Johnson", "given": "Anne", "initials": "A"}, {"family": "Sohrabi", "given": "Soroush", "initials": "S"}, {"family": "Smith", "given": "Alberto", "initials": "A"}, {"family": "Thompson", "given": "Matthew M", "initials": "MM"}, {"family": "van Bockxmeer", "given": "Frank M", "initials": "FM"}, {"family": "Waltham", "given": "Matthew", "initials": "M"}, {"family": "Matthiasson", "given": "Stefan E", "initials": "SE"}, {"family": "Thorleifsson", "given": "Gudmar", "initials": "G"}, {"family": "Thorsteinsdottir", "given": "Unnur", "initials": "U"}, {"family": "Blankensteijn", "given": "Jan D", "initials": "JD"}, {"family": "Teijink", "given": "Joep A W", "initials": "JA"}, {"family": "Wijmenga", "given": "Cisca", "initials": "C"}, {"family": "de Graaf", "given": "Jacqueline", "initials": "J"}, {"family": "Kiemeney", "given": "Lambertus A", "initials": "LA"}, {"family": "Assimes", "given": "Themistocles L", "initials": "TL"}, {"family": "McPherson", "given": "Ruth", "initials": "R"}, {"family": "CARDIoGRAM Consortium", "given": null, "initials": null}, {"family": "Global BPgen Consortium", "given": null, "initials": null}, {"family": "DIAGRAM Consortium", "given": null, "initials": null}, {"family": "VRCNZ Consortium", "given": null, "initials": null}, {"family": "Folkersen", "given": "Lasse", "initials": "L"}, {"family": "Franco-Cereceda", "given": "Anders", "initials": "A"}, {"family": "Palmen", "given": "Jutta", "initials": "J"}, {"family": "Smith", "given": "Andrew J", "initials": "AJ"}, {"family": "Sylvius", "given": "Nicolas", "initials": "N"}, {"family": "Wild", "given": "John B", "initials": "JB"}, {"family": "Refstrup", "given": "Mette", "initials": "M"}, {"family": "Edkins", "given": "Sarah", "initials": "S"}, {"family": "Gwilliam", "given": "Rhian", "initials": "R"}, {"family": "Hunt", "given": "Sarah E", "initials": "SE"}, {"family": "Potter", "given": "Simon", "initials": "S"}, {"family": "Lindholt", "given": "Jes S", "initials": "JS"}, {"family": "Frikke-Schmidt", "given": "Ruth", "initials": "R"}, {"family": "Tybj\u00e6rg-Hansen", "given": "Anne", "initials": "A"}, {"family": "Hughes", "given": "Anne E", "initials": "AE"}, {"family": "Golledge", "given": "Jonathan", "initials": "J"}, {"family": "Norman", "given": "Paul E", "initials": "PE"}, {"family": "van Rij", "given": "Andre", "initials": "A"}, {"family": "Powell", "given": "Janet T", "initials": "JT"}, {"family": "Eriksson", "given": "Per", "initials": "P"}, {"family": "Stefansson", "given": "Kari", "initials": "K"}, {"family": "Thompson", "given": "John R", "initials": "JR"}, {"family": "Humphries", "given": "Steve E", "initials": "SE"}, {"family": "Sayers", "given": "Robert D", "initials": "RD"}, {"family": "Deloukas", "given": "Panos", "initials": "P"}, {"family": "Samani", "given": "Nilesh J", "initials": "NJ"}], "type": "journal article", "published": "2011-11-11", "journal": {"volume": "89", "issn": "1537-6605", "issue": "5", "pages": "619-627", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1\u00a0\u00d7 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1\u00a0\u00d7 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52\u00a0\u00d7 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.", "doi": "10.1016/j.ajhg.2011.10.002", "pmid": "22055160", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (SNP&SEQ Technology Platform)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(11)00436-8"}, {"db": "pmc", "key": "PMC3213391"}], "notes": [], "created": "2017-05-04T15:00:39.530Z", "modified": "2020-01-21T13:56:04.313Z"}, {"entity": "publication", "iuid": "a59c07dadcad4fff829226e4e591f050", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a59c07dadcad4fff829226e4e591f050.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a59c07dadcad4fff829226e4e591f050"}}, "title": "Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function.", "authors": [{"family": "Bjursell", "given": "Magnus K", "initials": "MK"}, {"family": "Blom", "given": "Henk J", "initials": "HJ", "orcid": "0000-0002-5584-9170", "researcher": {"href": "https://publications.scilifelab.se/researcher/3ce356a74dc84e0ea6af85397f11d869.json"}}, {"family": "Cayuela", "given": "Jordi Asin", "initials": "JA"}, {"family": "Engvall", "given": "Martin L", "initials": "ML"}, {"family": "Lesko", "given": "Nicole", "initials": "N"}, {"family": "Balasubramaniam", "given": "Shanti", "initials": "S"}, {"family": "Brandberg", "given": "G\u00f6ran", "initials": "G"}, {"family": "Halldin", "given": "Maria", "initials": "M"}, {"family": "Falkenberg", "given": "Maria", "initials": "M"}, {"family": "Jakobs", "given": "Cornelis", "initials": "C"}, {"family": "Smith", "given": "Desiree", "initials": "D"}, {"family": "Struys", "given": "Eduard", "initials": "E"}, {"family": "von D\u00f6beln", "given": "Ulrika", "initials": "U"}, {"family": "Gustafsson", "given": "Claes M", "initials": "CM"}, {"family": "Lundeberg", "given": "Joakim", "initials": "J", "orcid": "0000-0003-4313-1601", "researcher": {"href": "https://publications.scilifelab.se/researcher/4a4e6ca0f29b4ead8569e2729481c3e0.json"}}, {"family": "Wedell", "given": "Anna", "initials": "A"}], "type": "case reports", "published": "2011-10-07", "journal": {"volume": "89", "issn": "1537-6605", "issue": "4", "pages": "507-515", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.", "doi": "10.1016/j.ajhg.2011.09.004", "pmid": "21963049", "labels": {"National Genomics Infrastructure": null, "NGI Stockholm (Genomics Applications)": null, "NGI Stockholm (Genomics Production)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(11)00394-6"}, {"db": "pmc", "key": "PMC3188832"}], "notes": [], "created": "2017-05-04T14:57:15.579Z", "modified": "2021-07-08T13:26:08.274Z"}, {"entity": "publication", "iuid": "e5d5b927ec6340288650334b6f1e3e0a", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e5d5b927ec6340288650334b6f1e3e0a.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e5d5b927ec6340288650334b6f1e3e0a"}}, "title": "Characterization of a 8q21.11 microdeletion syndrome associated with intellectual disability and a recognizable phenotype.", "authors": [{"family": "Palomares", "given": "Mar\u00eda", "initials": "M"}, {"family": "Delicado", "given": "Alicia", "initials": "A"}, {"family": "Mansilla", "given": "Elena", "initials": "E"}, {"family": "de Torres", "given": "Mar\u00eda Luisa", "initials": "ML"}, {"family": "Vallesp\u00edn", "given": "Elena", "initials": "E"}, {"family": "Fernandez", "given": "Luis", "initials": "L"}, {"family": "Martinez-Glez", "given": "Victor", "initials": "V"}, {"family": "Garc\u00eda-Mi\u00f1aur", "given": "Sixto", "initials": "S"}, {"family": "Nevado", "given": "Juli\u00e1n", "initials": "J"}, {"family": "Simarro", "given": "Fernando Santos", "initials": "FS"}, {"family": "Ruiz-Perez", "given": "Victor L", "initials": "VL"}, {"family": "Lynch", "given": "Sally Ann", "initials": "SA"}, {"family": "Sharkey", "given": "Freddie H", "initials": "FH"}, {"family": "Thuresson", "given": "Ann-Charlotte", "initials": "AC"}, {"family": "Anner\u00e9n", "given": "G\u00f6ran", "initials": "G"}, {"family": "Belligni", "given": "Elga F", "initials": "EF"}, {"family": "Mart\u00ednez-Fern\u00e1ndez", "given": "Mar\u00eda Luisa", "initials": "ML"}, {"family": "Bermejo", "given": "Eva", "initials": "E"}, {"family": "Nowakowska", "given": "Beata", "initials": "B"}, {"family": "Kutkowska-Kazmierczak", "given": "Anna", "initials": "A"}, {"family": "Bocian", "given": "Ewa", "initials": "E"}, {"family": "Obersztyn", "given": "Ewa", "initials": "E"}, {"family": "Mart\u00ednez-Fr\u00edas", "given": "Mar\u00eda Luisa", "initials": "ML"}, {"family": "Hennekam", "given": "Raoul C M", "initials": "RC"}, {"family": "Lapunzina", "given": "Pablo", "initials": "P"}], "type": "journal article", "published": "2011-08-12", "journal": {"volume": "89", "issn": "1537-6605", "issue": "2", "pages": "295-301", "title": "Am. J. Hum. Genet.", "issn-l": "0002-9297"}, "abstract": "We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.", "doi": "10.1016/j.ajhg.2011.06.012", "pmid": "21802062", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (Uppsala Genome Center)": null}, "xrefs": [{"db": "pii", "key": "S0002-9297(11)00266-7"}, {"db": "pmc", "key": "PMC3155189"}], "notes": [], "created": "2017-05-04T15:01:53.531Z", "modified": "2020-01-21T13:56:05.887Z"}], "created": "2017-05-09T09:12:01.909Z", "modified": "2020-11-27T13:14:04.962Z"}