Genetic architecture of subcortical brain structures in 38,851 individuals.

Satizabal CL, Adams HHH, Hibar DP, White CC, Knol MJ, Stein JL, Scholz M, Sargurupremraj M, Jahanshad N, Roshchupkin GV, Smith AV, Bis JC, Jian X, Luciano M, Hofer E, Teumer A, van der Lee SJ, Yang J, Yanek LR, Lee TV, Li S, Hu Y, Koh JY, Eicher JD, Desrivières S, Arias-Vasquez A, Chauhan G, Athanasiu L, Rentería ME, Kim S, Hoehn D, Armstrong NJ, Chen Q, Holmes AJ, den Braber A, Kloszewska I, Andersson M, Espeseth T, Grimm O, Abramovic L, Alhusaini S, Milaneschi Y, Papmeyer M, Axelsson T, Ehrlich S, Roiz-Santiañez R, Kraemer B, Håberg AK, Jones HJ, Pike GB, Stein DJ, Stevens A, Bralten J, Vernooij MW, Harris TB, Filippi I, Witte AV, Guadalupe T, Wittfeld K, Mosley TH, Becker JT, Doan NT, Hagenaars SP, Saba Y, Cuellar-Partida G, Amin N, Hilal S, Nho K, Mirza-Schreiber N, Arfanakis K, Becker DM, Ames D, Goldman AL, Lee PH, Boomsma DI, Lovestone S, Giddaluru S, Le Hellard S, Mattheisen M, Bohlken MM, Kasperaviciute D, Schmaal L, Lawrie SM, Agartz I, Walton E, Tordesillas-Gutierrez D, Davies GE, Shin J, Ipser JC, Vinke LN, Hoogman M, Jia T, Burkhardt R, Klein M, Crivello F, Janowitz D, Carmichael O, Haukvik UK, Aribisala BS, Schmidt H, Strike LT, Cheng CY, Risacher SL, Pütz B, Fleischman DA, Assareh AA, Mattay VS, Buckner RL, Mecocci P, Dale AM, Cichon S, Boks MP, Matarin M, Penninx BWJH, Calhoun VD, Chakravarty MM, Marquand AF, Macare C, Kharabian Masouleh S, Oosterlaan J, Amouyel P, Hegenscheid K, Rotter JI, Schork AJ, Liewald DCM, de Zubicaray GI, Wong TY, Shen L, Sämann PG, Brodaty H, Roffman JL, de Geus EJC, Tsolaki M, Erk S, van Eijk KR, Cavalleri GL, van der Wee NJA, McIntosh AM, Gollub RL, Bulayeva KB, Bernard M, Richards JS, Himali JJ, Loeffler M, Rommelse N, Hoffmann W, Westlye LT, Valdés Hernández MC, Hansell NK, van Erp TGM, Wolf C, Kwok JBJ, Vellas B, Heinz A, Olde Loohuis LM, Delanty N, Ho BC, Ching CRK, Shumskaya E, Singh B, Hofman A, van der Meer D, Homuth G, Psaty BM, Bastin ME, Montgomery GW, Foroud TM, Reppermund S, Hottenga JJ, Simmons A, Meyer-Lindenberg A, Cahn W, Whelan CD, van Donkelaar MMJ, Yang Q, Hosten N, Green RC, Thalamuthu A, Mohnke S, Hulshoff Pol HE, Lin H, Jack CR, Schofield PR, Mühleisen TW, Maillard P, Potkin SG, Wen W, Fletcher E, Toga AW, Gruber O, Huentelman M, Davey Smith G, Launer LJ, Nyberg L, Jönsson EG, Crespo-Facorro B, Koen N, Greve DN, Uitterlinden AG, Weinberger DR, Steen VM, Fedko IO, Groenewold NA, Niessen WJ, Toro R, Tzourio C, Longstreth WT, Ikram MK, Smoller JW, van Tol MJ, Sussmann JE, Paus T, Lemaître H, Schroeter ML, Mazoyer B, Andreassen OA, Holsboer F, Depondt C, Veltman DJ, Turner JA, Pausova Z, Schumann G, van Rooij D, Djurovic S, Deary IJ, McMahon KL, Müller-Myhsok B, Brouwer RM, Soininen H, Pandolfo M, Wassink TH, Cheung JW, Wolfers T, Martinot JL, Zwiers MP, Nauck M, Melle I, Martin NG, Kanai R, Westman E, Kahn RS, Sisodiya SM, White T, Saremi A, van Bokhoven H, Brunner HG, Völzke H, Wright MJ, van 't Ent D, Nöthen MM, Ophoff RA, Buitelaar JK, Fernández G, Sachdev PS, Rietschel M, van Haren NEM, Fisher SE, Beiser AS, Francks C, Saykin AJ, Mather KA, Romanczuk-Seiferth N, Hartman CA, DeStefano AL, Heslenfeld DJ, Weiner MW, Walter H, Hoekstra PJ, Nyquist PA, Franke B, Bennett DA, Grabe HJ, Johnson AD, Chen C, van Duijn CM, Lopez OL, Fornage M, Wardlaw JM, Schmidt R, DeCarli C, De Jager PL, Villringer A, Debette S, Gudnason V, Medland SE, Shulman JM, Thompson PM, Seshadri S, Ikram MA

Nat. Genet. 51 (11) 1624-1636 [2019-11-00; online 2019-10-21]

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

PubMed 31636452

DOI 10.1038/s41588-019-0511-y

Crossref 10.1038/s41588-019-0511-y

pii: 10.1038/s41588-019-0511-y
pmc: PMC7055269
mid: NIHMS1553652


Publications 6.6.6