Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Bentham J, Morris DL, Cunninghame Graham DS, Pinder CL, Tombleson P, Behrens TW, Martín J, Fairfax BP, Knight JC, Chen L, Replogle J, Syvänen AC, Rönnblom L, Graham RR, Wither JE, Rioux JD, Alarcón-Riquelme ME, Vyse TJ

Nat. Genet. 47 (12) 1457-1464 [2015-12-00; online 2015-10-27]

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

NGI Uppsala (SNP&SEQ Technology Platform)

QC bibliography QC xrefs

PubMed 26502338

DOI 10.1038/ng.3434

Crossref 10.1038/ng.3434

GEO GSE56035

mid EMS65418


pmc PMC4668589