Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

By Philip L. De Jager, Xiaoming Jia, Joanne Wang, P. D. de Bakker, L. Ottoboni, N. Aggarwal, L. Piccio, Soumya Raychaudhuri, Dong Tran, C. Aubin and 23 more. Nature Genetics, 2009

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We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/42e42e15d51be24929806becbdd6d8bb3d5ba5b7

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Citations in the corpus

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis (2013, neutral): “Genotyping We genotyped a total of 45,885 samples, with typing being performed in Boston (1,824), France (1,028), Germany (997), Miami (5,383), Virginia (5,416), Vanderbilt (3,817) and the Wellcome Trust Sanger Institute (WTSI, 27,420).”
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis (2011, neutral): “Modestly powered genome-wide association studies (GWAS”
R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment (2014, methodology): “The improved methods, including a covariate-adjusted analysis and revised phenotypes, yielded an OR more consistent with the largest published study on this association, which reported an OR of 2.75 (De Jager et al., 2009).”
Multiple Sclerosis Genomic Map implicates peripheral immune cells & microglia in susceptibility (2019, methodology): “MS variants clearly influence gene expression in this tissue, and we must now: (1) resolve the implicated cell types and whether pathways shared with immune cells are having their MS susceptibility effect in the periphery or in the brain and; (2) more deeply identify additional functional consequenc”
New IBD genetics: common pathways with other diseases (2011, background): “SNPs in linkage disequilibrium with those associated with Crohn’s disease are associated with ulcerative colitis,(28) and also appear to confer susceptibility to MS, but presently fall just short of genome-wide significance.(117) The ZMIZ1 locus in Crohn’s disease is also nominally associated with M”