Analysis of Immune-related Loci Identifies 48 New Susceptibility Variants for Multiple Sclerosis

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

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References

Gregory A, Dendrou C, Attfield K, Haghikia A, Xifara D, Butter F . TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature. 2012; 488(7412):508-511. PMC: 4268493. DOI: 10.1038/nature11307. View

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P . High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012; 44(12):1336-40. PMC: 3605761. DOI: 10.1038/ng.2462. View

Maier L, Lowe C, Cooper J, Downes K, Anderson D, Severson C . IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production. PLoS Genet. 2009; 5(1):e1000322. PMC: 2602853. DOI: 10.1371/journal.pgen.1000322. View

Hemminki K, Li X, Sundquist J, Hillert J, Sundquist K . Risk for multiple sclerosis in relatives and spouses of patients diagnosed with autoimmune and related conditions. Neurogenetics. 2008; 10(1):5-11. DOI: 10.1007/s10048-008-0156-y. View

Browning B, Yu Z . Simultaneous genotype calling and haplotype phasing improves genotype accuracy and reduces false-positive associations for genome-wide association studies. Am J Hum Genet. 2009; 85(6):847-61. PMC: 2790566. DOI: 10.1016/j.ajhg.2009.11.004. View

Cooper J, Simmonds M, Walker N, Burren O, Brand O, Guo H . Seven newly identified loci for autoimmune thyroid disease. Hum Mol Genet. 2012; 21(23):5202-8. PMC: 3490518. DOI: 10.1093/hmg/dds357. View

Patsopoulos N, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J . Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol. 2011; 70(6):897-912. PMC: 3247076. DOI: 10.1002/ana.22609. View

Willis T, Jadayel D, Du M, Peng H, Perry A, Price H . Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell. 1999; 96(1):35-45. DOI: 10.1016/s0092-8674(00)80957-5. View

Liu J, Tozzi F, Waterworth D, Pillai S, Muglia P, Middleton L . Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet. 2010; 42(5):436-40. PMC: 3612983. DOI: 10.1038/ng.572. View

10.

Juran B, Hirschfield G, Invernizzi P, Atkinson E, Li Y, Xie G . Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet. 2012; 21(23):5209-21. PMC: 3490520. DOI: 10.1093/hmg/dds359. View

11.

Howie B, Marchini J, Stephens M . Genotype imputation with thousands of genomes. G3 (Bethesda). 2012; 1(6):457-70. PMC: 3276165. DOI: 10.1534/g3.111.001198. View

12.

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

13.

Tsoi L, Spain S, Knight J, Ellinghaus E, Stuart P, Capon F . Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012; 44(12):1341-8. PMC: 3510312. DOI: 10.1038/ng.2467. View

14.

Davydov E, Goode D, Sirota M, Cooper G, Sidow A, Batzoglou S . Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010; 6(12):e1001025. PMC: 2996323. DOI: 10.1371/journal.pcbi.1001025. View

15.

Gourraud P, Harbo H, Hauser S, Baranzini S . The genetics of multiple sclerosis: an up-to-date review. Immunol Rev. 2012; 248(1):87-103. PMC: 5967887. DOI: 10.1111/j.1600-065X.2012.01134.x. View

16.

Nylander A, Hafler D . Multiple sclerosis. J Clin Invest. 2012; 122(4):1180-8. PMC: 3314452. DOI: 10.1172/JCI58649. View

17.

Shah T, Liu J, Floyd J, Morris J, Wirth N, Barrett J . optiCall: a robust genotype-calling algorithm for rare, low-frequency and common variants. Bioinformatics. 2012; 28(12):1598-603. PMC: 3371828. DOI: 10.1093/bioinformatics/bts180. View

18.

Johnson A, Handsaker R, Pulit S, Nizzari M, ODonnell C, de Bakker P . SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008; 24(24):2938-9. PMC: 2720775. DOI: 10.1093/bioinformatics/btn564. View

19.

Wegener E, Krappmann D . CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB. Sci STKE. 2007; 2007(384):pe21. DOI: 10.1126/stke.3842007pe21. View

20.

Lill C, Schjeide B, Graetz C, Liu T, Damotte V, Akkad D . Genome-wide significant association of ANKRD55 rs6859219 and multiple sclerosis risk. J Med Genet. 2013; 50(3):140-3. DOI: 10.1136/jmedgenet-2012-101411. View