Association Scan of 14,500 Nonsynonymous SNPs in Four Diseases Identifies Autoimmunity Variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Citing Articles

Bimekizumab in the Treatment of Axial Spondyloarthritis and Psoriatic Arthritis: A New Kid on the Block.

Sarrand J, Baglione L, Bouvy C, Soyfoo M Int J Mol Sci. 2025; 26(5).

PMID: 40076933 PMC: 11899827. DOI: 10.3390/ijms26052315.

Association of and gene polymorphisms and ERAP2 protein with the susceptibility and severity of rheumatoid arthritis in the Ukrainian population.

Kril I, Wisniewski A, Tarnowska A, Lishchuk-Yakymovych K, Bojko Y, Kusnierczyk P Front Immunol. 2025; 15:1519159.

PMID: 39906739 PMC: 11790443. DOI: 10.3389/fimmu.2024.1519159.

Elevated type-17 cytokines are present in axial spondyloarthritis stool.

Brough I, Thompson K, Latore C, Penkava F, Regan C, Pearson C Discov Immunol. 2024; 3(1):kyae005.

PMID: 38966778 PMC: 11222980. DOI: 10.1093/discim/kyae005.

A systems genomics and genetics approach to identify the genetic regulatory network for lignin content in seeds.

Zhang W, Higgins E, Robinson S, Clarke W, Boyle K, Sharpe A Front Plant Sci. 2024; 15:1393621.

PMID: 38903439 PMC: 11188405. DOI: 10.3389/fpls.2024.1393621.

Exploring the Pathogenesis of Spondylarthritis beyond HLA-B27: A Descriptive Review.

Nagit R, Rezus E, Cianga P Int J Mol Sci. 2024; 25(11).

PMID: 38892265 PMC: 11172491. DOI: 10.3390/ijms25116081.

References

Sims A, Barnardo M, Herzberg I, Bradbury L, Calin A, Wordsworth B . Non-B27 MHC associations of ankylosing spondylitis. Genes Immun. 2006; 8(2):115-23. DOI: 10.1038/sj.gene.6364362. View

Haiman C, Patterson N, Freedman M, Myers S, Pike M, Waliszewska A . Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007; 39(5):638-44. PMC: 2638766. DOI: 10.1038/ng2015. View

Kochi Y, Yamada R, Suzuki A, Harley J, Shirasawa S, Sawada T . A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet. 2005; 37(5):478-85. PMC: 1362949. DOI: 10.1038/ng1540. View

Scott L, Mohlke K, Bonnycastle L, Willer C, Li Y, Duren W . A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007; 316(5829):1341-5. PMC: 3214617. DOI: 10.1126/science.1142382. View

Dechairo B, Zabaneh D, Collins J, Brand O, Dawson G, Green A . Association of the TSHR gene with Graves' disease: the first disease specific locus. Eur J Hum Genet. 2005; 13(11):1223-30. DOI: 10.1038/sj.ejhg.5201485. View

Thomas D, Clayton D . Betting odds and genetic associations. J Natl Cancer Inst. 2004; 96(6):421-3. DOI: 10.1093/jnci/djh094. View

Hunter D, Kraft P, Jacobs K, Cox D, Yeager M, Hankinson S . A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007; 39(7):870-4. PMC: 3493132. DOI: 10.1038/ng2075. View

Cohen J, Kiss R, Pertsemlidis A, Marcel Y, McPherson R, Hobbs H . Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004; 305(5685):869-72. DOI: 10.1126/science.1099870. View

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

10.

Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D . A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007; 445(7130):881-5. DOI: 10.1038/nature05616. View

11.

Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y . Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005; 6(7):689-97. DOI: 10.1038/ni1208. View

12.

Zeggini E, Weedon M, Lindgren C, Frayling T, Elliott K, Lango H . Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007; 316(5829):1336-41. PMC: 3772310. DOI: 10.1126/science.1142364. View

13.

Jiang H, Hwenda L, Makinen K, Oetke C, Crocker P, Forrester J . Sialoadhesin promotes the inflammatory response in experimental autoimmune uveoretinitis. J Immunol. 2006; 177(4):2258-64. DOI: 10.4049/jimmunol.177.4.2258. View

14.

McGinnis R, Shifman S, Darvasi A . Power and efficiency of the TDT and case-control design for association scans. Behav Genet. 2002; 32(2):135-44. DOI: 10.1023/a:1015205924326. View

15.

Zanke B, Greenwood C, Rangrej J, Kustra R, Tenesa A, Farrington S . Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007; 39(8):989-94. DOI: 10.1038/ng2089. View

16.

Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K . A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007; 39(2):207-11. DOI: 10.1038/ng1954. View

17.

Purcell S, Daly M, Sham P . WHAP: haplotype-based association analysis. Bioinformatics. 2006; 23(2):255-6. DOI: 10.1093/bioinformatics/btl580. View

18.

. A haplotype map of the human genome. Nature. 2005; 437(7063):1299-320. PMC: 1880871. DOI: 10.1038/nature04226. View

19.

Cua D, Sherlock J, Chen Y, Murphy C, Joyce B, Seymour B . Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003; 421(6924):744-8. DOI: 10.1038/nature01355. View

20.

Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson J, Thorleifsson G, Manolescu A . Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007; 39(8):977-83. DOI: 10.1038/ng2062. View