Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene

Abstract

Objective: To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations. Methods:We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families.Results: Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; 2 ϭ 5.76, p ϭ 0.016).Conclusions: Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. Multiple sclerosis (MS) is a common, complex, neurologic condition with both environmental and genetic factors contributing to risk. Epidemiologic studies have highlighted the significant influence of latitude on MS prevalence and Epstein-Barr virus infection, smoking, and low vitamin D levels are strongly implicated environmental risk factors. 1,2 Genetic contributions are clear from family studies with 15%-20% of individuals with MS having an affected relative.3 Furthermore, monozygotic twins have a 25% concordance rate as compared to the 5% seen in dizygotic twins. 4 These and other familial studies have demonstrated that genes contribute significantly to the familial aggregation of MS.Despite a strong genetic component, it is extremely rare to find families with 5 or more individuals with MS in successive generations. We previously reported a family with up to 15 individuals with MS.5 MS was present in 4 generations and penetrance was relatively consistentFrom The

Multiple sclerosis genetics

“…Another example of exome sequencing's power to detect rare alleles of MS susceptibility genes is the discovery of a missense mutation in the TYK2 gene (Dyment et al, 2012). An allele of the TYK2 gene was previously found to be protective in GWAS (Australia and New Zealand Multiple Sclerosis Genetics Consortium, 2009;Ban et al, 2009;Mero et al, 2010).…”

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

“…Genome-wide association studies and more targeted candidate approaches have shown strong linkage of Tyk2 haplotypes or individual SNPs to systemic and organ-specific autoimmune diseases, namely systemic lupus erythematosus (SLE) (11)(12)(13)(14), multiple sclerosis (MS) (15)(16)(17)(18)(19), Crohn's disease (20)(21)(22), psoriasis (23), type 1 diabetes (24), endometriosis-related infertility (25), and primary biliary cirrhosis (26) (Table I). Interestingly, one rare MSassociated variant (rs34536443) is considered to be protective, whereas another (rs55762744) was recently identified as a risk allele (17). rs12720356, initially reported to be protective in SLE (13), was not confirmed in a replication study (12) and instead found to be a risk allele in Crohn's disease (20,22).…”

Therapeutic potential of tyrosine kinase 2 in autoimmunity

“…Reports from a number of investigators have shown the association of polymorphisms in genes of Tyk2 with susceptibility to human autoimmune diseases [54, [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83], but the controversial results exist. Details of these studies are summarized in Table 2.…”

“…No association observed [74] SLE British 870 5551 rs280519(A/G) rs280519A allele associated with SLE risk [75] MS European 5429 6167 rs34536443(C/G) rs34536443G allele associated with MS risk [76] MS European 3874 5723 rs8112449(A/G) rs8112449G allele associated with MS risk [77] MS Mixed 4234 2983 rs34536443(C/G) rs34536443G allele associated with MS risk [78] MS German NA NA rs55762744(C/T) rs55762744C allele associated with MS risk [79] MS Australian 350 498 rs34536443(C/G) rs34536443G allele associated with MS risk [54] MS French 726 522 rs34536443(C/G) rs34536443G allele associated with MS risk [80] RA Spanish 1631 1902 rs2304256(A/C) No association observed [81] RA Gauzzi et al [87] found that IFN-a-induced activation of Tyk2 needs phosphorylation of positive regulatory tyrosine by JAK1. In addition, analysis of the effect of NO synthase 2 (NOS2) and NO on the activation of Tyk2 indicated that NOS2-derived NO is indispensable for NK cells activation of Tyk2 [88].…”