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Multiple sclerosis (MS) is a genetically complex disease that shares a substantial proportion of risk loci with other autoimmune diseases.1 Along these lines, ANKRD55, originally implicated in rheumatoid arthritis, was recently reported as a potential novel MS risk gene (rs6859219, p=1.9×10−7).2 Here, we comprehensively validated this effect in independent datasets comprising 8846 newly genotyped subjects from Germany and France as well as 5003 subjects from two genome-wide association studies (GWAS). Upon meta-analysis of all available data (19 686 subjects), ANKRD55 rs6859219 now shows compelling evidence for association with MS at genome-wide significance (OR=1.19, p=3.1×10−11). Our study adds ANKRD55 to the list of established MS risk loci and extends previous evidence suggesting an overlapping genetic foundation across autoimmune diseases.
Ankyrin repeats are abundant in a large number of different proteins in humans and mediate protein–protein interactions. DNA-sequence variants in ankyrin repeat domain-containing proteins have been linked to a wide range of diseases; for example, KRIT1 mutations causative for cerebral cavernous malformations,3 NOTCH3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and RFXANK mutations in the bare lymphocyte syndrome.4 ANKRD55 (located on chromosome 5q11.2) encodes the ‘ankyrin repeat domain-containing protein 55’ the function of which is currently unknown. Single nucleotide polymorphism rs6859219 in ANKRD55 was implicated in a recent GWAS meta-analysis on rheumatoid arthritis.5 Furthermore, a joint analysis of datasets on rheumatoid arthritis and coeliac disease also indicated a role of ANKRD55 in the latter.6 Given the augmenting evidence suggesting an overlap in the genetic architecture of autoimmune diseases including MS, we have previously investigated 10 ‘autoimmune loci’ in 2895 Spanish MS cases and 2942 controls.2 In that study, rs6859219 emerged as a putative new MS locus albeit at subgenome-wide significance (p=1.9×10−7).2 Our failure to establish …