Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute1,2. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set3,4,5. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis6 (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect7,8,9,10.
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Genome data has been deposited at the European Genome–phenome Archive (http://www.ebi.ac.uk/ega/), which is hosted at the EBI, under accession number EGAS00001000476.
The study was primarily funded by the Medical Research Council (MRC G1001158 to D.A.v.H and V.P.), with further funding from Coeliac UK (to D.A.v.H). We thank C. Wijmenga and G. Trynka for sharing ImmunoChip data, and the International Multiple Sclerosis Genomics Consortium for ImmunoChip data and samples. J.N.B. and R.C.T. are supported by MRC grant G0601387. This research was supported by the National Institutes for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The study was supported by the Cambridge NIHR Biomedical Research Centre. We thank E. Gray and D. Jones (Wellcome Trust Sanger Institute) for sample preparation. We acknowledge use of DNA from The UK Blood Services collection of Common Controls (UKBS-CC collection), funded by the Wellcome Trust grant 076113/C/04/Z and by NIHR programme grant to NHS Blood and Transplant (RP-PG-0310-1002). The collection was established as part of the Wellcome Trust Case Control Consortium (WTCCC). We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the UK MRC grant G0000934 and the Wellcome Trust grant 068545/Z/02. We thank nurses and doctors for recruiting autoimmune thyroid disease (AITD) subjects into the AITD National Collection, funded by the Wellcome Trust grant 068181. We acknowledge use of DNA from the Cambridge BioResource. We acknowledge use of DNA from the Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Case-Series (GRID), funded by JDRF and the Wellcome Trust (grant references JDRF 4-2001-1008 and WT061858). The subjects were recruited in the UK by D. Dunger and his team with support from the British Society for Paediatric Endocrinology and Diabetes. The samples were prepared and provided by the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, UK. Psoriasis samples used were based on the WTCCC2 GWAS clinical panel, for which we thank D. Burden, C. Griffiths, M. Cork and R. McManus. Finally, we would like to thank all autoimmune disease and control subjects for participating in this study.
This file contains full results (for all tested phenotypes, all MAF, all single variants or pooled gene tests) for the data shown in Supplementary Table 4 and Figure 1.
About this article
Clinical & Translational Immunology (2018)