Negligible impact of rare autoimmune-locus coding-region variants on missing heritability

Karen A. Hunt, Vanisha Mistry, Nicholas A. Bockett, Tariq Ahmad, Maria Ban, Jonathan N. Barker, Jeffrey C. Barrett, Hannah Blackburn, Oliver Brand, Oliver Burren, Francesca Capon, Alastair Compston, Stephen C. L. Gough, Luke Jostins, Yong Kong, James C. Lee, Monkol Lek, Daniel G. MacArthur, John C. Mansfield, Christopher G. MathewCharles A. Mein, Muddassar Mirza, Sarah Nutland, Suna Onengut-Gumuscu, Efterpi Papouli, Miles Parkes, Stephen S. Rich, Steven Sawcer, Jack Satsangi, Matthew J. Simmonds, Richard C. Trembath, Neil M. Walker, Eva Wozniak, John A. Todd, Michael A. Simpson, Vincent Plagnol, David A. van Heel*

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review

158 Citations (Scopus)


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 contribute(1,2). 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 set(3-5). 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 hypothesis(6) (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 effect(7-10).

Original languageEnglish
Pages (from-to)232-235
Number of pages4
Issue number7453
Publication statusPublished - 13 Jun 2013


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