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

Hunt, K. A., Mistry, V., Bockett, N. A. , Ahmad, T., Ban, M., Barker, J. N., Barrett, J. C., Blackburn, H., Brand, O. J., Burren, O., Capon, F., Compston, A., Gough, S. C. L., Jostins, L., Kong, Y., Lee, J. C., Lek, M., MacArthur, D. G., Mansfield, J. C., Mathew, C. G., Mein, C. A., Mirza, M., Nutland, S., Onengut-Gumuscu, S., Papouli, E., Parkes, M., Rich, S. S., Sawcer, S., Satsangi, J., Simmonds, M. J., Trembath, R. C., Walker, N. M., Wozniak, E., Todd, J. A., Simpson, M. A., Plagnol, V. and van Heel, D. A. (2013) Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature, 498 (7453). pp. 232-235. ISSN 0028-0836

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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. 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. 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 (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. © 2013 Macmillan Publishers Limited. All rights reserved.

Keywords:allele, disease incidence, genetic analysis, genome, genotype, heritability, phenotype, sampling, amplicon, article, autoimmune disease, autoimmunity, controlled study, disease association, exon, gene linkage disequilibrium, gene locus, genetic association, genetic risk, genetic variability, high throughput sequencing, human, major clinical study, polymerase chain reaction, priority journal, sequence analysis, single nucleotide polymorphism, Autoimmune Diseases, European Continental Ancestry Group, Exons, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Great Britain, Humans, Models, Genetic, Mutation, Open Reading Frames, Sample Size, Europe
Subjects:C Biological Sciences > C420 Human Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:22598
Deposited On:19 Mar 2016 22:37

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