دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Negligible impact of rare autoimmune-locus coding-region variants on missing heritability.
المؤلفون: Hunt KA; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK., Mistry V, Bockett NA, Ahmad T, Ban M, Barker JN, Barrett JC, Blackburn H, Brand O, Burren O, Capon F, Compston A, Gough SC, Jostins L, Kong Y, Lee JC, Lek M, MacArthur DG, Mansfield JC, Mathew CG, Mein CA, Mirza M, Nutland S, Onengut-Gumuscu S, Papouli E, Parkes M, Rich SS, Sawcer S, Satsangi J, Simmonds MJ, Trembath RC, Walker NM, Wozniak E, Todd JA, Simpson MA, Plagnol V, van Heel DA
المصدر: Nature [Nature] 2013 Jun 13; Vol. 498 (7453), pp. 232-5. Date of Electronic Publication: 2013 May 22.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
أسماء مطبوعة: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
مواضيع طبية MeSH: Autoimmune Diseases/*genetics , Genetic Predisposition to Disease/*genetics , Genetic Variation/*genetics , Open Reading Frames/*genetics, Exons/genetics ; Gene Frequency ; Genome-Wide Association Study ; Humans ; Models, Genetic ; Mutation/genetics ; Phenotype ; Sample Size ; United Kingdom ; White People/genetics
مستخلص: 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.
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معلومات مُعتمدة: G0800675 United Kingdom MRC_ Medical Research Council; G1001158 United Kingdom MRC_ Medical Research Council; ETM/137 United Kingdom CSO_ Chief Scientist Office; ETM/75 United Kingdom CSO_ Chief Scientist Office; CZB/4/540 United Kingdom CSO_ Chief Scientist Office; G0601387 United Kingdom MRC_ Medical Research Council; G0000934 United Kingdom MRC_ Medical Research Council; 076113/C/04/Z United Kingdom WT_ Wellcome Trust; 100140 United Kingdom WT_ Wellcome Trust; JDRF 4-2001-1008 United Kingdom WT_ Wellcome Trust; G1001158(95979) United Kingdom MRC_ Medical Research Council; 068181 United Kingdom WT_ Wellcome Trust; G0600329 United Kingdom MRC_ Medical Research Council; 068545/Z/02 United Kingdom WT_ Wellcome Trust; WT061858 United Kingdom WT_ Wellcome Trust; G0800759 United Kingdom MRC_ Medical Research Council; 091157 United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust
فهرسة مساهمة: Indexing Agency: NLM Local ID #: EMS52853.
تواريخ الأحداث: Date Created: 20130524 Date Completed: 20130627 Latest Revision: 20240610
رمز التحديث: 20240610
مُعرف محوري في PubMed: PMC3736321
DOI: 10.1038/nature12170
PMID: 23698362
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4687
DOI:10.1038/nature12170