Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.
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Abstract | The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases. |
Year of Publication | 2012
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Journal | Nat Genet
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Volume | 44
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Issue | 5
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Pages | 483-9
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Date Published | 2012 Mar 25
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ISSN | 1546-1718
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URL | |
DOI | 10.1038/ng.2232
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PubMed ID | 22446960
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Grant list | R01-AR057108 / AR / NIAMS NIH HHS / United States
R01-AR44422 / AR / NIAMS NIH HHS / United States
MOP79321 / Canadian Institutes of Health Research / Canada
K08AR055688-01A1 / AR / NIAMS NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
R01-AR059648 / AR / NIAMS NIH HHS / United States
MC_U106179471 / Medical Research Council / United Kingdom
Intramural NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
R01 GM045295 / GM / NIGMS NIH HHS / United States
R01-AR056768 / AR / NIAMS NIH HHS / United States
N01-AR-2-2263 / AR / NIAMS NIH HHS / United States
R01 AR056768 / AR / NIAMS NIH HHS / United States
IIN-84042 / Canadian Institutes of Health Research / Canada
U01-GM092691 / GM / NIGMS NIH HHS / United States
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