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Nat Genet DOI:10.1038/ng.2232

Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.

Publication TypeJournal Article
Year of Publication2012
AuthorsStahl, EA, Wegmann, D, Trynka, G, Gutierrez-Achury, J, Do, R, Voight, BF, Kraft, P, Chen, R, Kallberg, HJ, Kurreeman, FAS, Kathiresan, S, Wijmenga, C, Gregersen, PK, Alfredsson, L, Siminovitch, KA, Worthington, J, de Bakker, PIW, Raychaudhuri, S, Plenge, RM
Corporate AuthorsDiabetes Genetics Replication and Meta-analysis Consortium, Myocardial Infarction Genetics Consortium
JournalNat Genet
Date Published2012 Mar 25
KeywordsArthritis, Rheumatoid, Bayes Theorem, Cardiovascular Diseases, Case-Control Studies, Celiac Disease, Diabetes Mellitus, Type 2, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide

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.


Alternate JournalNat. Genet.
PubMed ID22446960
Grant ListR01-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