title: Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.
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.
authors.affiliation: Division of Rheumatology Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. estahl@rics.bwh.harvard.edu
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.forename: Daniel
authors.initials: D
authors.lastname: Wegmann
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Kallberg
authors.forename: Fina A S
authors.initials: FA
authors.lastname: Kurreeman
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001499:Bayes Theorem; D002318:Cardiovascular Diseases / Q000235:genetics*; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*