Publication Date:
2012
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.
Iris type:
1.1 Articolo in rivista
Keywords:
STATISTICS; GENETICS; MULTI FACTORIAL ILLNESSES; GENOME-WIDE
List of contributors:
Stahl, Ea; Wegmann, D; Trynka, G; Gutierrez Achury, J; Do, R; Voight, Bf; Kraft, P; Chen, R; Kallberg, Hj; Kurreeman, Fa; Diabetes Genetics, Replication; Meta analysis, Consortium; Myocardial Infarction Genetics, Consortium; Kathiresan, S; Wijmenga, C; Gregersen, Pk; Alfredsson, L; Siminovitch, Ka; Worthington, J; de Bakker, Pi; Raychaudhuri, S; Plenge, Rm; Voight, Bf; Scott, Lj; Steinthorsdottir, V; Morris, Ap; Dina, C; Welch, Rp; Zeggini, E; Huth, C; Aulchenko, Ys; Thorleifsson, G; Mcculloch, Lj; Ferreira, T; Grallert, H; Amin, N; Wu, G; Willer, Cj; Raychaudhuri, S; Mccarroll, Sa; Langenberg, C; Hofmann, Om; Dupuis, J; Qi, L; Segrè, Av; van Hoek, M; Navarro, P; Ardlie, K; Balkau, B; Benediktsson, R; Bennett, Aj; Blagieva, R; Boerwinkle, E; Bonnycastle, Ll; Boström, Kb; Bravenboer, B; Bumpstead, S; Burtt, Np; Charpentier, G; Chines, Ps; Cornelis, M; Couper, Dj; Crawford, G; Doney, As; Elliott, Ks; Elliott, Al; Erdos, Mr; Fox, Cs; Franklin, Cs; Ganser, M; Gieger, C; Grarup, N; Green, T; Griffin, S; Groves, Cj; Guiducci, C; Hadjadj, S; Hassanali, N; Herder, C; Isomaa, B; Jackson, Au; Johnson, Pr; Jørgensen, T; Kao, Wh; Klopp, N; Kong, A; Kraft, P; Kuusisto, J; Lauritzen, T; Li, M; Lieverse, A; Lindgren, Cm; Lyssenko, V; Marre, M; Meitinger, T; Midthjell, K; Morken, Ma; Narisu, N; Nilsson, P; Owen, Kr; Payne, F; Perry, Jr; Petersen, Ak; Platou, C; Proença, C; Prokopenko, I; Rathmann, W; Rayner, Nw; Robertson, Nr; Rocheleau, G; Roden, M; Sampson, Mj; Saxena, R; Shields, Bm; Shrader, P; Sigurdsson, G; Sparsø, T; Strassburger, K; Stringham, Hm; Sun, Q; Swift, Aj; Thorand, B; Tichet, J; Tuomi, T; van Dam, Rm; van Haeften, Tw; van Herpt, T; van Vliet Ostaptchouk, Jv; Walters, Gb; Weedon, Mn; Wijmenga, C; Witteman, J; Bergman, Rn; Cauchi, S; Collins, Fs; Gloyn, Al; Gyllensten, U; Hansen, T; Hide, Wa; Hitman, Ga; Hofman, A; Hunter, Dj; Hveem, K; Laakso, M; Mohlke, Kl; Morris, Ad; Palmer, Cn; Pramstaller, Pp; Rudan, I; Sijbrands, E; Stein, Ld; Tuomilehto, J; Uitterlinden, A; Walker, M; Wareham, Nj; Watanabe, Rm; Abecasis, Gr; Boehm, Bo; Campbell, H; Daly, Mj; Hattersley, At; Hu, Fb; Meigs, Jb; Pankow, Js; Pedersen, O; Wichmann, He; Barroso, I; Florez, Jc; Frayling, Tm; Groop, L; Sladek, R; Thorsteinsdottir, U; Wilson, Jf; Illig, T; Froguel, P; van Duijn, Cm; Stefansson, K; Altshuler, D; Boehnke, M; Mccarthy, Mi; Kathiresan, S; Meigs, Jb; Williams, G; Nathan, Dm; Macrae, Ca; O'Donnell, Cj; Ardissino, D; Merlini, Pa; Berzuini, C; Bernardinelli, Luisa; Peyvandi, F; Tubaro, M; Celli, P; Ferrario, M; Fetiveau, R; Marziliano, N; Casari, G; Galli, M; Ribichini, F; Rossi, M; Bernardi, F; Zonzin, P; Piazza, A; Mannucci, Pm; Schwartz, Sm; Siscovick, Ds; Yee, J; Friedlander, Y; Elosua, R; Marrugat, J; Lucas, G; Subirana, I; Sala, J; Ramos, R; Salomaa, V; Havulinna, As; Peltonen, L; Melander, O; Berglund, G; Voight, Bf; Kathiresan, S; Hirschhorn, Jn; Asselta, R; Duga, S; Spreafico, M; Musunuru, K; Daly, Mj; Purcell, S; Schwartz, Sm; Yee, J; Kathiresan, S; Lucas, G; Subirana, I; Elosua, R; Surti, A; Guiducci, C; Gianniny, L; Mirel, D; Parkin, M; Burtt, N; Gabriel, S. B.
Published in: