Polygenic architecture of rare coding variation across 394,783 exomes.
Polygenic architecture of rare coding variation across 394,783 exomes.
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DOI：
10.1038/s41586-022-05684-z
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发表时间：
2023-02
期刊：
影响因子：
64.8
通讯作者：
O'Connor, Luke. J. J.
中科院分区：
文献类型：
--
作者：
Weiner, Daniel. J. J.;Nadig, Ajay;Jagadeesh, Karthik. A. A.;Dey, Kushal. K. K.;Neale, Benjamin. M. M.;Robinson, Elise. B. B.;Karczewski, Konrad. J. J.;O'Connor, Luke. J. J.
Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have discovered thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes. However, rare-variant genetic architecture is not well characterized, and the relationship between common- and rare-variant architecture is unclear. Here, we quantify the heritability explained by gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes. Rare coding variants (AF < 1e-3) explain 1.3% (SE = 0.03%) of phenotypic variance on average – much less than common variants – and most burden heritability is explained by ultra-rare loss-of-function variants (AF < 1e-5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
5
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Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
9.8
作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL