Signatures of negative selection in the genetic architecture of human complex traits

被引：237

作者：

Zeng, Jian ^{[1
]}

de Vlaming, Ronald ^{[2
,3
]}

Wu, Yang ^{[1
]}

Robinson, Matthew R. ^{[1
,4
]}

Lloyd-Jones, Luke R. ^{[1
]}

Yengo, Loic ^{[1
]}

Yap, Chloe X. ^{[1
]}

Xue, Angli ^{[1
]}

Sidorenko, Julia ^{[1
,5
]}

McRae, Allan F. ^{[1
]}

Powell, Joseph E. ^{[1
]}

Montgomery, Grant W. ^{[1
]}

Metspalu, Andres ^{[5
]}

Esko, Tonu ^{[5
]}

Gibson, Greg ^{[6
,7
]}

Wray, Naomi R. ^{[1
,8
]}

Visscher, Peter M. ^{[1
,8
]}

Yang, Jian ^{[1
,8
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[2] Vrije Univ Amsterdam, Sch Business & Econ, Amsterdam, Netherlands

[3] Erasmus Univ, Rotterdam Inst Behav & Biol, Rotterdam, Netherlands

[4] Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland

[5] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia

[6] Georgia Inst Technol, Sch Biol Sci, Atlanta, GA 30332 USA

[7] Georgia Inst Technol, Ctr Integrat Genom, Atlanta, GA 30332 USA

[8] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

来源：

NATURE GENETICS | 2018年 / 50卷 / 05期

基金：

美国国家卫生研究院; 英国医学研究理事会; 澳大利亚研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; MISSING HERITABILITY; HUMAN ADAPTATION; RARE VARIANTS; COMMON; POPULATION; REGRESSION; MUTATION; HEIGHT;

D O I：

10.1038/s41588-018-0101-4

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits.

引用

页码：746 / +

页数：10

共 70 条

[1] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[2] Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[3]

[Anonymous], 2015, UK BIOB GEN QUAL CON

[4] A Population Genetic Signal of Polygenic Adaptation [J].

Berg, Jeremy J. ;

Coop, Graham .

PLOS GENETICS, 2014, 10 (08)

[5] An atlas of genetic correlations across human diseases and traits [J].

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (11) :1236-+

[6] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

[7] Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112151) [J].

Davies, G. ;

Marioni, R. E. ;

Liewald, D. C. ;

Hill, W. D. ;

Hagenaars, S. P. ;

Harris, S. E. ;

Ritchie, S. J. ;

Luciano, M. ;

Fawns-Ritchie, C. ;

Lyall, D. ;

Cullen, B. ;

Cox, S. R. ;

Hayward, C. ;

Porteous, D. J. ;

Evans, J. ;

McIntosh, A. M. ;

Gallacher, J. ;

Craddock, N. ;

Pell, J. P. ;

Smith, D. J. ;

Gale, C. R. ;

Deary, I. J. .

MOLECULAR PSYCHIATRY, 2016, 21 (06) :758-767

[8] Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair [J].

Day, Felix R. ;

Ruth, Katherine S. ;

Thompson, Deborah J. ;

Lunetta, Kathryn L. ;

Pervjakova, Natalia ;

Chasman, Daniel I. ;

Stolk, Lisette ;

Finucane, Hilary K. ;

Sulem, Patrick ;

Bulik-Sullivan, Brendan ;

Esko, Tonu ;

Johnson, Andrew D. ;

Elks, Cathy E. ;

Franceschini, Nora ;

He, Chunyan ;

Altmaier, Elisabeth ;

Brody, Jennifer A. ;

Franke, Lude L. ;

Huffman, Jennifer E. ;

Keller, Margaux F. ;

McArdle, Patrick F. ;

Nutile, Teresa ;

Porcu, Eleonora ;

Robino, Antonietta ;

Rose, Lynda M. ;

Schick, Ursula M. ;

Smith, Jennifer A. ;

Teumer, Alexander ;

Traglia, Michela ;

Vuckovic, Dragana ;

Yao, Jie ;

Zhao, Wei ;

Albrecht, Eva ;

Amin, Najaf ;

Corre, Tanguy ;

Hottenga, Jouke-Jan ;

Mangino, Massimo ;

Smith, Albert V. ;

Tanaka, Toshiko ;

Abecasis, Goncalo R. ;

Andrulis, Irene L. ;

Anton-Culver, Hoda ;

Antoniou, Antonis C. ;

Arndt, Volker ;

Arnold, Alice M. ;

Barbieri, Caterina ;

Beckmann, Matthias W. ;

Beeghly-Fadiel, Alicia ;

Benitez, Javier ;

Bernstein, Leslie .

NATURE GENETICS, 2015, 47 (11) :1294-+

[9] Additive Genetic Variation in Schizophrenia Risk Is Shared by Populations of African and European Descent [J].

de Candia, Teresa R. ;

Lee, S. Hong ;

Yang, Jian ;

Browning, Brian L. ;

Gejman, Pablo V. ;

Levinson, Douglas F. ;

Mowry, Bryan J. ;

Hewitt, John K. ;

Goddard, Michael E. ;

O'Donovan, Michael C. ;

Purcell, Shaun M. ;

Posthuma, Danielle ;

Visscher, Peter M. ;

Wray, Naomi R. ;

Keller, Matthew C. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 93 (03) :463-470

[10] Waist circumference and waist-to-hip ratio as predictors of cardiovascular events: meta-regression analysis of prospective studies [J].

de Koning, Lawrence ;

Merchant, Anwar T. ;

Pogue, Janice ;

Anand, Sonia S. .

EUROPEAN HEART JOURNAL, 2007, 28 (07) :850-856

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