[{"_id":"7722","title":"Signatures of negative selection in the genetic architecture of human complex traits","author":[{"last_name":"Zeng","full_name":"Zeng, Jian","first_name":"Jian"},{"first_name":"Ronald","last_name":"de Vlaming","full_name":"de Vlaming, Ronald"},{"full_name":"Wu, Yang","last_name":"Wu","first_name":"Yang"},{"id":"E5D42276-F5DA-11E9-8E24-6303E6697425","first_name":"Matthew Richard","full_name":"Robinson, Matthew Richard","last_name":"Robinson","orcid":"0000-0001-8982-8813"},{"first_name":"Luke R.","last_name":"Lloyd-Jones","full_name":"Lloyd-Jones, Luke R."},{"last_name":"Yengo","full_name":"Yengo, Loic","first_name":"Loic"},{"last_name":"Yap","full_name":"Yap, Chloe X.","first_name":"Chloe X."},{"full_name":"Xue, Angli","last_name":"Xue","first_name":"Angli"},{"first_name":"Julia","full_name":"Sidorenko, Julia","last_name":"Sidorenko"},{"full_name":"McRae, Allan F.","last_name":"McRae","first_name":"Allan F."},{"full_name":"Powell, Joseph E.","last_name":"Powell","first_name":"Joseph E."},{"first_name":"Grant W.","last_name":"Montgomery","full_name":"Montgomery, Grant W."},{"full_name":"Metspalu, Andres","last_name":"Metspalu","first_name":"Andres"},{"last_name":"Esko","full_name":"Esko, Tonu","first_name":"Tonu"},{"full_name":"Gibson, Greg","last_name":"Gibson","first_name":"Greg"},{"full_name":"Wray, Naomi R.","last_name":"Wray","first_name":"Naomi R."},{"last_name":"Visscher","full_name":"Visscher, Peter M.","first_name":"Peter M."},{"first_name":"Jian","last_name":"Yang","full_name":"Yang, Jian"}],"doi":"10.1038/s41588-018-0101-4","abstract":[{"text":"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.","lang":"eng"}],"issue":"5","year":"2018","date_updated":"2021-01-12T08:15:06Z","publication_identifier":{"issn":["1061-4036","1546-1718"]},"publication":"Nature Genetics","page":"746-753","article_type":"original","publication_status":"published","status":"public","month":"04","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"mla":"Zeng, Jian, et al. “Signatures of Negative Selection in the Genetic Architecture of Human Complex Traits.” <i>Nature Genetics</i>, vol. 50, no. 5, Springer Nature, 2018, pp. 746–53, doi:<a href=\"https://doi.org/10.1038/s41588-018-0101-4\">10.1038/s41588-018-0101-4</a>.","chicago":"Zeng, Jian, Ronald de Vlaming, Yang Wu, Matthew Richard Robinson, Luke R. Lloyd-Jones, Loic Yengo, Chloe X. Yap, et al. “Signatures of Negative Selection in the Genetic Architecture of Human Complex Traits.” <i>Nature Genetics</i>. Springer Nature, 2018. <a href=\"https://doi.org/10.1038/s41588-018-0101-4\">https://doi.org/10.1038/s41588-018-0101-4</a>.","ama":"Zeng J, de Vlaming R, Wu Y, et al. Signatures of negative selection in the genetic architecture of human complex traits. <i>Nature Genetics</i>. 2018;50(5):746-753. doi:<a href=\"https://doi.org/10.1038/s41588-018-0101-4\">10.1038/s41588-018-0101-4</a>","short":"J. Zeng, R. de Vlaming, Y. Wu, M.R. Robinson, L.R. Lloyd-Jones, L. Yengo, C.X. Yap, A. Xue, J. Sidorenko, A.F. McRae, J.E. Powell, G.W. Montgomery, A. Metspalu, T. Esko, G. Gibson, N.R. Wray, P.M. Visscher, J. Yang, Nature Genetics 50 (2018) 746–753.","ista":"Zeng J, de Vlaming R, Wu Y, Robinson MR, Lloyd-Jones LR, Yengo L, Yap CX, Xue A, Sidorenko J, McRae AF, Powell JE, Montgomery GW, Metspalu A, Esko T, Gibson G, Wray NR, Visscher PM, Yang J. 2018. Signatures of negative selection in the genetic architecture of human complex traits. Nature Genetics. 50(5), 746–753.","ieee":"J. Zeng <i>et al.</i>, “Signatures of negative selection in the genetic architecture of human complex traits,” <i>Nature Genetics</i>, vol. 50, no. 5. Springer Nature, pp. 746–753, 2018.","apa":"Zeng, J., de Vlaming, R., Wu, Y., Robinson, M. R., Lloyd-Jones, L. R., Yengo, L., … Yang, J. (2018). Signatures of negative selection in the genetic architecture of human complex traits. <i>Nature Genetics</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41588-018-0101-4\">https://doi.org/10.1038/s41588-018-0101-4</a>"},"day":"16","oa_version":"None","date_created":"2020-04-30T10:44:57Z","date_published":"2018-04-16T00:00:00Z","extern":"1","publisher":"Springer Nature","intvolume":"        50","article_processing_charge":"No","volume":50,"type":"journal_article","language":[{"iso":"eng"}],"quality_controlled":"1"},{"publication":"Nature Genetics","date_updated":"2021-01-12T08:15:11Z","page":"481-487","article_type":"original","oa":1,"year":"2016","publisher":"Springer Nature","intvolume":"        48","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1038/ng.3538"}],"language":[{"iso":"eng"}],"type":"journal_article","quality_controlled":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","extern":"1","date_published":"2016-03-28T00:00:00Z","date_created":"2020-04-30T10:50:26Z","publication_identifier":{"issn":["1061-4036","1546-1718"]},"publication_status":"published","status":"public","title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","author":[{"last_name":"Zhu","full_name":"Zhu, Zhihong","first_name":"Zhihong"},{"last_name":"Zhang","full_name":"Zhang, Futao","first_name":"Futao"},{"last_name":"Hu","full_name":"Hu, Han","first_name":"Han"},{"last_name":"Bakshi","full_name":"Bakshi, Andrew","first_name":"Andrew"},{"first_name":"Matthew Richard","id":"E5D42276-F5DA-11E9-8E24-6303E6697425","last_name":"Robinson","full_name":"Robinson, Matthew Richard","orcid":"0000-0001-8982-8813"},{"last_name":"Powell","full_name":"Powell, Joseph E","first_name":"Joseph E"},{"first_name":"Grant W","full_name":"Montgomery, Grant W","last_name":"Montgomery"},{"first_name":"Michael E","last_name":"Goddard","full_name":"Goddard, Michael E"},{"last_name":"Wray","full_name":"Wray, Naomi R","first_name":"Naomi R"},{"full_name":"Visscher, Peter M","last_name":"Visscher","first_name":"Peter M"},{"full_name":"Yang, Jian","last_name":"Yang","first_name":"Jian"}],"_id":"7737","abstract":[{"text":"Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.","lang":"eng"}],"issue":"5","doi":"10.1038/ng.3538","volume":48,"article_processing_charge":"No","citation":{"chicago":"Zhu, Zhihong, Futao Zhang, Han Hu, Andrew Bakshi, Matthew Richard Robinson, Joseph E Powell, Grant W Montgomery, et al. “Integration of Summary Data from GWAS and EQTL Studies Predicts Complex Trait Gene Targets.” <i>Nature Genetics</i>. Springer Nature, 2016. <a href=\"https://doi.org/10.1038/ng.3538\">https://doi.org/10.1038/ng.3538</a>.","mla":"Zhu, Zhihong, et al. “Integration of Summary Data from GWAS and EQTL Studies Predicts Complex Trait Gene Targets.” <i>Nature Genetics</i>, vol. 48, no. 5, Springer Nature, 2016, pp. 481–87, doi:<a href=\"https://doi.org/10.1038/ng.3538\">10.1038/ng.3538</a>.","short":"Z. Zhu, F. Zhang, H. Hu, A. Bakshi, M.R. Robinson, J.E. Powell, G.W. Montgomery, M.E. Goddard, N.R. Wray, P.M. Visscher, J. Yang, Nature Genetics 48 (2016) 481–487.","ama":"Zhu Z, Zhang F, Hu H, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. <i>Nature Genetics</i>. 2016;48(5):481-487. doi:<a href=\"https://doi.org/10.1038/ng.3538\">10.1038/ng.3538</a>","ista":"Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, Montgomery GW, Goddard ME, Wray NR, Visscher PM, Yang J. 2016. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nature Genetics. 48(5), 481–487.","ieee":"Z. Zhu <i>et al.</i>, “Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets,” <i>Nature Genetics</i>, vol. 48, no. 5. Springer Nature, pp. 481–487, 2016.","apa":"Zhu, Z., Zhang, F., Hu, H., Bakshi, A., Robinson, M. R., Powell, J. E., … Yang, J. (2016). Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. <i>Nature Genetics</i>. Springer Nature. <a href=\"https://doi.org/10.1038/ng.3538\">https://doi.org/10.1038/ng.3538</a>"},"day":"28","month":"03","oa_version":"Published Version"},{"quality_controlled":"1","type":"journal_article","language":[{"iso":"eng"}],"volume":47,"article_processing_charge":"No","intvolume":"        47","publisher":"Springer Nature","date_created":"2020-04-30T10:58:23Z","oa_version":"None","extern":"1","date_published":"2015-09-14T00:00:00Z","month":"09","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","day":"14","citation":{"ieee":"M. R. Robinson <i>et al.</i>, “Population genetic differentiation of height and body mass index across Europe,” <i>Nature Genetics</i>, vol. 47, no. 11. Springer Nature, pp. 1357–1362, 2015.","apa":"Robinson, M. R., Hemani, G., Medina-Gomez, C., Mezzavilla, M., Esko, T., Shakhbazov, K., … Visscher, P. M. (2015). Population genetic differentiation of height and body mass index across Europe. <i>Nature Genetics</i>. Springer Nature. <a href=\"https://doi.org/10.1038/ng.3401\">https://doi.org/10.1038/ng.3401</a>","ama":"Robinson MR, Hemani G, Medina-Gomez C, et al. Population genetic differentiation of height and body mass index across Europe. <i>Nature Genetics</i>. 2015;47(11):1357-1362. doi:<a href=\"https://doi.org/10.1038/ng.3401\">10.1038/ng.3401</a>","ista":"Robinson MR, Hemani G, Medina-Gomez C, Mezzavilla M, Esko T, Shakhbazov K, Powell JE, Vinkhuyzen A, Berndt SI, Gustafsson S, Justice AE, Kahali B, Locke AE, Pers TH, Vedantam S, Wood AR, van Rheenen W, Andreassen OA, Gasparini P, Metspalu A, Berg LH van den, Veldink JH, Rivadeneira F, Werge TM, Abecasis GR, Boomsma DI, Chasman DI, de Geus EJC, Frayling TM, Hirschhorn JN, Hottenga JJ, Ingelsson E, Loos RJF, Magnusson PKE, Martin NG, Montgomery GW, North KE, Pedersen NL, Spector TD, Speliotes EK, Goddard ME, Yang J, Visscher PM. 2015. Population genetic differentiation of height and body mass index across Europe. Nature Genetics. 47(11), 1357–1362.","short":"M.R. Robinson, G. Hemani, C. Medina-Gomez, M. Mezzavilla, T. Esko, K. Shakhbazov, J.E. Powell, A. Vinkhuyzen, S.I. Berndt, S. Gustafsson, A.E. Justice, B. Kahali, A.E. Locke, T.H. Pers, S. Vedantam, A.R. Wood, W. van Rheenen, O.A. Andreassen, P. Gasparini, A. Metspalu, L.H. van den Berg, J.H. Veldink, F. Rivadeneira, T.M. Werge, G.R. Abecasis, D.I. Boomsma, D.I. Chasman, E.J.C. de Geus, T.M. Frayling, J.N. Hirschhorn, J.J. Hottenga, E. Ingelsson, R.J.F. Loos, P.K.E. Magnusson, N.G. Martin, G.W. Montgomery, K.E. North, N.L. Pedersen, T.D. Spector, E.K. Speliotes, M.E. Goddard, J. Yang, P.M. Visscher, Nature Genetics 47 (2015) 1357–1362.","mla":"Robinson, Matthew Richard, et al. “Population Genetic Differentiation of Height and Body Mass Index across Europe.” <i>Nature Genetics</i>, vol. 47, no. 11, Springer Nature, 2015, pp. 1357–62, doi:<a href=\"https://doi.org/10.1038/ng.3401\">10.1038/ng.3401</a>.","chicago":"Robinson, Matthew Richard, Gibran Hemani, Carolina Medina-Gomez, Massimo Mezzavilla, Tonu Esko, Konstantin Shakhbazov, Joseph E Powell, et al. “Population Genetic Differentiation of Height and Body Mass Index across Europe.” <i>Nature Genetics</i>. Springer Nature, 2015. <a href=\"https://doi.org/10.1038/ng.3401\">https://doi.org/10.1038/ng.3401</a>."},"article_type":"original","page":"1357-1362","status":"public","publication_status":"published","date_updated":"2021-01-12T08:15:13Z","publication_identifier":{"issn":["1061-4036","1546-1718"]},"publication":"Nature Genetics","doi":"10.1038/ng.3401","year":"2015","issue":"11","abstract":[{"lang":"eng","text":"Across-nation differences in the mean values for complex traits are common1,2,3,4,5,6,7,8, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10−8; BMI, P < 5.95 × 10−4), and we find an among-population genetic correlation for tall and slender individuals (r = −0.80, 95% CI = −0.95, −0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58)."}],"_id":"7742","author":[{"orcid":"0000-0001-8982-8813","id":"E5D42276-F5DA-11E9-8E24-6303E6697425","first_name":"Matthew Richard","full_name":"Robinson, Matthew Richard","last_name":"Robinson"},{"first_name":"Gibran","full_name":"Hemani, Gibran","last_name":"Hemani"},{"first_name":"Carolina","last_name":"Medina-Gomez","full_name":"Medina-Gomez, Carolina"},{"first_name":"Massimo","full_name":"Mezzavilla, Massimo","last_name":"Mezzavilla"},{"first_name":"Tonu","full_name":"Esko, Tonu","last_name":"Esko"},{"last_name":"Shakhbazov","full_name":"Shakhbazov, Konstantin","first_name":"Konstantin"},{"full_name":"Powell, Joseph E","last_name":"Powell","first_name":"Joseph E"},{"last_name":"Vinkhuyzen","full_name":"Vinkhuyzen, Anna","first_name":"Anna"},{"full_name":"Berndt, Sonja I","last_name":"Berndt","first_name":"Sonja I"},{"last_name":"Gustafsson","full_name":"Gustafsson, Stefan","first_name":"Stefan"},{"full_name":"Justice, Anne E","last_name":"Justice","first_name":"Anne E"},{"last_name":"Kahali","full_name":"Kahali, Bratati","first_name":"Bratati"},{"full_name":"Locke, Adam E","last_name":"Locke","first_name":"Adam E"},{"full_name":"Pers, Tune H","last_name":"Pers","first_name":"Tune H"},{"full_name":"Vedantam, Sailaja","last_name":"Vedantam","first_name":"Sailaja"},{"full_name":"Wood, Andrew R","last_name":"Wood","first_name":"Andrew R"},{"last_name":"van Rheenen","full_name":"van Rheenen, Wouter","first_name":"Wouter"},{"last_name":"Andreassen","full_name":"Andreassen, Ole A","first_name":"Ole A"},{"last_name":"Gasparini","full_name":"Gasparini, Paolo","first_name":"Paolo"},{"first_name":"Andres","full_name":"Metspalu, Andres","last_name":"Metspalu"},{"first_name":"Leonard H van den","full_name":"Berg, Leonard H van den","last_name":"Berg"},{"last_name":"Veldink","full_name":"Veldink, Jan H","first_name":"Jan H"},{"first_name":"Fernando","full_name":"Rivadeneira, Fernando","last_name":"Rivadeneira"},{"last_name":"Werge","full_name":"Werge, Thomas M","first_name":"Thomas M"},{"last_name":"Abecasis","full_name":"Abecasis, Goncalo R","first_name":"Goncalo R"},{"first_name":"Dorret I","full_name":"Boomsma, Dorret I","last_name":"Boomsma"},{"first_name":"Daniel I","last_name":"Chasman","full_name":"Chasman, Daniel I"},{"last_name":"de Geus","full_name":"de Geus, Eco J C","first_name":"Eco J C"},{"full_name":"Frayling, Timothy M","last_name":"Frayling","first_name":"Timothy M"},{"first_name":"Joel N","last_name":"Hirschhorn","full_name":"Hirschhorn, Joel N"},{"last_name":"Hottenga","full_name":"Hottenga, Jouke Jan","first_name":"Jouke Jan"},{"first_name":"Erik","last_name":"Ingelsson","full_name":"Ingelsson, Erik"},{"first_name":"Ruth J F","full_name":"Loos, Ruth J F","last_name":"Loos"},{"last_name":"Magnusson","full_name":"Magnusson, Patrik K E","first_name":"Patrik K E"},{"full_name":"Martin, Nicholas G","last_name":"Martin","first_name":"Nicholas G"},{"first_name":"Grant W","last_name":"Montgomery","full_name":"Montgomery, Grant W"},{"last_name":"North","full_name":"North, Kari E","first_name":"Kari E"},{"first_name":"Nancy L","last_name":"Pedersen","full_name":"Pedersen, Nancy L"},{"full_name":"Spector, Timothy D","last_name":"Spector","first_name":"Timothy D"},{"full_name":"Speliotes, Elizabeth K","last_name":"Speliotes","first_name":"Elizabeth K"},{"first_name":"Michael E","full_name":"Goddard, Michael E","last_name":"Goddard"},{"last_name":"Yang","full_name":"Yang, Jian","first_name":"Jian"},{"last_name":"Visscher","full_name":"Visscher, Peter M","first_name":"Peter M"}],"title":"Population genetic differentiation of height and body mass index across Europe"}]