Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

James J. Lee; Robbee Wedow; Aysu Okbay; Edward Kong; Omeed Maghzian; Meghan Zacher; Tuan Anh Nguyen-Viet; Peter Bowers; Julia Sidorenko; Richard Karlsson Linnér; Mark Alan Fontana; Tushar Kundu; Chanwook Lee; Hui Li; Ruoxi Li; Rebecca Royer; Pascal N. Timshel; Raymond K. Walters; Emily A. Willoughby; Loïc Yengo; Michelle Agee; Babak Alipanahi; Adam Auton; Robert K. Bell; Katarzyna Bryc; Sarah L. Elson; Pierre Fontanillas; David A. Hinds; Jennifer C. McCreight; Karen E. Huber; Nadia K. Litterman; Matthew H. McIntyre; Joanna L. Mountain; Elizabeth S. Noblin; Carrie A.M. Northover; Steven J. Pitts; J. Fah Sathirapongsasuti; Olga V. Sazonova; Janie F. Shelton; Suyash Shringarpure; Chao Tian; Vladimir Vacic; Catherine H. Wilson; Jonathan P. Beauchamp; Tune H. Pers; Cornelius A. Rietveld; Patrick Turley; Guo Bo Chen; Valur Emilsson; S. Fleur W. Meddens; 23andMe Research team; COGENT (Cognitive Genomics Consortium); Social Science Genetic Association Consortium; Jan Staessen

doi:10.1038/s41588-018-0147-3

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

James J. Lee, Robbee Wedow, Aysu Okbay^*, Edward Kong, Omeed Maghzian, Meghan Zacher, Tuan Anh Nguyen-Viet, Peter Bowers, Julia Sidorenko, Richard Karlsson Linnér, Mark Alan Fontana, Tushar Kundu, Chanwook Lee, Hui Li, Ruoxi Li, Rebecca Royer, Pascal N. Timshel, Raymond K. Walters, Emily A. Willoughby, Loïc YengoMichelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, David A. Hinds, Jennifer C. McCreight, Karen E. Huber, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Vladimir Vacic, Catherine H. Wilson, Jonathan P. Beauchamp, Tune H. Pers, Cornelius A. Rietveld, Patrick Turley, Guo Bo Chen, Valur Emilsson, S. Fleur W. Meddens, 23andMe Research team, COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium, Jan Staessen

^*Corresponding author for this work

Epidemiologie

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Original language	English
Pages (from-to)	1112-1121
Number of pages	10
Journal	Nature Genetics
Volume	50
Issue number	8
DOIs	https://doi.org/10.1038/s41588-018-0147-3
Publication status	Published - 1 Aug 2018

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Lee, J. J., Wedow, R., Okbay, A., Kong, E., Maghzian, O., Zacher, M., Nguyen-Viet, T. A., Bowers, P., Sidorenko, J., Karlsson Linnér, R., Fontana, M. A., Kundu, T., Lee, C., Li, H., Li, R., Royer, R., Timshel, P. N., Walters, R. K., Willoughby, E. A., ... Staessen, J. (2018). Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nature Genetics, 50(8), 1112-1121. https://doi.org/10.1038/s41588-018-0147-3

@article{381921beb3d74ff6a05990520b6bea0f,

title = "Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals",

abstract = "Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.",

author = "Lee, {James J.} and Robbee Wedow and Aysu Okbay and Edward Kong and Omeed Maghzian and Meghan Zacher and Nguyen-Viet, {Tuan Anh} and Peter Bowers and Julia Sidorenko and {Karlsson Linn{\'e}r}, Richard and Fontana, {Mark Alan} and Tushar Kundu and Chanwook Lee and Hui Li and Ruoxi Li and Rebecca Royer and Timshel, {Pascal N.} and Walters, {Raymond K.} and Willoughby, {Emily A.} and Lo{\"i}c Yengo and Michelle Agee and Babak Alipanahi and Adam Auton and Bell, {Robert K.} and Katarzyna Bryc and Elson, {Sarah L.} and Pierre Fontanillas and Hinds, {David A.} and McCreight, {Jennifer C.} and Huber, {Karen E.} and Litterman, {Nadia K.} and McIntyre, {Matthew H.} and Mountain, {Joanna L.} and Noblin, {Elizabeth S.} and Northover, {Carrie A.M.} and Pitts, {Steven J.} and Sathirapongsasuti, {J. Fah} and Sazonova, {Olga V.} and Shelton, {Janie F.} and Suyash Shringarpure and Chao Tian and Vladimir Vacic and Wilson, {Catherine H.} and Beauchamp, {Jonathan P.} and Pers, {Tune H.} and Rietveld, {Cornelius A.} and Patrick Turley and Chen, {Guo Bo} and Valur Emilsson and Meddens, {S. Fleur W.} and {23andMe Research team} and {COGENT (Cognitive Genomics Consortium)} and {Social Science Genetic Association Consortium} and Jan Staessen",

note = "Funding Information: This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC). The research has also been conducted using the UK Biobank Resource under application numbers 11425 and 12512. We acknowledge the Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by the Karolinska Institutet and receives funding through the Swedish Research Council under the grant number 2017-00641. This study was supported by funding from the Ragnar S{\"o}derberg Foundation (E9/11, E42/15), the Swedish Research Council (421-2013-1061), The Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, The Open Philanthropy Project (2016-152872), and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810 and T32-AG000186-23 to N.B.E.R. and R01-AG042568 to U.S.C. A full list of acknowledgments is provided in the Supplementary Note. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = aug,

day = "1",

doi = "10.1038/s41588-018-0147-3",

language = "English",

volume = "50",

pages = "1112--1121",

journal = "Nature Genetics",

issn = "1061-4036",

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Lee, JJ, Wedow, R, Okbay, A, Kong, E, Maghzian, O, Zacher, M, Nguyen-Viet, TA, Bowers, P, Sidorenko, J, Karlsson Linnér, R, Fontana, MA, Kundu, T, Lee, C, Li, H, Li, R, Royer, R, Timshel, PN, Walters, RK, Willoughby, EA, Yengo, L, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Hinds, DA, McCreight, JC, Huber, KE, Litterman, NK, McIntyre, MH, Mountain, JL, Noblin, ES, Northover, CAM, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Vacic, V, Wilson, CH, Beauchamp, JP, Pers, TH, Rietveld, CA, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, 23andMe Research team, COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium & Staessen, J 2018, 'Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals', Nature Genetics, vol. 50, no. 8, pp. 1112-1121. https://doi.org/10.1038/s41588-018-0147-3

TY - JOUR

T1 - Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

AU - Lee, James J.

AU - Wedow, Robbee

AU - Okbay, Aysu

AU - Kong, Edward

AU - Maghzian, Omeed

AU - Zacher, Meghan

AU - Nguyen-Viet, Tuan Anh

AU - Bowers, Peter

AU - Sidorenko, Julia

AU - Karlsson Linnér, Richard

AU - Fontana, Mark Alan

AU - Kundu, Tushar

AU - Lee, Chanwook

AU - Li, Hui

AU - Li, Ruoxi

AU - Royer, Rebecca

AU - Timshel, Pascal N.

AU - Walters, Raymond K.

AU - Willoughby, Emily A.

AU - Yengo, Loïc

AU - Agee, Michelle

AU - Alipanahi, Babak

AU - Auton, Adam

AU - Bell, Robert K.

AU - Bryc, Katarzyna

AU - Elson, Sarah L.

AU - Fontanillas, Pierre

AU - Hinds, David A.

AU - McCreight, Jennifer C.

AU - Huber, Karen E.

AU - Litterman, Nadia K.

AU - McIntyre, Matthew H.

AU - Mountain, Joanna L.

AU - Noblin, Elizabeth S.

AU - Northover, Carrie A.M.

AU - Pitts, Steven J.

AU - Sathirapongsasuti, J. Fah

AU - Sazonova, Olga V.

AU - Shelton, Janie F.

AU - Shringarpure, Suyash

AU - Tian, Chao

AU - Vacic, Vladimir

AU - Wilson, Catherine H.

AU - Beauchamp, Jonathan P.

AU - Pers, Tune H.

AU - Rietveld, Cornelius A.

AU - Turley, Patrick

AU - Chen, Guo Bo

AU - Emilsson, Valur

AU - Meddens, S. Fleur W.

AU - 23andMe Research team

AU - COGENT (Cognitive Genomics Consortium)

AU - Social Science Genetic Association Consortium

AU - Staessen, Jan

N1 - Funding Information: This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC). The research has also been conducted using the UK Biobank Resource under application numbers 11425 and 12512. We acknowledge the Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by the Karolinska Institutet and receives funding through the Swedish Research Council under the grant number 2017-00641. This study was supported by funding from the Ragnar Söderberg Foundation (E9/11, E42/15), the Swedish Research Council (421-2013-1061), The Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, The Open Philanthropy Project (2016-152872), and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810 and T32-AG000186-23 to N.B.E.R. and R01-AG042568 to U.S.C. A full list of acknowledgments is provided in the Supplementary Note. Publisher Copyright: © 2018, The Author(s).

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

AB - Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

U2 - 10.1038/s41588-018-0147-3

DO - 10.1038/s41588-018-0147-3

M3 - Article

SN - 1061-4036

VL - 50

SP - 1112

EP - 1121

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

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