Cited by 2,513Genetic Associations and EpidemiologyCognitive Abilities and TestingGenetic Mapping and Diversity in Plants and Animals

The DOI matches its Crossref record; 55 of the 56 references it cites were found in a registry or an index; 20 of the 28 sources its claims cite were checked for support.

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

Open access

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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This study expands a GWAS of educational attainment to ~1.1 million individuals, identifying 1,271 autosomal lead SNPs and 10 X-chromosome lead SNPs. Joint multi-phenotype analysis yields polygenic scores explaining 11–13% of educational-attainment variance and 7–10% of cognitive-performance variance.

Key findings

  • The primary EduYears GWAS (N = 1,131,881) identified 1,271 approximately independent genome-wide-significant SNPs (995 at the stricter P < 1×10−8 threshold); median lead-SNP effect size was 1.7 weeks of schooling per allele (5th–95th percentiles: 1.1–2.6 weeks).
  • Lead SNPs showed heterogeneous effects across cohorts: the joint null of homogeneous cohort-level effects was rejected (P = 9.7×10−12), and the inverse-variance-weighted mean cross-cohort genetic correlation was 0.72 (SE = 0.14), distinguishable from one (P = 0.03).
  • X-chromosome analyses (N = 694,894) identified 10 lead SNPs and estimated X-chromosome SNP heritability of ~0.3% in both men and women, consistent with partial dosage compensation.
  • Polygenic prediction: an LDpred score had incremental R² of 12.7% in Add Health and 10.6% in HRS (weighted average 11.4%); MTAG-based scores explained 11–13% of EduYears variance and 7–10% of cognitive-performance variance. In an African-American HRS sample (N = 1,519), the score’s incremental R² was 1.6%, an 85% attenuation.

Methods

  • Sample-size-weighted meta-analysis of 71 quality-controlled cohort-level results files using METAL, restricted to European-ancestry individuals with EduYears measured at age ≥30; ~10 million SNPs from 1000 Genomes phase 3, with LD Score regression intercept used to inflation-adjust test statistics.
  • Additional analyses included within-family association in 22,135 sibling pairs, X-chromosome GWAS in UK Biobank and 23andMe, GWAS of cognitive performance (N = 257,841), math ability (N = 564,698), and highest math (N = 430,445), and MTAG joint analysis of the four phenotypes.
  • Polygenic scores were constructed with LDpred and evaluated in Add Health (N = 4,775), HRS (N = 8,609), and WLS; biological annotation used DEPICT, stratified LD Score regression, and CAVIARBF fine-mapping.

Limitations

  • The paper states that cross-cohort genetic correlation is imperfect for environmentally contingent phenotypes like EA, that within-family effect sizes were roughly 40% smaller than GWAS effect sizes with assortative-mating adjustment explaining at most one third of the deflation, and that GWAS estimates may be biased upward by correlation between EA and rearing environment.
  • The paper states that the score has much lower predictive power in an African-American sample and is expected to have reduced power in other non-European-ancestry groups; it also cautions that the score should not be interpreted as a measure of genetic endowment without controls for environmental amplification.
  • Evident from the text: all primary association analyses were restricted to European-ancestry individuals, and the X-chromosome heritability analysis could not distinguish whether lower heritability reflects smaller per-allele effects or haploidy/partial X-inactivation.

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Integrity signals

Registry

Crossref · 10.1038/s41588-018-0147-3

Cites

55 of 56 references verified0 citation errors · 1 not checkable

Statistics

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Verification

Claims the paper makes

44 Own result · 15 Own interpretation · 10 Own method · 7 Supported · 6 Partly supported · 2 Sources not found · 2 No full text of the sources · 2 Not checked yet · 1 Supported so far · 1 Not supported · 1 Couldn’t confirm · 1 No basis given · accuracy not yet measured

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  • Probably not a substantial claim. 20
  • It may state two separate claims as one. 19
  • The quote only partly states this claim. 1
37 of 37
  • The authors state this as an assumption.

    The marginal effect size of each SNP is drawn from a mixture distribution with a point mass at zero and a normal component for non-null SNPs.

    “We assume that the marginal effect size of each SNP is drawn from the following mixture distribution: βj~{N(0,τ2)withprobabilityπ0otherwise, where τ2 is the effect-size variance for non-null SNPs and π is the fraction of non-null SNPs in our data.”
  • The paper relies on this without support.

    Add Health is a representative sample of American adolescents and HRS is a representative sample of Americans over age 50.

    “the National Longitudinal Study of Adolescent to Adult Health (Add Health, N = 4,775), a representative sample of American adolescents; and the Health and Retirement Study (HRS, N = 8,609), a representative sample of Americans over age 50.”
  • The authors state this as an assumption.

    The effective number of SNPs (Meff) is the same in males and females for X chromosome SNP heritability estimation.

    “Meff is the effective number of SNPs (which is assumed to be the same in males and females).”
  • The authors state this as an assumption.

    The fraction of causal variants used in LDpred for polygenic score construction is equal to 1.

    “assuming a fraction of causal variants equal to 1”
  • The paper relies on this without support.

    Z1 and Z2 are independent for the replication formula to interpret Z2 as additional information.

    “Because this formula holds when Z1 and Z2 are independent, the implicitly-defined Z2 is interpreted as the additional information contained in the new data.”
5 of 5

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Citations

Cites

Show all 50 references

Research works printed but not linked: 1

  1. Henmon, V. A. C. & Nelson, M. J. Henmon–Nelson Tests of Mental Ability, High School Examination—Grades 7 to 12—Forms A, B, and C. Teacher’s Manual. (Houghton-Mifflin, Boston, 1946).

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Metadata

Authors
23andMe Research Team, Lee, J. J., COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium, 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., Yengo, L., Alver, M., Bao, Y., Clark, D. W., Day, F. R., Furlotte, N. A., Joshi, P. K., Kemper, K. E., Kleinman, A., Langenberg, C., Mägi, R., Trampush, J. W., Verma, S. S., Wu, Y., Lam, M., Zhao, J. H., Zheng, Z., Boardman, J. D., Campbell, H., Freese, J., Harris, K. M., Hayward, C., Herd, P., Kumari, M., Lencz, T., Luan, J., Malhotra, A. K., Metspalu, A., Milani, L., Ong, K. K., Perry, J. R. B., Porteous, D. J., Ritchie, M. D., Smart, M. C., Smith, B. H., Tung, J. Y., Wareham, N. J., Wilson, J. F., Beauchamp, J. P., Conley, D. C., Esko, T., Lehrer, S. F., Magnusson, P. K. E., Oskarsson, S., Pers, T. H., Robinson, M. R., Thom, K., Watson, C., Chabris, C. F., Meyer, M. N., Laibson, D. I., Yang, J., Johannesson, M., Koellinger, P. D., Turley, P., Visscher, P. M., Benjamin, D. J., & Cesarini, D.
Affiliations
  • University of Minnesota (US)
  • University of Colorado Boulder (US)
  • Vrije Universiteit Amsterdam (NL)
  • Harvard University (US)
  • University of Southern California (US)
  • The University of Queensland (AU)
  • Statens Serum Institut (DK)
  • Broad Institute (US)
  • University of Tartu (EE)
  • University of Essex (GB)
  • University of Edinburgh (GB)
  • University of Cambridge (GB)
  • 23andMe (United States) (US)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Geisinger Medical Center (US)
  • Institute of Mental Health (SG)
  • University of North Carolina at Chapel Hill (US)
  • Institute of Genetics and Cancer (GB)
  • Feinstein Institute for Medical Research (US)
  • University of Dundee (GB)
  • University of Toronto (CA)
  • Princeton University (US)
  • National Bureau of Economic Research (US)
  • Karolinska Institutet (SE)
  • Uppsala University (SE)
  • New York University (US)
  • Autism & Developmental Medicine Institute (US)
  • Stockholm School of Economics (SE)
Corresponding author
  • Okbay, Aysu
  • Visscher, Peter M.
  • Benjamin, Daniel J.
Venue
Nature Genetics
Published
2018-07-23
Volume
50
Issue
8
Pages
1112-1121
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2883573930
Cited by
2,470
References
50
Citations by year
2026: 155 · 2025: 271 · 2024: 392 · 2023: 328 · 2022: 375 · 2021: 363 · 2020: 292 · 2019: 244 · 2018: 43
FWCI
132.81
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • Research Publications (Maastricht University) (acceptedVersion, cc-by)
  • Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
  • Open Access at Essex (University of Essex) (acceptedVersion)
  • IRIS (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Max Planck Digital Library (submittedVersion)
  • Lirias (submittedVersion)
  • Site cant be reached (submittedVersion, other-oa)
  • Publikationen an der Universität Bielefeld (Universität Bielefeld) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
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  • OPUS (Augsburg University) (submittedVersion)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • NOVA (University of Newcastle Australia) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Apollo
Funders
  • Brigham and Women's Hospital
  • Rush University
  • Queen Mary University of London
  • Wellcome Trust (213422/Z/18/Z)
  • Broad Institute
  • Open Philanthropy Project (2016-152872)
  • National Institute for Health and Care Research (NF-SI-0507-10228, NF-SI-0514-10027, NF-SI-0512-10135, NF-SI-0617-10149, NIHR-RP-R3-12-013)
  • University of Warwick
  • University of Oxford
  • University of Manchester
  • University of Aberdeen
  • Rijksuniversiteit Groningen
  • Lundbeckfonden (R190 2014-3904)
  • Karolinska Institutet (2017-00641)
  • King Abdulaziz University
  • Vetenskapsrådet (421-2013-1061, 2017-00641, 00641)
  • Westfälische Wilhelms-Universität Münster
  • Universitair Medisch Centrum Groningen
  • Universität Regensburg
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • Novo Nordisk Fonden (NNF16OC0021496)
  • National Institutes of Health (2017-00641, 5r01ag015819-21, 5t32ag000186-35, 5p2chd050924-20, R01AG042568, AG042568, 5p01ag005842-36)
  • Medical Research Council (1811434, MR/N01104X/1, MC_PC_13048, MR/K026992/1, MC_UU_12015/2, MR/N01104X/2, MC_UU_12015/1, MC_UU_00007/10)
  • Biotechnology and Biological Sciences Research Council (BB/F022441/1, BB/F019394/1)
  • Economic and Social Research Council (ES/N00812X/1, ES/K005774/1, ES/M008592/1, ES/S008349/1)
  • Warwick Medical School
  • Diamantina Institute, University of Queensland
  • National Institute on Aging (T32–AG000186, T32-AG000186-23, R01 AG042568, P30 AG012810, AG005842, P30AG010161, R01 AG055406, P01-AG005842, P01-AG005842-20S2, R01-AG015819)
  • National Institute of Mental Health (L30 MH104879)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development ([P2C HD050924], R01HD073342, P2CHD066613, P2CHD047879)
  • H2020 European Research Council (647648)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
educational attainment, polygenic risk score, genetic association, single nucleotide polymorphisms, cognitive performance, brain development, X chromosome, dosage compensation, heritability, gene discovery
MeSH terms
Adult, Aged, Aged, 80 and over, Educational Status, Female, Humans, Male, Middle Aged, Phenotype, Cohort Studies, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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