Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Abstract

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3,4,5,6,7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer’s disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

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Fig. 1: SNP-based associations with intelligence in the GWAS meta-analysis of n = 269,867 independent individuals.
Fig. 2: Cross-locus interactions for genomic regions associated with intelligence in 269,867 independent individuals.
Fig. 3: Implicated genes, pathways, and tissue and cell expression profiles for intelligence in 269,867 independent individuals.

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Acknowledgements

This work was funded by the Netherlands Organization for Scientific Research through the following grants: NWO Brain and Cognition 433­-09-228 (D.P.), NWO MagW VIDI 452­-12-­014 (S.v.d.S.), NWO VICI 453-13-005 (D.P.), and 645­-000-­003 (D.P.). P.R.J. was funded by the Sophia Foundation for Scientific Research (SSWO, grant S14-27 to P.R.J.). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO: 480-05-003 to D.P.), Vrije Universiteit, Amsterdam, The Netherlands, and the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services, SurfSARA. J.H.-­L. was funded by the Swedish Research Council (Vetenskapsrådet, award 2014­3863), StratNeuro, the Wellcome Trust (108726/Z/15/Z), and the Swedish Brain Foundation (Hjärnfonden). N.G.S. was supported by the Wellcome Trust (108726/Z/15/Z). J.B. was funded by the Swiss National Science Foundation. This research has been conducted using the UK Biobank resource under application 16406. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. Additional acknowledgements can be found in the Supplementary Information.

Author information

D.P., J.E.S., and P.R.J. performed the analyses. D.P. conceived the idea of the study and supervised analyses. S. Stringer performed quality control on the UK Biobank data and wrote the analysis pipeline. K.W. constructed and applied the FUMA pipeline for performing follow-up analyses. J.B. conducted the single-cell enrichment analyses. C.A.d.L., M. Nagel, A.R. Hammerschlag, T.J.C.P., and S.v.d.S. assisted with pipeline development and data analysis. S.A., P.B.B., J.R.I.C., K.L.G., J.A.K., R.K., E. Krapohl, M.L., M. Nygaard, C.A.R., J.W.T., H.Y., D.Z., S.H., N.K.H., I.K.K., S.L., G.W.M., A.B.M.-M., E.B.Q., G.S., N.G.S., B.T.W., D.E.A., D.K., D.A., R.M.B., P.B., K.E.B., T.D.C., O.C.-F., A. Christoforou, E.T.C., E.C., A. Corvin, G. Davies, I.J.D., P.D., D.D., S.D., G. Donohoe, E.D.C., J.G.E., T.E., N.A.F., D.C.G., I.G., M.G., S.G., A.R. Hariri, A. Hatzimanolis, M.C.K., E. Knowles, B.K., J.L., S.L.-H., T.L., D.C.L., E.L., A.J.L., A.K.M., I.M., D.M., A.C.N., W.O., A. Palotie, A. Payton, N.P., R.A.P., K.R., I.R., P.R., D.R., F.W.S., M.A.S., O.B.S., N.S., J.M.S., V.M.S., N.C.S., R.E.S., K.S., A.N.V., D.R.W., E.W., J.Y., G.A., O.A.A., G.B., L.C., B.D., D.M.D., A. Heinz, J.H.-L., M.A.I., K.S.K., N.G.M., S.E.M., N.L.P., R.P., T.J.C.P., S.R., P.F.S., H.T., S.I.V., and M.J.W. contributed data. T.W. read and commented on the paper. D.P., J.E.S., and P.R.J. wrote the paper. All authors critically reviewed the paper.

Correspondence to Danielle Posthuma.

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Competing interests

P.F.S. reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (scientific advisory board member), and Roche (grant recipient, speaker reimbursement). G.B. reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. J.H.-L. reports interests from Cartana (scientific advisor) and Roche (grant recipient). T.D.C. is a consultant to Boehringer Ingelheim Pharmaceuticals and Lundbeck. All other authors declare no financial interests or potential conflicts of interest.

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Savage, J.E., Jansen, P.R., Stringer, S. et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet 50, 912–919 (2018). https://doi.org/10.1038/s41588-018-0152-6

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