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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Polderman, T. J. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47, 702–709 (2015).
Wraw, C., Deary, I. J., Gale, C. R. & Der, G. Intelligence in youth and health at age 50. Intelligence 53, 23–32 (2015).
Davies, G. et al. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N = 53949). Mol. Psychiatry 20, 183–192 (2015).
Davies, G. et al. Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N = 112 151). Mol. Psychiatry 21, 758–767 (2016).
Sniekers, S. et al. Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence. Nat. Genet. 49, 1107–1112 (2017).
Trampush, J. W. et al. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol. Psychiatry 22, 336–345 (2017).
Zabaneh, D. et al. A genome-wide association study for extremely high intelligence. Mol. Psychiatry 23, 1226–1232 (2018).
Jensen, A.R. The G Factor: The Science of Mental Ability (Praeger, Westport, CT, US, 1998).
Carroll, J. B. Human Cognitive Abilities: A Survey of Factor-Analytic Studies. (Cambridge University Press, Cambridge, UK, 1993).
Spearman, C. “General intelligence,” objectively determined and measured. Am. J. Psychol. 15, 201–292 (1904).
Plomin, R. & Kovas, Y. Generalist genes and learning disabilities. Psychol. Bull. 131, 592–617 (2005).
Plomin, R. & von Stumm, S. The new genetics of intelligence. Nat. Rev. Genet. 19, 148–159 (2018).
Johnson, W., Bouchard, T. J., Krueger, R. F., McGue, M. & Gottesman, I. I. Just one g: consistent results from three test batteries. Intelligence 32, 95–107 (2004).
Johnson, W., Nijenhuis, Jt & Bouchard, T. J. Still just 1 g: consistent results from five test batteries. Intelligence 36, 81–95 (2008).
Deary, I. J., Penke, L. & Johnson, W. The neuroscience of human intelligence differences. Nat. Rev. Neurosci. 11, 201–211 (2010).
Deary, I. J. Intelligence. Annu. Rev. Psychol. 63, 453–482 (2012).
Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
Deary, I. J., Strand, S., Smith, P. & Fernandes, C. Intelligence and educational achievement. Intelligence 35, 13–21 (2007).
Rietveld, C. A. et al. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science 340, 1467–1471 (2013).
Euesden, J., Lewis, C. M. & O’Reilly, P. F. PRSice: Polygenic Risk Score software. Bioinformatics 31, 1466–1468 (2015).
Vilhjálmsson, B. J. et al. Modeling linkage disequilibrium increases accuracy of polygenic risk scores. Am. J. Hum. Genet. 97, 576–592 (2015).
Hill, W. D. et al. Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions. Transl. Psychiatry 6, e980 (2016).
Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).
Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).
de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015).
Ashburner, M. et al. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000).
Posthuma, D. et al. The association between brain volume and intelligence is of genetic origin. Nat. Neurosci. 5, 83–84 (2002).
MacArthur, J. et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 45(D1), D896–D901 (2017).
Zhu, Z. et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat. Commun. 9, 224 (2018).
Johnson, W., Deary, I. J. & Iacono, W. G. Genetic and environmental transactions underlying educational attainment. Intelligence 37, 466–478 (2009).
Richards, M. & Sacker, A. Is education causal? Yes. Int. J. Epidemiol. 40, 516–518 (2011).
Kendler, K. S., Ohlsson, H., Sundquist, J. & Sundquist, K. IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk. Am. J. Psychiatry 172, 259–265 (2015).
Le Hellard, S. et al. Identification of gene loci that overlap between schizophrenia and educational attainment. Schizophr. Bull. 43, 654–664 (2017).
Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
Peloso, G. M. et al. Phenotypic extremes in rare variant study designs. Eur. J. Hum. Genet. 24, 924–930 (2016).
Purcell, S., Cherny, S. S. & Sham, P. C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).
Coleman, J.R.I. et al. Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals. Mol. Psychiatry https://doi.org/10.1038/s41380-018-0040-6 (2018).
König, I. R., Loley, C., Erdmann, J. & Ziegler, A. How to include chromosome X in your genome-wide association study. Genet. Epidemiol. 38, 97–103 (2014).
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
Okbay, A. et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533, 539–542 (2016).
Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).
Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).
Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).
Boyle, A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).
Ernst, J. & Kellis, M. ChromHMM: automating chromatin-state discovery and characterization. Nat. Methods 9, 215–216 (2012).
Kundaje, A. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).
Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016).
GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
Westra, H. J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).
Zhernakova, D. V. et al. Identification of context-dependent expression quantitative trait loci in whole blood. Nat. Genet. 49, 139–145 (2017).
Schmitt, A. D. et al. A compendium of chromatin contact maps reveals spatially active regions in the human genome. Cell Rep. 17, 2042–2059 (2016).
Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).
Skene, N. G. et al. Genetic identification of brain cell types underlying schizophrenia. Nat. Genet. 50, 825–833 (2018).
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.
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.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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) doi:10.1038/s41588-018-0152-6
Philosophical Transactions of the Royal Society B: Biological Sciences (2020)
Epilepsy & Behavior (2020)
Association of Alzheimer’s Disease Genetic Risk Loci with Cognitive Performance and Decline: A Systematic Review
Journal of Alzheimer's Disease (2019)
The American Journal of Human Genetics (2019)
A 3’ UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction
PLOS ONE (2019)