Significance We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits).

Abstract We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

Footnotes Author contributions: D.J.B., D. Cesarini, and P.D.K. designed research; C.A.R., T.E., G.D., T.H.P., P.T., B.B., V.E., A.D.J., J.J.L., C.d.L., R.E.M., S.E.M., M.B.M., O.R., S.J.v.d.L., A.A.E.V., N.A., D. Conley, J.D., R.F., L.F., C.H., C.I.-V., J.K., D.C.L., P.K.E.M., G.M., D.P., M.T., M.E.W., M.J., P.M.V., and D. Cesarini analyzed data; C.A.R., T.E., P.T., C.F.C., D.L., D.J.B., D. Cesarini, and P.D.K. wrote the paper; C.F.C., C.M.v.D., E.L.G., W.G.I., V.J., D.L., P.L., N.G.M., M.M., N.L.P., S.P., D.P., J.M.S., H.T., F.C.V., M.J.W., G.D.S., I.J.D., M.J., and R.P. performed data collection; J.J.L., M.B.M., C.M.v.D., N.K.H., P.K.E.M., D.J.P., B.H.S., J.M.S., H.T., N.J.T., M.J.W., I.J.D., and M.J. performed phenotyping; and G.D., M.B.M., C.M.v.D., C.H., V.J., D.C.L., P.K.E.M., N.G.M., D.J.P., F.R., N.J.T., and A.G.U. performed genotyping.

See SI Appendix for further details.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: Genetic summary data on which our work is based are posted on the website of our research consortium (www.ssgac.org).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1404623111/-/DCSupplemental.