Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

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.

Fig. 1.

The relationship between standardized coefficients from the first-stage regression of years of schooling on the education-associated SNPs in the Education Sample (x axis) and standardized coefficients from the second-stage regression of cognitive performance on these SNPs in the Cognitive Performance Sample (y axis). The reference allele is chosen such that the coefficient on years of schooling is positive. Each point represents 1 of the 69 education-associated SNPs. (The cloud of points is bounded away from zero effect on years of schooling, because the criterion for including an SNP was reaching P < 10⁻⁵ in the GWAS on years of schooling in the Education Sample.) Because the SD of years of schooling is ∼3, a coefficient of 0.03—a typical size for a years of schooling standardized coefficient (before correcting for the winner’s curse)—means that each reference allele is associated with an increase of 0.03 × 3 ∼ 0.09 y of educational attainment. In conventional IQ units that have an SD of 15, a standardized regression coefficient on cognitive performance of 0.03 corresponds to ∼0.45 IQ points.

Fig. 2.

A Q–Q plot for a regression of cognitive performance on the education-associated SNPs (black circles) with a 95% confidence interval around the null hypothesis (gray shaded region) and a Q–Q plot for a regression of cognitive performance on the theory-based SNPs (red circles) with a 95% confidence interval around the null hypothesis (orange shaded region).

Fig. 3.

Coefficients from regression of standardized cognitive phenotype (total word recall or total mental status) on standardized polygenic score within age category controlling for sex and clustering SEs by individual (details in SI Appendix, section 14). Error bars show ±1 SE.