Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151)

Abstract

People's differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal-numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal-numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer's disease and schizophrenia.

Figure 1

(a) Manhattan and (b) Q–Q plots of P-values of the SNP-based association analyses for each of the cognitive phenotypes: educational attainment, verbal–numerical reasoning, reaction time and memory. The red line indicates the threshold for genome-wide significance (P<5 × 10⁻⁸); the grey line indicates the threshold for suggestive significance (P<1 × 10⁻⁵). SNP, single-nucleotide polymorphism.

Figure 2

Heat maps of associations between the polygenic profile scores for cognitive phenotypes in UK Biobank and cognitive ability in Generation Scotland (a) and the Lothian Birth Cohort 1936 (b). Stronger associations are indicated by darker shades. The amount of variance (%) explained is indicated for each association. Further information can be found in Supplementary Table 4.