Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

Abstract

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

Figure 1

a) Manhattan plot and b) QQ plot of meta-analysis results.

Figure 2

Heritability enrichment of genomic annotations (dots) +/- 1 standard error (bars). Horizontal line is p = 8.62x10^-4, Bonferroni-corrected threshold for 58 annotations. Vertical line is enrichment = 1 (that is, no enrichment).

Figure 3

Results of tissue- and cell-specific analyses. a) Whole-body analyses; b) Brain tissue analyses; c) KI level 1 cell analyses; d) KI level 2 cell analyses (only those significant in MAGMA competitive analyses after correction for multiple testing shown). Vertical lines are the Bonferroni threshold for each analysis. Results shown are from MAGMA analyses - tissues and cell-types also significant in LDSC analyses are indicated with †. Full results are shown in Supplementary Table 3.

Figure 4

Conditional cell-type enrichment analysis. X-axis lists target cell-types. Y-axis lists other cell-types. Colors correspond to the enrichment probability of the other cell type after conditioning (P). Values of log(P) approaching zero indicate no enrichment after conditioning. Barplot on the right shows the minimum value of P for each cell-type across all conditional analyses (excluding analyses of the target cell-type with itself); the vertical line marks p=0.05. Red box highlights the loss of significant enrichment in CA1 pyramidal neurons when conditioning on somatosensory (SS) neurons.