Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

SNP-based associations with intelligence in the GWAS meta-analysis of N=269,867 independent individuals.(a) Manhattan plot showing the −log10 transformed two-tailed P-value of each SNP from the GWAS meta-analysis (of linear and logistic regression statistics) on the y-axis and base pair positions along the chromosomes on the x-axis. The dotted red line indicates Bonferroni-corrected genome-wide significance (P<5×10−8); the blue line the threshold for suggestive associations (P<1×10−5). Independent lead SNPs are indicated by a diamond. (b) Heritability enrichment of 28 functional annotation categories for SNPs in the meta-analysis, calculated with stratified LD score regression. Error bars show 95% confidence intervals around the enrichment estimate. The dashed horizontal line indicates no enrichment of the annotation category. Red dots indicate significant Bonferroni-corrected two-tailed P-values and beige dots indicate suggestive (P<.05) values. UTR=untranslated region; TSS=transcription start site; CTCF=CCCTC-binding factor; DHS=DNaseI Hypersensitive Site; TFBS=transcription factor binding site; DGF=DNaseI digital genomic footprint. (c) Distribution of functional consequences of SNPs in genomic risk loci in the meta-analysis. (d) Distribution of RegulomeDB score for SNPs in genomic risk loci, with a low score indicating a higher likelihood of having a regulatory function (Online methods). (e) The minimum chromatin state across 127 tissue and cell types for SNPs in genomic risk loci, with lower states indicating higher accessibility and states 1–7 referring to open chromatin states (Online Methods).

Cross-locus interactions for genomic regions associated with intelligence in 269,867 independent individuals.Circos plots showing genes on chromosomes 2 (a), 5 (b), 6 (c), 9 (d), and 22 (e) that were linked to genomic risk loci in the GWAS meta-analysis (blue regions) by eQTL mapping (green lines connecting an eQTL SNP to its associated gene), and/or chromatin interactions (orange lines connecting two interacting regions) and showed evidence of interaction across two independent genomic risk loci. Genes implicated by eQTL are in green, by chromatin interactions in orange, and by both eQTL and chromatin interactions mapping in red. The outer layer shows a Manhattan plot containing the −log10 transformed two-tailed P-value of each SNP from the GWAS meta-analysis (of linear and logistic regression statistics), with genome-wide significant SNPs colored according to linkage disequilibrium patterns with the lead SNP. Circos plots for all chromosomes are provided in Supplementary Fig. 8.

Implicated genes, pathways, and tissue- and cell- expression profiles for intelligence in 269,867 independent individuals.(a) Manhattan plot of the genome-wide gene-based association analysis (GWGAS). The y-axis shows the −log10 transformed two-tailed P-value of each gene from a linear model, and the chromosomal position on the x-axis. The red dotted line indicates the Bonferroni-corrected threshold for genome-wide significance of the gene-based test (P<2.76×10−6; 0.05/18,128 genes), and the blue line indicates the suggestive threshold (P<2.76×10−5; 0.5/18,128 genes) (b) Venn diagram showing overlap of genes implicated by positional mapping, eQTL mapping, chromatin interaction mapping, and GWGAS. (c) Gene expression profiles of associated genes in 53 tissue types. The y-axis shows the −log10 transformed two-tailed P-value of association of GWGAS test statistics with tissue-specific gene expression levels in a linear model. Expression data were extracted from the Genotype-Tissue Expression (GTEx) database. Expression values (RPKM) were log2 transformed with pseudocount 1 after winsorization at 50 and averaged per tissue. The dotted blue line indicates the Bonferroni-corrected significance threshold (P=0.05/7,323 gene-sets=6.83×10−6). (d) Single-cell gene-expression analysis of genes related to intelligence in 24 cell-types. The x-axis shows the −log10 transformed two-tailed P-value of association of GWGAS test statistics with cell-specific gene expression levels in a linear model. The dotted blue line indicates the Bonferroni-corrected significance threshold (P=0.05/7,323 gene-sets=6.83×10−6).