GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence

Abstract

4Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence [3][4][5][6][7] , but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons.Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimer's dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.We performed a genome wide meta-analysis of 16 independent cohorts totaling 279,930 participants of European ancestry and 9,398,186 genetic variants passing quality control (Online 4.4% had a RegulomeDB 14 score of 1a-1f (Figure 1d), suggesting a regulatory function, and the majority of SNPs (81.6%) were in open chromatin regions 15,16 , as indicated by a minimum chromatin state of 1-7 (Figure 1e). We performed genome-wide gene-based association analysis (GWGAS) using MAGMA 17 (Online Methods). This approach provides aggregate association P-values based on all SNPs in a gene, .ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/184853 doi: bioRxiv preprint first posted online Sep. 6, CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/184853 doi: bioRxiv preprint first posted online Sep. 6, 2017; GWAS META-ANALYSIS OF INTELLIGENCE 8 whereas FUMA annotates individually significant SNPs to genes. GWGAS identified 524 associated genes (467 novel) (Figure 3a; Supplementary Table 13; Supplementary Results 2.4.1), of which 159 were outside of the GWAS risk loci, and 365 were also mapped by FUMA (Figure 3b). In total, 92 genes were implicated by all four strategies (Supplementary Table 14).In gene-set analysis using the GWGAS results (Online Methods), Table 15). Conditional analysis indicated that there were three independent associations, for the neurogenesis, central nervous system neuron differenti...

The new genetics of intelligence

“…This GWAS analysis increased the number of identified genome-wide significant regions from 18 to 20633. A GPS derived from these GWAS analyses, IQ3, predicts about 4% of the variance of intelligence in independent samples33. Other meta-analytic GWAS using the UK Biobank data, which were released in June 2017 and are publicly available, yield similar results34.…”

“…This GWAS analysis increased the number of identified genome-wide significant regions from 18 to 20633. A GPS derived from these GWAS analyses, IQ3, predicts about 4% of the variance of intelligence in independent samples33.…”

“…The current limit for the variance that can be predicted by GPS is SNP heritability, which estimates the extent to which phenotypic variance for a trait can be explained by SNPs across the genome without identifying specific SNP associations. For intelligence, SNP heritability is about 25%33,40. It is safe to assume that GPS for intelligence using current SNP chips can approach the SNP heritability limit of 25% by amassing ever-larger GWAS samples and by using multi-trait GWAS that include traits related to intelligence such as years of education.…”

“…Instead, it uses chance genomic similarities across hundreds of thousands of SNPs genotyped on a SNP chip for thousands of unrelated individuals to estimate the extent to which genomic covariance accounts for phenotypic covariance in these individuals. For intelligence, SNP heritability is about 25%22,33,40.…”

“…Moreover, EA GPS predict intelligence much better than IQ GPS predict intelligence themselves. The IQ3 GPS from the most recent GWAS of intelligence predicts 4% of the variance of intelligence33 but the EA3 GPS predicts more than 10% of the variance in intelligence (P. D. Koellinger, personal communication).…”