Genome-wide meta-analysis of brain volume identifies genomic loci and genes shared with intelligence

Philip R Jansen,Jeanne E Savage,Kyoko Watanabe,Mats Nagel,Danielle Posthuma,Christiaan A De Leeuw,Sophie Van Der Sluis,Yongbin Wei,Martijn P Van Den Heuvel

doi:10.1038/s41467-020-19378-5

Abstract

The phenotypic correlation between human intelligence and brain volume (BV) is considerable (r ≈ 0.40), and has been shown to be due to shared genetic factors. To further examine specific genetic factors driving this correlation, we present genomic analyses of the genetic overlap between intelligence and BV using genome-wide association study (GWAS) results. First, we conduct a large BV GWAS meta-analysis (N = 47,316 individuals), followed by functional annotation and gene-mapping. We identify 18 genomic loci (14 not previously associated), implicating 343 genes (270 not previously associated) and 18 biological pathways for BV. Second, we use an existing GWAS for intelligence (N = 269,867 individuals), and estimate the genetic correlation (rg) between BV and intelligence to be 0.24. We show that the rg is partly attributable to physical overlap of GWAS hits in 5 genomic loci. We identify 92 shared genes between BV and intelligence, which are mainly involved in signaling pathways regulating cell growth. Out of these 92, we prioritize 32 that are most likely to have functional impact. These results provide information on the genetics of BV and provide biological insight into BV’s shared genetic etiology with intelligence.

Highlights

The phenotypic correlation between human intelligence and brain volume (BV) is considerable (r ≈ 0.40), and has been shown to be due to shared genetic factors
genome-wide association study (GWAS) analyses in UK Biobank (UKB) were corrected for the Townsend deprivation index (TDI)[18], a measure that correlates with socioeconomic and health-related factors[19,20], as well as for age, sex, genotype array, assessment center, standing height, and the first 10 genetic principal components (PCs)
We studied the genetics of BV and report 14 loci and 270 genes that had not been previously associated to BV

Summary

Introduction

The phenotypic correlation between human intelligence and brain volume (BV) is considerable (r ≈ 0.40), and has been shown to be due to shared genetic factors. To further examine specific genetic factors driving this correlation, we present genomic analyses of the genetic overlap between intelligence and BV using genome-wide association study (GWAS) results. We identify 92 shared genes between BV and intelligence, which are mainly involved in signaling pathways regulating cell growth. Out of these 92, we prioritize 32 that are most likely to have functional impact. With the availability of larger genotype data and genome-wide association studies (GWAS) that identify increasing numbers of genes related to BV11–13 and intelligence[14,15,16], analysis of the shared genes and pathways has become feasible. A series of follow-up analyses prioritizes 32 out of these 92 genes that are most likely to have functional impact based on the properties of these genes

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