Multivariate genome-wide analysis reveals shared genetic architecture and brain structural correlates of human cognitive abilities

Limited knowledge currently exists regarding the shared genetic architecture influencing human cognitive ability-related traits. We utilized Genomic Structural Equation Modeling (Genomic-SEM) along with multiple post-GWAS methods to estimate potentially causal single nucleotide polymorphisms (SNPs) associated with cognitive ability phenotypic variation. Our study identified 3,842 genome-wide significant loci, including 275 novel loci. Applying multiple transcriptome-wide association methods, we analyzed susceptibility gene signal loci highly correlated with cognitive ability GWAS from tissue, cellular, and genomic element perspectives, identifying 13 high-confidence candidate causal genes and related functional element information. Subsequently, we systematically evaluated 80-90% of currently known human common disease data in the IEU database, along with 3,935 brain imaging-derived phenotypes from UK Biobank and cortical morphological features from 51,665 individuals in the ENIGMA database to determine cognitive ability-related susceptibility factors. We applied the BrainXcan pipeline for brain imaging genetic analysis of cognitive abilities. Additionally, we used summary data-based polygenic scoring methods to systematically analyze the genetic contribution of different chromosomes to cognitive abilities and their risk prediction value. Our study, through multivariate GWAS analysis of cognitive ability common genetic factors, contributes to mapping the shared genetic architecture of human cognitive abilities.