Investigating cognitive performance genetic architecture of cortical and subcortical brain tissues

Although the mechanisms underlying cognitive performance (CP) are increasingly understood, the genetic basis of the cerebral cortex and subcortical brain tissues and association with cognitive behaviors remain unclear. This study utilized the summarized expression quantitative trait loci (eQTL) data from the genotype-tissue expression (GTEx) v8 database along with CP data from genome-wide association studies (GWAS) on OpenGWAS. A total of 117 genes related to CP were identified, distributed across 9 brain regions: amygdala, anterior cingulate cortex, cortex, frontal cortex BA9, hippocampus, hypothalamus, accumbens, and caudate. Among them, 9 genes were present in at least 6 brain regions. Gene functional annotation revealed that these identified genes are primarily enriched in neuro-related pathways, associated with distinct brain cell types, and exhibit expression in peripheral tissues. The phenome-wide association study (PheWAS) highlighted the significance of genes related to CP for human health in multiple aspects, while the cognitive-behavioral association analysis revealed the association between 26 genes and specific cognitive behaviors. Furthermore, mendelian randomization (MR) analyses validated 9 genes (AFF3, TRIOBP, TYW5, CEP192, CHST10, WBP2NL, ANAPC4, GRK4, and LRPPRC) as biomarkers for CP. Notably, this study identified genes associated with CP in cortical and subcortical brain tissues and demonstrated that these genes are significantly associated with changes in cognitive behaviors. This crucial discovery offers new insights into the prevention and control of early cognitive deterioration in European-ancestry populations.