Nine Genes Tied to Cognitive Performance Across Cortical and Subcortical Brain Tissues

A genetic analysis of human brain tissue has identified 117 genes linked to cognitive performance, with nine of them validated as candidate biomarkers through mendelian randomization. The study, published in Biogerontology by Mingyi Chen, Yuefang Chen and Bing Qin, combined expression quantitative trait loci data from the GTEx v8 database with genome-wide association study statistics on cognitive performance drawn from the OpenGWAS repository. Because the analysis relied on summarized genetic data rather than new brain samples, its findings are associations and model-based estimates, not direct measurements of gene activity in living brains.

The identified genes were distributed across nine brain regions, including the amygdala, anterior cingulate cortex, cortex, frontal cortex Brodmann area 9, hippocampus, hypothalamus, nucleus accumbens and caudate. Nine genes appeared in at least six of these regions, suggesting that a small set of genes may influence cognitive performance through multiple cortical and subcortical structures rather than through a single area. Functional annotation showed that the genes are primarily enriched in neuro-related pathways, are associated with distinct brain cell types, and also show expression in peripheral tissues, hinting that some of their effects may extend beyond the nervous system.

To probe the wider health relevance of these genes, the researchers performed a phenome-wide association study, which highlighted the significance of cognitive-performance-related genes for human health across multiple aspects. A separate cognitive-behavioral association analysis linked 26 of the identified genes to specific cognitive behaviors. The mendelian randomization analyses then validated nine genes as biomarkers for cognitive performance: AFF3, TRIOBP, TYW5, CEP192, CHST10, WBP2NL, ANAPC4, GRK4 and LRPPRC. Because these results come from statistical modeling of summarized genetic data, the nine genes should be viewed as candidate biomarkers pending further validation.

The authors report that the study demonstrates these genes are significantly associated with changes in cognitive behaviors, and they describe the work as offering new insights into the prevention and control of early cognitive deterioration in European-ancestry populations. That ancestry framing is an important limitation: the findings are reported as relevant to people of European descent, and generalization to other populations was not established in this study. The analysis also covered only the cortical and subcortical tissues available in GTEx, leaving other brain regions untested. Within those bounds, the work connects gene expression in specific brain structures to cognitive performance and to measurable cognitive behaviors, providing a gene-level map that future experimental and clinical studies can investigate.

Subject of Research: Genetic architecture of cognitive performance in cortical and subcortical brain tissues

Article Title: Investigating cognitive performance genetic architecture of cortical and subcortical brain tissues

Article References: Chen, M., Chen, Y., & Qin, B. (2026). Investigating cognitive performance genetic architecture of cortical and subcortical brain tissues. Biogerontology, 27(6), Article 188. https://doi.org/10.1007/s10522-026-10534-w

Image Credits: AI Generated

DOI: 10.1007/s10522-026-10534-w

Keywords: cognitive performance, genetics, GTEx, eQTL, GWAS, mendelian randomization, brain tissue, biogerontology, PheWAS, biomarkers, cognitive behaviors, Investigating