Genetic landscape of adult executive function reveals a cell-type specific developmental origin

Executive function is an essential cognitive domain for typical human behavior which is disrupted in neurodevelopmental and neurodegenerative disorders, but little is known about its underlying molecular basis. To address this, we performed genome-wide association studies (GWAS) using three different measures of executive function in UK Biobank (N=84,238) and NIHR BioResource’s Genes and Cognition (N=9,932) study participants, followed by a meta-analysis. The trail-making alphanumeric (TMA) measure was the most heritable phenotype (h²=7-26%), associated with 18 independent loci that exhibited a similar direction of effect in both cohorts. Across these loci, in-silico follow-up implicated 178 genes, of which NT5DC2 and RP11-579E24.2 were independently replicated prior to meta-analysis. TMA was linked to pan-cerebral differences in brain structure, with brain-enriched genes showing a biphasic expression profile from early development through to later life. Our data implicate specific cell types, histone modifications and butyrophilin immunoglobulin family proteins as potential targets for promoting cognitive resilience.