Executive functions (EFs) are top-down cognitive control mechanisms that direct goalorientated behaviors. EF deficits are associated with psychopathology and neurological disorders, but little is known about the molecular bases of EF individual differences. Existing genome-wide association studies (GWAS) of EFs used small sample sizes and/or individual tasks, which are mixtures of higher and lower order cognitive mechanisms. To remedy these limitations, we conducted a GWAS of a "Common EF" (cEF) factor based on multiple tasks in the UK Biobank (N=93,027-427,037), finding 299 independent loci. Gene-based analysis found synaptic, potassium channel and GABA pathways associated with cEF. cEF genetically correlated with almost all psychiatric traits and with behavioral and health outcomes. These patterns of genetic correlations were different than those previously found for intelligence. Our results suggest that cEF is neurologically complex and that fast-neuronal processes form a basis for genetically influenced cognitive outcomes in health and psychiatric dysfunction.

BackgroundSocial processes are associated with depression, particularly understanding and responding to others, deficits in which can manifest as callousness/unemotionality (CU). Thus, CU may reflect some of the genetic risk to depression. Further, this vulnerability likely reflects the neurological substrates of depression, presenting biomarkers to capture genetic vulnerability of depression severity. However, heritability varies within brain regions, so a high-resolution genetic perspective is needed. MethodIn a sample of 258 same-sex twin pairs from the Colorado Longitudinal Twin Study (LTS), we developed a toolbox that maps genetic and environmental associations between brain and behavior at high resolution. We used this toolbox to estimate brain areas that are genetically associated with both depressive symptoms and CU. We then overlapped the two maps to generate coordinates that allow for tests of downstream effects of genes influencing our clusters.