Molecular genetic influences on sustained attention and executive processes and their links with psychopathology in the AFFECT study.

Abstract

Both sustained attention (SA) and executive functioning (EF) are critical for adaptive behavior and compromised across a range of psychiatric disorders, yet their etiological relationships remain underexplored. Here, we report the first multivariate characterization of molecular genetic influences on SA (vigilance, lapse recovery cost, lapse propensity) and EF (processing speed, response selection, working memory). In collaboration with 23andMe, we report previously unpublished genome-wide association studies of these phenotypes in a single cohort of more than 20,000 individuals enriched for diagnoses of major depressive disorder and bipolar disorder. We used Genomic Structural Equation Modeling to formally model patterns of genetic covariance among these task-based measures of cognition, and their relationships with other cognitive, clinical, and imaging-derived phenotypes. We identified two distinct latent genetic factors: one influencing EF and one influencing SA. Both the EF and SA factors were genetically correlated with cognitive and clinical phenotypes, with each latent factor uniquely linked to liability for psychiatric disorders, including attention-deficit/hyperactivity disorder. However, genetic correlations with imaging-derived neuroanatomical phenotypes were modest and non-significant after correction for multiple comparisons. Collectively, these results provide an initial multivariate genetic characterization of SA and EF, though replication in larger and more diverse samples will be important. They suggest that genetic influences on sustained attention are generally distinct from those that influence executive function. The EF and SA factors show distinct patterns of genetic overlap with multiple cognitive and psychiatric outcomes, underscoring the need for more granular cognitive phenotyping to generate new insights into the genetic architecture of cognition and the etiology of psychopathology.