Background: Attentional control is a critical component of executive functioning involved in numerous psychiatric and neurological disorders, yet its etiological relationships with many cognitive and behavioral phenotypes remain underexplored. Methods: We conducted the first multivariate characterization of molecular genetic influences on attentional control and other executive processes in a cohort of more than 20,000 individuals enriched for mood disorders. We used Genomic Structural Equation Modeling to formally model patterns of genetic covariance among these task-based measures of cognition, as well as their relationships with other cognitive, clinical, and imaging-derived phenotypes. Results: We identified two independent latent genetic factors: one broadly influencing executive function and one narrowly influencing attentional control. Both the Common Executive Function (CEF) and Attentional Control (AC) factors were genetically correlated with cognitive and clinical phenotypes, with each latent factor uniquely linked to liability for psychiatric disorders. For example, we observed myriad relationships between the factors and psychopathology, including robust and conditionally independent genetic associations with ADHD. However, despite clear links to brain-related phenotypes, genetic correlations with imaging-derived phenotypes themselves were modest and non-significant after correcting for multiple comparisons. Conclusions: Overall, the results of our study suggest that genetic influences on attentional control are generally distinct from those that influence broader aspects of executive function. The CEF and AC factors show distinct patterns of genetic overlap with multiple cognitive and psychiatric outcomes, underscoring the need for more detailed phenotyping of cognition to generate new insights into the etiology of psychopathology.

Y.J., J.M.G., and D.H. are employed by and hold stock or stock options in 23andMe, Inc. M.D. and N.P. are employees of MUNA Therapeutics. L.H-H. is an employee of H. Lundbeck A/S. J.W.S. is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received an honorarium for an internal seminar Tempus Labs.

J.D.T. was supported by the Mass General Brigham Training Program in Precision and Genomic Medicine (T32HG010464). T.T.M. is supported by NIH grant K08MH135343. The AFFECT study was funded by H. Lundbeck A/S and the Milken Institute.

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