The positive end of the polygenic score distribution for ADHD: a low risk or a protective factor?

Abstract

Polygenic scores (PGS) are widely used to characterize genetic liability for heritable mental disorders, including attention-deficit/hyperactivity disorder (ADHD). However, little is known about the effects of a low burden of genetic liability for ADHD, including whether this functions as a low risk or protective factor for ADHD and related functional outcomes in later life. The current study examines the association of low ADHD PGS and functional outcomes in adulthood. Participants were from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) (N = 7088; mean age = 29, s.d. = 1.74). ADHD PGS was computed from an existing genome-wide association study, and adult functional outcomes, including cognition, educational attainment, mental health, and physical health were assessed during in-home interviews. Individuals at the lowest end of the ADHD PGS distribution (i.e. lowest 20th percentile) had the lowest probabilities of ADHD, exhibiting a 17-19% reduction in risk for ADHD relative to the observed 8.3% prevalence rate of ADHD in Add Health. Furthermore, individuals with low ADHD PGS had higher cognitive performance, greater levels of educational attainment, and lower BMI relative to individuals representing the rest of the ADHD PGS distribution, including those who were in the medium and high-PGS groups. Findings indicate that psychiatric PGS likely capture far more than just the risk and the absence of risk for a psychiatric outcome; where one lies along the PGS distribution may predict diverging functional consequences, for better and for worse.