ADHD genetic burden associates with older epigenetic age: mediating roles of education, behavioral and sociodemographic factors among older adults.

Background: Shortened lifespans are associated with having Attention Deficit Hyperactivity Disorder (ADHD), which is likely mediated by related behavioral and sociodemographic factors that are also associated with accelerated physiological aging. Such factors include exhibiting more depressive symptoms, more cigarette smoking, higher body mass index, lower educational attainment, lower income in adulthood, and more challenges with cognitive processes compared to the general population. A higher polygenic score for ADHD (ADHD-PGS) is associated with having more characteristic features of ADHD. The degree to which (1) the ADHD-PGS associates with an epigenetic biomarker developed to predict accelerated aging and earlier mortality is unknown, as are whether (2) an association would be mediated by behavioral and sociodemographic correlates of ADHD, or (3) an association would be mediated first by educational attainment, then by behavioral and sociodemographic correlates. We evaluated these relationships in a population-based sample from the US Health and Retirement Study, among N = 2311 adults age 50 and older, of European-ancestry, with blood-based epigenetic and genetic data. The ADHD-PGS was calculated from a prior genomewide meta-analysis. Epigenome-wide DNA methylation levels that index biological aging and earlier age of mortality were quantified by a blood-based biomarker called GrimAge. We used a structural equation modeling approach to test associations with single and multi-mediation effects of behavioral and contextual indicators on GrimAge, adjusted for covariates.

Results: The ADHD-PGS was significantly and directly associated with GrimAge when adjusting for covariates. In single mediation models, the effect of the ADHD-PGS on GrimAge was partially mediated via smoking, depressive symptoms, and education. In multi-mediation models, the effect of the ADHD-PGS on GrimAge was mediated first through education, then smoking, depressive symptoms, BMI, and income.

Conclusions: Findings have implications for geroscience research in elucidating lifecourse pathways through which ADHD genetic burden and symptoms can alter risks for accelerated aging and shortened lifespans, when indexed by an epigenetic biomarker. More education appears to play a central role in attenuating negative effects on epigenetic aging from behavioral and sociodemographic risk factors related to ADHD. We discuss implications for the potential behavioral and sociodemographic mediators that may attenuate negative biological system effects.