The hidden switches: unlocking ADHD through epigenetics

Attention deficit/-hyperactivity disorder (ADHD) is a common neurodevelopmental condition that persists into adulthood in at least 50% of cases. ADHD is highly heritable, but the genetic component of the condition is complex - genetic variation in several to multiple genes contributes to ADHD in the vast majority of affected individuals. In addition to genetic vulnerability, also environmental risk (and protective) factors contribute to ADHD. Research at the molecular level has provided information on several genetic variants and genes acting as risk factors for ADHD; finding from those data-driven, hypothesis-generating studies implicate (among others) dopaminergic neurons in the etiology of ADHD [PMID:36702997]. Since both genetics and environment act jointly on risk, the study of epigenetic factors is also interesting for understanding ADHD’s etiology and potentially providing information supporting patient stratification. Most studies so far have assessed a specific type of epigenetic factor, i.e. DNA-methylation. We have found that ADHD-associated DNA-methylation provides complementary information to ADHD-associated genetic factors [PMID:36566803], and we have identified several genes in which epigenetic risk factors for ADHD symptoms reside [PMID:41145087]. Recent findings now highlight an additional type of epigenetic modification that might provide novel insights into ADHD: as Ian Maze (plenary speaker PL01) and his team showed, dopamine and other monoamines can also act as epigenetic modifications by binding to histones, which regulate gene-activity. This non-canonical signaling by monoamines has not been explored for ADHD thus far, but has shown to e.g. regulate relapse from addiction in mouse models [PMID:32273471].