ATTENTIVE · Distinguishing genetic overlap and causal relationship among attention deficit-hyperactivity disorder and substance use disorders

Distinguishing genetic overlap and causal relationship among attention deficit-hyperactivity disorder and substance use disorders

The aim of the project was to understand the genetic basis of the comorbidity between attention deficit-hyperactivity disorder (ADHD) and substance use disorders (SUDs). ADHD and SUDs are complex disorders, hence both genetic and environmental factors contribute to their development. Both ADHD and SUDs present a significant public health burden, especially when they occur concurrently. The risk to develop SUDs increases during the adolescence of patients with ADHD, with a faster progression rate compared to others. Identifying which individuals with ADHD present a higher risk to develop SUDs will ease some of this burden by offering the opportunity for early action and prevention. Apart from the epidemiological evidence, several previous studies suggested shared genetic architecture between ADHD and SUDs, including cannabis use disorder, nicotine dependence, and alcohol dependence. However, inconsistent findings were observed. In the current study, we aimed to investigate this relationship, using genetic datasets with large sample size, and hence adequate power to detect reliable associations. We included two main SUDs, cannabis use disorder and opioid use disorder, and problematic substance uses problematic alcohol use and problematic tobacco use. The overall objectives of this project were to investigate a comprehensive genetic relationship between ADHD and SUDs including i) genome-wide genetic correlation, ii) bi-directional genetic causality, iii) shared genetic variants, iiii) the sum of the genetic effects (i.e., polygenic risk) to develop SUDs calculated for patients with ADHD, and iv) validating the molecular function of shared variants in an experimental setting. Apart from the scientific goals, an important objective for the researcher was to develop individual research lines and ideas, and build a network with world-known experts on the field, which were successfully met. Considering the findings generated by different analytic approaches applied in this study, we hypothesize that horizontal and vertical pleiotropy (shared genetic mechanisms and possible causal effects, respectively) both contribute to ADHD-SUD comorbidities with differences among substances. Specifically, ADHD-CanUD comorbidity could be mainly due to shared genetic mechanisms (horizontal pleiotropy supported by the bidirectional relationship observed in MR analysis and the multiple pleiotropic loci identified by PolarMorphism approach), while ADHD-PAU comorbidity is primarily driven by possible causal effects (vertical pleiotropy supported by PAU→ADHD effect identified by MR and only one locus identified by PolarMorphism approach). The ADHD-PTU relationship seems to be related to a combination of different pleiotropic pathways (supported by results from genomic SEM, MR, and PolarMorphism analyses). While these patterns in ADHD-SUD pleiotropy have to be confirmed by further studies, understanding the genetic factors contributing to ADHD-SUD comorbidity could enhance preventive strategies that alter possible causal relationships and yield more effective treatments based on specific ADHD-SUD molecular targets. In conclusion, this project highlights the complex genetic relationships underlying the comorbidity between ADHD and SUDs, with differences in pleiotropic mechanisms across specific substances. By uncovering shared genetic pathways and potential causal effects, the findings contribute to a deeper understanding of ADHD-SUD interactions and lay the basis for targeted preventive and therapeutic strategies.

Data: CORDIS, © European Union