Disentangling heterogeneity in Substance Use Disorders: Insights from Genome-Wide Polygenic Scores

Substance use disorder (SUD) is a global health problem with significant impact on individuals and society. The presentation of SUD is diverse, involving various substances, ages at onset, comorbid conditions, and disease trajectories. Current treatments for SUD struggle to address this heterogeneity, resulting in high relapse rates. SUD often co-occurs with other psychiatric and mental-health related conditions that contribute to the heterogeneity of the disorder and predispose to adverse disease trajectories. Family and genetic studies highlight the role of genetic and environmental factors in the course of SUD, and point to a shared genetic liability between SUDs and comorbid psychopathology. In this study, we aimed to disentangle SUD heterogeneity using a deeply phenotyped SUD cohort and polygenic scores (PGSs) for psychiatric disorders and related traits. We explored associations between PGSs and various SUD-related phenotypes, as well as PGS-environment interactions using information on lifetime emotional, physical and/or sexual abuse. Our results revealed different patterns of associations between the genetic liability for mental-health related traits and SUD-related phenotypes, which may help explain part of the heterogeneity observed in SUD. In our SUD sample, we found associations linking the genetic liability for ADHD with lower educational attainment, the genetic liability for PTSD with higher rates of unemployment, the genetic liability for educational attainment with lower rates of criminal records and unemployment and the genetic liability for well-being with lower rates of outpatient treatments and fewer problems related to family and social relationships. We also found evidence of PGS-environment interactions showing that genetic liability for suicide attempt worsened the psychiatric status in SUD individuals with a history of emotional physical and/or sexual abuse. Collectively, these data contribute to a better understanding of the role of the genetic liability for mental health-related conditions and adverse life experiences in SUD heterogeneity.