Association of Stress‐Related Genetic Polymorphisms and Stressful Life Events With Alcohol Use Disorder in a Brazilian Population

Alcohol Use Disorder (AUD) is a multifactorial condition shaped by genetic predispositions and neurophysiological, behavioural, and environmental factors. Chronic stress and trauma are key drivers of harmful alcohol use. This study aimed to investigate, in a Brazilian admixed population, the associations and interactions between genetic variants related to the CRFergic, noradrenergic, and glucocorticoid receptor systems and exposure to childhood and adulthood stressors, as well as perceived stress, in individuals with and without AUD. We evaluated 227 inpatients with AUD and 174 controls. Alcohol involvement was assessed using the AUDIT and IDS-42. Childhood trauma, adult-life stressors, and perceived stress were measured using the CTQ, LES, and PSS, respectively. Genetic variants were characterised using next-generation sequencing. Individuals with AUD showed more severe childhood trauma, more adverse adult-life experiences, and higher perceived stress. Two CRHR2 variants were significantly associated with AUD after correction for multiple testing (rs8175360 increasing risk; rs41417745 decreasing risk). Stress-related genetic variation, particularly in CRHR2, was associated with AUD diagnosis in interaction with environmental stressors across the lifespan. These findings highlight the importance of integrating genetic and environmental factors to better understand the heterogeneity of AUD and may inform future approaches to personalised prevention and intervention strategies.