Alcohol Dependence Moderates the Genetic Influences Underlying Neuroticism

Aspects of personality have been widely discussed as putative endophenotypes for psychiatric disorders, including alcohol and other substance use disorders. A recent meta-analysis provided an average heritability estimate of... [ view full abstract ]

Aspects of personality have been widely discussed as putative endophenotypes for psychiatric disorders, including alcohol and other substance use disorders. A recent meta-analysis provided an average heritability estimate of 0.40 across personality traits, and multivariate twin studies have suggested that traits, such as neuroticism, can explain a portion of the shared etiology between many psychiatric disorders, supporting their use as endophenotypes. Nonetheless, there is also evidence suggesting that heavy alcohol consumption and other substance use leads to substantial changes in personality, which could reduce the utility of personality traits as endophenotypes. To evaluate this possible limitation, the present study used GWAS summary data from the Genetics of Personality Consortium analysis of neuroticism to create polygenic risk scores (PRSs) for this trait in an independent sample and evaluate whether the ability of the PRS to predict neuroticism was moderated by the presence of DSM-IV Alcohol Dependence. The independent sample consisted of 590 participants from the UCSF Family Alcoholism Study with available genotype and phenotype data. Genotype data were obtained from low-coverage whole genome sequencing. Alcohol dependence was assessed using the Semi-Structured Interview for the Genetics of Alcoholism (SSAGA), and neuroticism was assessed using the Big Five Inventory. Data-analysis was conducted using a linear mixed model approach with ancestry estimates for the four major continental populations included as covariates to account for population and family structure. Across a range of significance thresholds used to determine variant inclusion (p<0.50-<0.01), the neuroticism PRS significantly predicted neuroticism in the UCSF sample. The presence of alcohol dependence was also positively related to neuroticism (p-values=0.03-5e-08). Notably, these main effects were qualified by a significant interaction such that the relation between the neuroticism PRS and neuroticism scores was reduced among UCSF participants diagnosed with Alcohol Dependence relative to those who were not (p-values=0.02-0.001). These results suggest that chronic, heavy alcohol consumption may act as an environmental exposure that increases levels of neuroticism and potentially reduces the genetic contributions to this personality trait. If confirmed, this result suggests a potential limitation to the use of personality traits as endophenotypes for psychiatric disorders.