Friday, May 9, 2025
5/9/2025
Characterizing the phenotypic spectrum associated with genetic liability for alcohol use disorder - PROJECT SUMMARY Individuals with alcohol use disorder (AUD) are at increased risk of comorbid psychiatric and medical disorders. Comorbidity of disease poses a challenge to both the diagnosis and treatment of AUD, but the etiologic factors underlying comorbidity are not well understood. Recent large-scale genome-wide association studies (GWAS) have identified common risk markers for AUD and several other traits. Genetic correlations between AUD and psychiatric disorders have identified genetic overlap across multiple loci. These findings suggest that there are common loci or biological pathways that increase risk for multiple disorders. Identifying these loci will provide insight into the etiologic pathways for comorbid disorders, and could advance efforts to accurately diagnose, categorize, prevent, and treat AUD and co-occurring medical and psychiatric conditions. Research to date has been limited by the lack of resources with well characterized phenotypic information alongside genetic data for large numbers of individuals. The project proposed in this K-award application uses information collected with a comprehensive psychiatric interview schedule in a sample of >15,000 individuals enriched for substance use disorders to create a multi-phenotype dataset for phenome-wide association analysis. Polygenic risk scores for the same set of individuals will be used to characterize the genetic liability for disease. We will: 1) identify phenotypes associated with genetic liability for AUD; 2) identify whether genetic liability for other traits is associated with AUD; 3) incorporate biological information to identify pathways that underlie comorbid risk; and 4) include environmental factors to test for gene-environment interactions. Our ethnically diverse sample (nearly equal numbers of African and European ancestry) will allow us to establish the genetic liability for comorbidities in both ancestral populations. In the context of conducting this research, this career development award will enable the applicant to obtain fundamental training in the phenomenology and assessment of psychiatric phenotypes to allow the accurate translation of the phenotypic records into a dataset for high-throughput genetic analysis. Additionally, the applicant will acquire the necessary skills in genetic epidemiology to develop models for genetic liability and comorbid disease. The proposed project will provide a foundation for future studies that would allow stratification of individuals into personalized treatment programs based on their disease etiology, along with the promise of early identification of at-risk individuals to target with intervention strategies.
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