Whole-genome sequencing study of alcohol use disorder across biobanks and ancestries - Abstract Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. A deeper understanding of the genetic mechanisms underlying AUD could significantly improve the diagnosis, prevention, and treatment, thereby reducing the burden of AUD-related problems. Although genome-wide association studies (GWAS) have identified a growing number of genetic variants and pathways associated with AUD, key gaps remain unaddressed. First, current GWAS predominantly focuses on common variants, neglecting rare and structural variants due to technical limitations. Second, the top associated variants identified in GWAS loci may not be the true causal variants driving AUD risk. Third, another critical gap lies in the limited predictive performance of polygenic risk score (PRS) for AUD based on GWAS common variants. Fourth, the expression perturbation in specific cell subtypes or cellular processes in the human brain affecting the AUD risk is poorly understood. To address these gaps, we propose this innovative study leveraging large-scale whole-genome sequencing (WGS) data from biobanks, publicly available single-cell RNA sequencing (scRNA-seq) data in brain cells, and state-of-the-art statistical methods to improve the understanding of AUD genetics, response to the Notice of Special Interest: Secondary Analyses of Existing Alcohol Research Data (NOT-AA-23-011). It aims to uncover novel rare, common, and structural variants associated with AUD and recover the missing heritability (Aim 1); identify causal variants through cross-ancestry fine-mapping and improve disease prediction using a novel whole-genome PRS framework (Aim 2); and map the WGS results to existing scRNA-seq data to identify key brain cell subtypes and processes involved in AUD (Aim 3). The proposed research is timely and in line with NIAAA’s mission, promises to substantially enhance our understanding of the genetic architecture of AUD, and will lay the foundation for developing precision interventions to prevent and treat alcohol-related diseases.
