Finding the missing parts of human genetics of substance use disorders

Yale University, New Haven CT

Investigators

Abstract

Abstract Substance use disorders (SUDs) are leading causes of death and disability worldwide. A better understanding of the genetic mechanisms underlying SUD risk could improve their diagnosis, prevention, and treatment, ultimately reducing the costly and disabling addiction-related problems. Recently, substantial progress has been made in identifying genetic variants associated with SUDs through gene discovery efforts, particularly genome-wide association studies (GWAS) in large cohorts. Although these findings considerably advance our knowledge of SUD genetics, key questions remain unanswered. Current GWAS studies predominantly rely on SNP arrays and post hoc imputation to identify common variants, leaving certain genomic regions unexamined due to technical limitations. Whole-genome sequencing (WGS), which can detect both common and rare variants in large cohorts, offers the potential to recover much of the missing heritability. However, to our knowledge, no large WGS study of SUDs has been conducted to date. Another significant gap is the estimated SNP-based heritability of SUDs is low, and as a result, polygenic risk scores (PRS) based on common variants have limited predictive power in independent cohorts. While statistically significant, these PRS are numerically weak and not yet clinically useful. To address these gaps and respond to the Cutting-Edge Basic Research Awards, we propose an innovative study using publicly available WGS data on SUDs from biobanks such as the All of Us and UK Biobank. This project aims to leverage large-scale WGS datasets to identify novel rare and common variants associated with SUDs and recover missing heritability (Aim 1). Additionally, the study will enhance disease prediction through the development of a novel whole-genome multi-ancestry PRS framework (Aim 2). The proposed research is both timely and aligned with the National Institute on Drug Abuse's mission. It will substantially enhance our understanding of the genetic architecture of SUDs and lay the groundwork for the development of precision interventions to prevent and treat alcohol-related diseases.