# Project 5 - Genetic architecture of alcohol use disorder using cross-trait genetic correlations and public next-generation sequencing studies

> **NIH NIH P50** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $176,539

## Abstract

Project Summary – Project 5
Recent advances in the study of human complex traits include 1) a growing catalog of robustly associated
common variants found using genome-wide association studies (GWAS), 2) the ability to assess the
contribution of rare variation through genome sequencing studies of both whole exomes (WES) and genomes
(WGS), and 3) wide-spread cross-trait genetic correlation. For alcohol use disorder (AUD) and related
phenotypes, there is an opportunity to discover novel rare variation and understand the overall pattern of
evidence across the allele frequency spectrum including common and rare variation. One lesson from GWAS
is that most robust associations do not create protein coding changes and some robust genome-wide
significant variation does not reside in genes at all. As WES expands to include untranslated regions (UTRs)
and WGS becomes affordable, there is a significant challenge in analyzing the variation that does not impact
protein coding directly. Fortunately, there is a growing catalog of functional elements across the genome that
can be interrogated to determine which harbor variants influencing AUD. For sequencing based analyses of
rare variation, these functional elements showing enrichment can be leveraged to improve detection. As more
variants associated with AUD are discovered and the catalog of traits with genetic correlations grows,
determining how specific these variants are to AUD becomes more important. For example, do discovered loci
influence a) addiction in general, b) alcohol consumption, or c) AUD specifically or do they non-specifically
influence many physical or mental health outcomes. In addition to determining if loci, in aggregate or
individually, can be considered primary or secondary AUD risk loci, understanding the direction of causation
across traits and time is critically important to identifying opportunities for intervention. One powerful approach
to investigate causative relationships is through Mendelian Randomization analysis. The overall goal of this
project is to leverage existing twin, family, epidemiological, and molecular data in novel ways to a) discover loci
harboring rare variants that influencing AUD without new molecular data generation, b) differentiate loci that
influence common versus specific AUD liability factors, and c) understand the architecture of AUD using an
integrated and iterative approach.

## Key facts

- **NIH application ID:** 9882702
- **Project number:** 2P50AA022537-06
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** BRADLEY Todd WEBB
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $176,539
- **Award type:** 2
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882702

## Citation

> US National Institutes of Health, RePORTER application 9882702, Project 5 - Genetic architecture of alcohol use disorder using cross-trait genetic correlations and public next-generation sequencing studies (2P50AA022537-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882702. Licensed CC0.

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