Date of Award

Spring 2026

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Computer Science

Committee Director

Jiangwen Sun

Committee Member

Lusi Li

Committee Member

Jing He

Abstract

Alcohol Use Disorder (AUD) is a pervasive condition characterized by complex interplay among genetic, phenotypic, and environmental factors. Although previous studies have identi fied genetic loci associated with alcohol consumption, these efforts have not captured the genetic heterogeneity and gene-environment interactions underlying AUD pathogenesis. To address this critical gap, we developed a novel statistical methodology that integrates phenotypic, genotypic, and environmental data through an environmentally modified Genetic Relationship Matrix (GRM) to derive AUD-related traits with enhanced heritability.

This approach demonstrated superior performance in both simulated and real-world datasets. Traits derived using the environmentally modified GRM exhibited significantly higher estimated heritability than those obtained with unmodified genetic data. We further developed a clinically interpretable AUD severity index that maintained high heritability while improving generalizabil ity across independent datasets. Cluster analysis revealed clinically relevant subgroups showing moderate alignment with established addiction medicine criteria, supporting the potential clinical utility of this approach.

We conducted genome-wide association analyses using both the derived trait and DSM-IV symptom count in African American (n = 4,563) and European American (n = 5,224) popu lations, with replication in an independent sample. In the discovery phase, six SNPs reached genome-wide significance for the derived trait, while no associations were found for symptom count. Meta-analysis combining discovery and replication cohorts identified novel loci, includ ing five SNPs in CCL28 in European Americans (p =2.2–4.4×10−8) with consistent replication, and two SNPs in African Americans including rs555799382 at BCL9L (p = 5.2×10−8). In con trast, analysis of symptom count identified only the well-established ADH1B variant rs1229984 (p =1.6×10−9). Notably, the derived trait identified loci in stress-responsive pathways distinct from alcohol metabolism, including CCL28 (neuroimmune/gut-brain axis) and BCL9L (Wnt sig naling/neurodevelopment).

Rights

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).

ISBN

9798197809452

Download

Share

COinS