Integrative Analysis of Proteome-wide Association Studies and Functional Enrichment Analysis to Identify Genes and Chemicals Associated with Alcohol Dependence

Abstract

Objectives Alcohol dependence accounts for a large proportion of the global burden of disease and disability. This study aims to investigate the candidate genes and chemicals associated with alcohol dependence. Methods Using data from published alcohol dependence genome-wide association studies, we first conducted a proteome-wide association study of alcohol dependence by integrating alcohol dependence genome-wide association studies with 2 human brain reference proteomes of dorsolateral prefrontal cortex from the Religious Order Study and Rush Memory and Aging Project and the Banner Sun Health Research Institute. Then, based on the identified genes in proteome-wide association study, we conducted functional enrichment analysis and chemical-related functional enrichment analysis to detect the related Gene Ontology terms and chemicals. Results Proteome-wide association study identified several potential candidate genes for alcohol dependence, such as GOT2 (P = 7.59 × 10-6) and C3orf33 (P = 5.00 × 10-3). Furthermore, functional enrichment analysis identified multiple candidate Gene Ontology terms associated with alcohol dependence, such as glyoxylate metabolic process (adjusted P = 2.99 × 10-6) and oxoglutarate metabolic process (adjusted P = 9.95 × 10-6). Chemical-related functional enrichment analysis detected several alcohol dependence-related candidate chemicals, such as pitavastatin (P = 2.00 × 10-4), cannabinoids (P = 4.00 × 10-4), 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (P = 4.00 × 10-4), and gabapentin (P = 2.00 × 10-3). Conclusions Our study reports multiple candidate genes and chemicals associated with alcohol dependence, providing novel clues for understanding the biological mechanism of alcohol dependence.