Rare and common variants associated with alcohol consumption identify a conserved molecular network

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Genome-wide association studies (GWAS) have identified numerous common genetic variants linked to alcohol consumption.
• Genetic studies focusing on rare variants for alcohol consumption are less advanced.
• Previous research has not explored whether common and rare variants affect the same genes or molecular networks.

Purpose of the Study:

• To investigate the overlap in genes and molecular networks identified by common and rare genetic variants associated with alcohol consumption.
• To determine if distinct biological pathways are implicated by different types of genetic variants.
• To integrate findings from common and rare variant analyses for a comprehensive understanding of alcohol consumption genetics.

Main Methods:

• Utilized publicly available alcohol consumption GWAS summary statistics (N=666,978) and whole exome sequencing data (N=393,099).
• Performed gene-based analysis to identify genes associated with common and rare variants.
• Applied network colocalization to map identified genes onto a shared molecular network.

Main Results:

• Identified 294 genes from common variants and 35 genes from rare variants, including key ethanol metabolizing genes.
• Network colocalization revealed significant overlap between genes identified by common and rare variants.
• The shared network highlighted gene families involved in alcohol metabolism and identified genes previously linked to neuropsychiatric and substance use disorders.

Conclusions:

• Network colocalization demonstrates shared biological underpinnings for alcohol consumption identified through common and rare genetic variants.
• This shared biology also contributes to neuropsychiatric traits and substance use disorders comorbid with alcohol use.
• Provides a more holistic understanding of alcohol consumption by integrating diverse genetic evidence.