Genetic loci for alcohol-related life events and substance-induced affective symptoms: indexing the \u201cdark side\u201d of addiction

Qian Peng,Ian R Gizer,Cindy L Ehlers,Chris Bizon,Kirk C Wilhelmsen

doi:10.1038/s41398-019-0397-6

Abstract

A limited number of genetic variants have been identified in traditional GWAS as risk or protective factors for alcohol use disorders (AUD) and related phenotypes. We herein report whole-genome association and rare-variant analyses on AUD traits in American Indians (AI) and European Americans (EA). We evaluated 742 AIs and 1711 EAs using low-coverage whole-genome sequencing. Phenotypes included: (1) a metric based on the occurrence of 36 alcohol-related life events that reflect AUD severity; (2) two alcohol-induced affective symptoms that accompany severe AUDs. We identified two new loci for alcohol-related life events with converging evidence from both cohorts: rare variants of K2P channel gene KCNK2, and rare missense and splice-site variants in pro-inflammatory mediator gene PDE4C. A NAF1-FSTL5 intergenic variant and an FSTL5 variant were respectively associated with alcohol-related life events in AI and EA. PRKG2 of serine/threonine protein kinase family, and rare variants in interleukin subunit gene EBI3 (IL-27B) were uniquely associated with alcohol-induced affective symptoms in AI. LncRNA LINC02347 on 12q24.32 was uniquely associated with alcohol-induced depression in EA. The top GWAS findings were primarily rare/low-frequency variants in AI, and common variants in EA. Adrenal gland was the most enriched in tissue-specific gene expression analysis for alcohol-related life events, and nucleus accumbens was the most enriched for alcohol-induced affective states in AI. Prefrontal cortex was the most enriched in EA for both traits. These studies suggest that whole-genome sequencing can identify novel, especially uncommon, variants associated with severe AUD phenotypes although the findings may be population specific.

Highlights

Alcohol use disorders (AUDs) are highly prevalent, disabling disorders that often go untreated in the USA1
While several studies provide data to demonstrate that a substantial genetic component for risk for AUD exists in the select American Indians (AI) tribes that have been studied[15], little is known as to the exact genes and genetic variants that may confer this possibly elevated risk, with the exception of the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) loci[16,17,18]
The present study utilized low-coverage whole-genome sequence data to identify potential variants and pathways underlying two types of phenotypes associated with severe AUD: the severity of the clinical course of AUD and alcohol-induced affective symptoms, in an American Indian and a Euro-American populations

Summary

Introduction

Alcohol use disorders (AUDs) are highly prevalent, disabling disorders that often go untreated in the USA1. GWAS have yielded an additional small yet diverse set of single-nucleotide polymorphisms (SNPs) that have been associated with alcohol dependence, alcohol consumption, and related traits in a number of ethnic groups[5,6,7,8,9,10,11]. Among these recent findings, β-Klotho (KLB) has been repeatedly associated with alcohol consumption in large population studies of European. While several studies provide data to demonstrate that a substantial genetic component for risk for AUD exists in the select AI tribes that have been studied[15], little is known as to the exact genes and genetic variants that may confer this possibly elevated risk, with the exception of the ADH and ALDH loci[16,17,18]

Methods

Results

Conclusion