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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 K 2P  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.

Genetic loci for alcohol-related life events and substance-induced affective symptoms: indexing the “dark side” of addiction