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. 2019 Apr 2;10(1):1499.
doi: 10.1038/s41467-019-09480-8.

Genome-wide Association Study of Alcohol Consumption and Use Disorder in 274,424 Individuals From Multiple Populations

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Free PMC article

Genome-wide Association Study of Alcohol Consumption and Use Disorder in 274,424 Individuals From Multiple Populations

Henry R Kranzler et al. Nat Commun. .
Free PMC article

Erratum in

Abstract

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

Conflict of interest statement

H.R.K. is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which in the past three years was supported by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. H.R.K. and J.G. are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed 24 January 2018. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Manhattan plots for age-adjusted mean AUDIT-C score and AUD diagnosis. a Manhattan plot of the genome-wide association meta-analysis of AUDIT-C across all five populations (N = 272,842). b Manhattan plot of the genome-wide association meta-analysis of AUD across five populations (55,584 cases and 218,807 controls). Red lines show the genome-wide significance level (5.0 × 10−8). EA: European American, AA: African American, LA: Hispanic or Latino, EAA: East Asian American, SAA: South Asian American. Labeled genes at the top of the peaks indicate completely independent signals after conditional analysis in meta-analysis. Population-specific loci are labeled at the bottom of the circles in the lower part of each figure. []: no genes within 500 kb to the lead SNP
Fig. 2
Fig. 2
Heritability estimate, partitioning enrichments of heritability, and genetic correlation analyses using LD score regression. a SNP-based heritability for AUDIT-C and AUD in the three populations and sex-stratified samples adequate in size for the analysis. b Partitioned heritability enrichment of cell type groups for AUDIT-C and AUD. Ten cell types tested were corrected for multiple testing. The black dashed line is the cutoff for Bonferroni-corrected significance. The gray dashed line is the cutoff for FDR < 0.05. c Genetic correlations with other traits. Data from 714 publicly available datasets (221 published and 493 unpublished from UK Biobank) were tested and corrected for multiple comparisons. The significantly correlated traits presented are for published data. Black lines are the cutoff for Bonferroni-corrected significance, with asterisks showing traits significant after correction. The traits are grouped into different categories and sorted by the genetic correlations with AUDIT-C (upper panel) or AUD (lower panel). CNS central nervous system, ADHD attention deficit hyperactivity disorder, MDD major depressive disorder

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