Assessing the impact of alcohol consumption on the genetic contribution to mean corpuscular volume



Thompson, Andrew ORCID: 0000-0002-7087-9415, King, Katharine, Morris, Andrew P and Pirmohamed, Munir ORCID: 0000-0002-7534-7266
(2021) Assessing the impact of alcohol consumption on the genetic contribution to mean corpuscular volume. HUMAN MOLECULAR GENETICS, 30 (21). pp. 2040-2051.

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Abstract

The relationship between the genetic loci that influence mean corpuscular volume (MCV) and those associated with excess alcohol drinking is unknown. We used white British participants from the UK Biobank (n = 362 595) to assess the association between alcohol consumption and MCV, and whether this was modulated by genetic factors. Multivariable regression was applied to identify predictors of MCV. GWAS, with and without stratification for alcohol consumption, determined how genetic variants influence MCV. SNPs in ADH1B, ADH1C and ALDH1B were used to construct a genetic score to test the assumption that acetaldehyde formation is an important determinant of MCV. Additional investigations using Mendelian randomization and phenome-wide association analysis were conducted. Increasing alcohol consumption by 40 g/week resulted in a 0.30% [95% confidence interval CI: 0.30-0.31%] increase in MCV (P < 1.0 × 10-320). Unstratified (irrespective of alcohol intake) GWAS identified 212 loci associated with MCV, of which 108 were novel. There was no heterogeneity of allelic effects by drinking status. No association was found between MCV and the genetic score generated from alcohol metabolizing genes. Mendelian randomization demonstrated a causal effect for alcohol on MCV. Seventy-one SNP-outcome pairs reached statistical significance in phenome-wide association analysis, with evidence of shared genetic architecture for MCV and thyroid dysfunction, and mineral metabolism disorders. MCV increases linearly with alcohol intake in a causal manner. Many genetic loci influence MCV, with new loci identified in this analysis that provide novel biological insights. However, there was no interaction between alcohol consumption and the allelic variants associated with MCV.

Item Type: Article
Uncontrolled Keywords: Humans, Genetic Predisposition to Disease, Erythrocyte Indices, Population Surveillance, Alcohol Drinking, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Aged, Middle Aged, Female, Male, Metabolic Networks and Pathways, Genome-Wide Association Study, Genetic Association Studies, Mendelian Randomization Analysis, Health Impact Assessment
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 24 Jan 2022 10:11
Last Modified: 18 Jan 2023 21:14
DOI: 10.1093/hmg/ddab147
Open Access URL: https://doi.org/10.1093/hmg/ddab147
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3147528