Positive selection acts on regulatory genetic variants in populations of European ancestry that affect ALDH2 gene expression

Helmut Schaschl,Tobias Göllner,David L Morris

doi:10.1038/s41598-022-08588-0

Helmut Schaschl, Tobias Göllner + Show 1 more

Open Access

https://doi.org/10.1038/s41598-022-08588-0

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Journal: Scientific Reports	Publication Date: Mar 16, 2022
Citations: 4	License type: open-access

Affiliation: University of Vienna, King's College London

Abstract

ALDH2 is a key enzyme in alcohol metabolism that protects cells from acetaldehyde toxicity. Using iHS, iSAFE and FST statistics, we identified regulatory acting variants affecting ALDH2 gene expression under positive selection in populations of European ancestry. Several SNPs (rs3184504, rs4766578, rs10774625, rs597808, rs653178, rs847892, rs2013002) that function as eQTLs for ALDH2 in various tissues showed evidence of strong positive selection. Very large pairwise FST values indicated high genetic differentiation at these loci between populations of European ancestry and populations of other global ancestries. Estimating the timing of positive selection on the beneficial alleles suggests that these variants were recently adapted approximately 3000–3700 years ago. The derived beneficial alleles are in complete linkage disequilibrium with the derived ALDH2 promoter variant rs886205, which is associated with higher transcriptional activity. The SNPs rs4766578 and rs847892 are located in binding sequences for the transcription factor HNF4A, which is an important regulatory element of ALDH2 gene expression. In contrast to the missense variant ALDH2 rs671 (ALDH2*2), which is common only in East Asian populations and is associated with greatly reduced enzyme activity and alcohol intolerance, the beneficial alleles of the regulatory variants identified in this study are associated with increased expression of ALDH2. This suggests adaptation of Europeans to higher alcohol consumption.

Highlights

ALDH2 is a key enzyme in alcohol metabolism that protects cells from acetaldehyde toxicity
From the GTEx database, we obtained in total 1591 cis-QTLs that influence ALDH2 gene expression (Supplementary Table 1); of these cis-QTLs, we identified 204, 217 and 53 eQTLs that had significant (p < 0.01) integrated Haplotype Score (iHS) scores in the European samples GBR, TSI and FIN, respectively (Supplementary Table 2)
We further identified seven SNPs that are under positive selection in European populations that have very large global locus-specific FST values > 0.3, i.e. are outlier loci (Table 1)

Summary

Introduction

ALDH2 is a key enzyme in alcohol metabolism that protects cells from acetaldehyde toxicity. The positive selection on the derived allele was estimated to have occurred about 7000–15,000 years ago[16,28,29], which overlaps with the time-frame of the origin and expansion of Neolithic agriculture in East Asia It remains unclear whether the driving selective force acting on this genetic polymorphism emanates from the protective effect against alcohol dependence or from the higher efficiency of this polymorphism in metabolizing EtOH. The ALDH2*2 variant is found only in individuals of East Asian ancestry, reaching frequencies of up to 40% in some East Asian populations such as Han Chinese and Japanese[13,36,37] This allele significantly affects alcohol metabolism because it results in an inactive enzyme and an excess of the toxic acetaldehyde in cells, even with moderate alcohol consumption. Several lines of evidence indicate that recent positive selection is acting on regulatory variants that influence ALDH2 gene expression in populations of European ancestry

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