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Meta-Analysis
. 2024 Jan 26;10(4):eade2780.
doi: 10.1126/sciadv.ade2780. Epub 2024 Jan 26.

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people

Yuriko N Koyanagi  1 , Masahiro Nakatochi  2 , Shinichi Namba  3 , Isao Oze  1 , Hadrien Charvat  4   5   6 , Akira Narita  7 , Takahisa Kawaguchi  8 , Hiroaki Ikezaki  9   10 , Asahi Hishida  11 , Megumi Hara  12 , Toshiro Takezaki  13 , Teruhide Koyama  14 , Yohko Nakamura  15 , Sadao Suzuki  16 , Sakurako Katsuura-Kamano  17 , Kiyonori Kuriki  18 , Yasuyuki Nakamura  19 , Kenji Takeuchi  11   20   21 , Atsushi Hozawa  22 , Kengo Kinoshita  7 , Yoichi Sutoh  23 , Kozo Tanno  24   25 , Atsushi Shimizu  23   26 , Hidemi Ito  27   28 , Yumiko Kasugai  1   29 , Yukino Kawakatsu  1 , Yukari Taniyama  27 , Masahiro Tajika  30 , Yasuhiro Shimizu  31 , Etsuji Suzuki  32   33 , Yasuyuki Hosono  34 , Issei Imoto  35 , Yasuharu Tabara  8   36 , Meiko Takahashi  8 , Kazuya Setoh  8 ; BioBank Japan Project  37 ; Koichi Matsuda  38 , Shiori Nakano  39 , Atsushi Goto  39   40 , Ryoko Katagiri  41   42 , Taiki Yamaji  39 , Norie Sawada  41 , Shoichiro Tsugane  41   42 , Kenji Wakai  11 , Masayuki Yamamoto  7 , Makoto Sasaki  43   44 , Fumihiko Matsuda  8 , Yukinori Okada  3   45   46   47   48   49 , Motoki Iwasaki  39   41 , Paul Brennan  50 , Keitaro Matsuo  1   29
Affiliations
Meta-Analysis

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people

Yuriko N Koyanagi et al. Sci Adv. .

Abstract

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

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Figures

Fig. 1.
Fig. 1.. Manhattan plots of the GWAS of daily alcohol intake.
The results for (A) unstratified, (B) rs671 wild-type homozygotes (GG), (C) rs671 heterozygotes (GA), and (D) interaction with rs671 are shown. The position on each chromosome (x axis) and the observed −log10(P value) (y axis) of all tested genetic variants are shown. The solid red line indicates genome-wide significance level. Blue triangles represent loci containing SNPs with P values of <1 × 10−50. *ADH1B P value (A): 5.89 × 10−91; **ALDH2 P value (A): 8.71 × 10−6987; †ADH1B P value (C): 3.12 × 10−101; ‡ALDH1B1 P value (C): 2.00 × 10−54.
Fig. 2.
Fig. 2.. Genomic loci reaching genome-wide significance in either analysis for association with daily alcohol intake.
Direction of effects of identified variants other than rs671 is presented as a heatmap. Estimates with a single asterisk show genome-wide significance (P < 5.0 × 10−8). Lead SNP in each locus is highlighted, with its estimates in bold. SNP, single-nucleotide polymorphism; Ref, reference allele; Alt, alternative allele; freq., frequency; SE, standard error; HetP, P value from test of heterogeneity. †rs79463616 was not itself lead SNP in the interaction GWAS, but was in perfect LD with the lead SNP, rs4646777 [β (SE) = −0.127 (0.012), P = 4.45 × 10−27] (r2 = 1.00 in 1KGP-JPT).
Fig. 3.
Fig. 3.. Regional association plots of the identified ALDH2 and GOT2 regions.
Regional association plots for daily alcohol intake in rs671 heterozygotes are shown. The vertical axis indicates the –log10(P value) for the assessment of the association of each SNP with daily alcohol intake. Black line represents genome-wide significance threshold of 5.0 × 10−8. The colors indicate the LD (r2) between each lead SNP and neighboring SNPs based on the JPT population in the 1000 Genomes Project Phase 3.
Fig. 4.
Fig. 4.. Impact of identified variants on esophageal cancer risk and assessment of additive interaction of each SNP (1-allele change) with rs671 (GA versus GG).
ORs for esophageal cancer per 1-allele change in eight SNPs on three different subject groups [entire population (unstratified), subjects with the rs671 GG genotype only (GG), and subjects with the rs671 GA genotype only (GA)] were calculated by a random effects model by pooling study-specific ORs adjusted for sex, age, the first 10 principal components (for the BBJ Study), and study version (for the HERPACC Study). Stacked bar charts on assessment of additive interaction are presented as ORs partitioned into relative excess risks due to 1-allele change in each SNP other than rs671 (light gray), rs671 (GA versus GG) (gray), and their interaction (RERI) (purple). Statistical significance was set at the Bonferroni corrected threshold of P < 0.05/8 (=0.00625), and suggestive significance was set at P < 0.05. RERI was considered to achieve suggestive significance (P < 0.05) when its confidence interval did not include 0. Estimates in bold show statistical significance with Bonferroni correction (P < 0.00625). The HERPACC Study included 692 cases and 995 controls; the BBJ Study included 416 cases and 86,515 controls. OR, odds ratio; CI, confidence interval; BBJ, BioBank Japan; HERPACC, Hospital-based Epidemiologic Research Program at Aichi Cancer Center.
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