Dietary habits are important factors in our lifestyle, and confer both susceptibility to and protection from a variety of human diseases. We performed genome-wide association studies for 13 dietary habits including consumption of alcohol (ever versus never drinkers and drinks per week), beverages (coffee, green tea and milk) and foods (yoghurt, cheese, natto, tofu, fish, small whole fish, vegetables and meat) in Japanese individuals (n = 58,610–165,084) collected by BioBank Japan, the nationwide hospital-based genome cohort. Significant associations were found in nine genetic loci (MCL1-ENSA, GCKR, AGR3-AHR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, CYP1A2-CSK and ADORA2A-AS1) for 13 dietary traits (P < 3.8 × 10−9). Of these, ten associations between five loci and eight traits were new findings. Furthermore, a phenome-wide association study revealed that five of the dietary trait-associated loci have pleiotropic effects on multiple human complex diseases and clinical measurements. Our findings provide new insight into the genetics of habitual consumption.
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Johnson, K. E. & Voight, B. F. Patterns of shared signatures of recent positive selection across human populations. Nat. Ecol. Evol. 2, 713–720 (2018).
Okada, Y. et al. Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese. Nat. Commun. 9, 1631 (2018).
Okada, Y. eLD: entropy-based linkage disequilibrium index between multiallelic sites. Hum. Genome Var. 5, 29 (2018).
Baik, I., Cho, N. H., Kim, S. H., Han, B.-G. & Shin, C. Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am. J. Clin. Nutr. 93, 809–816 (2011).
Takeuchi, F. et al. Confirmation of ALDH2 as a major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ. J. 75, 911–918 (2011).
Schumann, G. et al. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proc. Natl Acad. Sci. USA 113, 14372–14377 (2016).
Yang, X. et al. Common variants at 12q24 are associated with drinking behavior in Han Chinese. Am. J. Clin. Nutr. 97, 545–551 (2013).
Jorgenson, E. et al. Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study. Mol. Psychiatry 22, 1359–1367 (2017).
Clarke, T. K. et al. Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N = 112117). Mol. Psychiatry 22, 1376–1384 (2017).
Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237–244 (2019).
Zhong, V. W. et al. A genome-wide association study of bitter and sweet beverage consumption. Hum. Mol. Genet. 28, 2449–2457 (2019).
Sulem, P. et al. Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Hum. Mol. Genet 20, 2071–2077 (2011).
Amin, N. et al. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM. Mol. Psychiatry 17, 1116–1129 (2012).
Coffee and Caffeine Genetics Consortiumet al. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Mol. Psychiatry 20, 647–656 (2015).
Pirastu, N. et al. Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption. Sci. Rep. 6, 31590 (2016).
Nakagawa-Senda, H. et al. A genome-wide association study in the japanese population identifies the 12q24 locus for habitual coffee consumption: the J-MICC study. Sci. Rep. 8, 1493 (2018).
Mozaffarian, D. et al. Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. PLoS One 12, e0186456 (2017).
Jiang, L., Penney, K. L., Giovannucci, E., Kraft, P. & Wilson, K. M. A genome-wide association study of energy intake and expenditure. PLoS One 13, e0201555 (2018).
Nagai, A. et al. Overview of the BioBank Japan project: study design and profile. J. Epidemiol. 27, S2–S8 (2017).
Nakachi, K., Matsuyama, S., Miyake, S., Suganuma, M. & Imai, K. Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention. BioFactors 13, 49–54 (2000).
Uemura, H. et al. Inverse association between soy food consumption, especially fermented soy products intake and soy isoflavone, and arterial stiffness in Japanese men. Sci. Rep. 8, 9667 (2018).
Tsugane, S. & Sawada, N. The JPHC study: design and some findings on the typical Japanese diet. Jpn. J. Clin. Oncol. 44, 777–782 (2014).
Akiyama, M. et al. Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. Nat. Genet. 49, 1458–1467 (2017).
Kanai, M. et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390–400 (2018).
Bulik-Sullivan, B. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
Cornelis, M. C. et al. Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption. PLoS Genet. 7, e1002033 (2011).
Cornelis, M. C. et al. Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior. Hum. Mol. Genet. 25, ddw334 (2016).
Yin, G. et al. ALDH2 polymorphism is associated with fasting blood glucose through alcohol consumption in Japanese men. Nagoya J. Med. Sci. 78, 183–193 (2016).
Gelernter, J. et al. Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol. Psychiatry 19, 41–49 (2014).
Canela-Xandri, O., Rawlik, K. & Tenesa, A. An atlas of genetic associations in UK Biobank. Nat. Genet. 50, 1593–1599 (2018).
Lonsdale, J. et al. The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).
Kim, Y. K. et al. Evaluation of pleiotropic effects among common genetic loci identified for cardio-metabolic traits in a Korean population. Cardiovasc. Diabetol. 15, 20 (2016).
Sakaue, S. et al. Functional variants in ADH1B and ALDH2 are non-additively associated with all-cause mortality in Japanese population. Eur. J. Hum. Genet. https://doi.org/10.1038/s41431-019-0518-y (2019).
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Researchet al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
Hirata, J. et al. Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population. Nat. Genet. 51, 470–480 (2019).
Lamparter, D. et al. Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics. PLoS Comput. Biol. 12, e1004714 (2016).
Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).
Kennedy, O. J. et al. Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis. Aliment. Pharmacol. Ther. 47, 562–5 (2016).
Inoue, M., Yoshimi, I., Sobue, T. & Tsugane, S. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. J. Natl Cancer Inst. 97, 293–300 (2005).
Panahi, S., Fernandez, M. A., Marette, A. & Tremblay, A. Yogurt, diet quality and lifestyle factors. Eur. J. Clin. Nutr. 71, 573–579 (2017).
D’Addezio, L., Mistura, L., Sette, S. & Turrini, A. Sociodemographic and lifestyle characteristics of yogurt consumers in Italy: results from the INRAN-SCAI 2005-06 survey. Med. J. Nutr. Metab. 8, 119–129 (2015).
Kot, M. & Daniel, W. A. Effect of cytochrome P450 (CYP) inducers on caffeine metabolism in the rat. Pharmacol. Rep. 59, 296–305 (2007).
Zanger, U. M. & Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 138, 103–141 (2013).
Berthou, F. et al. Evidence for the involvement of several cytochromes P-450 in the first steps of caffeine metabolism by human liver microsomes. Drug Metab. Dispos. 19, 561–567 (1991).
Wang, L.-X., Wen, S., Wang, C.-C., Zhou, B. & Li, H. Molecular adaption of alcohol metabolism to agriculture in East Asia. Quat. Int. 426, 187–194 (2016).
Way, M. J., Ali, M. A., McQuillin, A. & Morgan, M. Y. Genetic variants in ALDH1B1 and alcohol dependence risk in a British and Irish population: a bioinformatic and genetic study. PLoS One 12, e0177009 (2017).
Linneberg, A. et al. Genetic determinants of both ethanol and acetaldehyde metabolism influence alcohol hypersensitivity and drinking behaviour among Scandinavians. Clin. Exp. Allergy 40, 123–130 (2009).
Husemoen, L. L. N. et al. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors. Alcohol. Clin. Exp. Res. 32, 1984–1991 (2008).
Cornelis, M. C., El-Sohemy, A. & Campos, H. Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am. J. Clin. Nutr. 86, 240–244 (2007).
Matoba, N. et al. GWAS of smoking behaviour in 165,436 Japanese people reveals seven new loci and shared genetic architecture. Nat. Hum. Behav. 3, 471–477 (2019).
We are grateful to all participants enrolled in BBJ. We thank all the clinicians and organizations that contributed to the collection of samples and clinical information. This research was supported by the Tailor-Made Medical Treatment Programme (BBJ) of the Ministry of Education, Culture, Sports, Science and Technology and the Japan Agency for Medical Research and Development (AMED; grant nos. JP17km0305002, JP19km0405201 and JP19km045208), and by the Strategic Research Programme for Brain Sciences of AMED (no. JP19dm0107097). Y.O. was supported by the Japan Society for the Promotion of Science, KAKENHI (nos. 15H05911 and 19H01021), AMED (nos. JP19gm6010001, JP19ek0410041, JP19ek0109413 and JP19km0405211), Takeda Science Foundation and the Bioinformatics Initiative of Osaka University Graduate School of Medicine, Osaka University and Osaka University Centre of Medical Data Science, Advanced Clinical Epidemiology Investigator’s Research Project. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
The authors declare no competing interests.
Editor recognition statement Primary handling editor: Stavroula Kousta
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Supplementary Figs. 1–13 and Supplementary Tables 1, 5, 8 and 9.
Supplementary Table 2. Summary of current studies.
Supplementary Table 3. Covariates used in each association test.
Supplementary Table 4. Associations of previously reported loci.
Supplementary Table 6. Look-up results in UK BioBank.
Supplementary Table 7. Effect of taste sensitivity-related SNPs.
Supplementary Table 10. Full results of cross-trait LDSC analysis across dietary habits.
Supplementary Table 11. Description of complex diseases and laboratory measurements used in PheWAS.
Supplementary Table 12. PheWAS results.
Supplementary Table 13. Full results of heritability enrichment in ten cell type groups.
Supplementary Table 14. Full results of pathway enrichment analysis.
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Matoba, N., Akiyama, M., Ishigaki, K. et al. GWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits. Nat Hum Behav 4, 308–316 (2020). https://doi.org/10.1038/s41562-019-0805-1
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