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Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study

Molecular Psychiatry volume 22, pages 1359–1367 (2017)Cite this article

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Abstract

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects’ alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10−72) in East Asians, and also an effect on drinks/week (beta=−0.17, P=5.42 × 10−4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10−20 for drinker status and beta=−0.19, P=1.91 × 10−35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10−7 and beta=−0.21, P=2.58 × 10−6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=−0.04, P=3.41 × 10−10 for drinks/week and OR=0.96, P=4.08 × 10−5 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10−8 for drinks/week and OR=1.04, P=5 × 10−4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

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References

  1. Dawson DA . The link between family history and early onset alcoholism: earlier initiation of drinking or more rapid development of dependence? J Stud Alcohol 2000; 61: 637–646.

    Article  CAS  PubMed  Google Scholar 

  2. Grant BF, Stinson FS, Harford TC . Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: a 12-year follow-up. J Subst Abuse 2001; 13: 493–504.

    Article  CAS  PubMed  Google Scholar 

  3. Sartor CE, Lynskey MT, Heath AC, Jacob T, True W . The role of childhood risk factors in initiation of alcohol use and progression to alcohol dependence. Addiction 2007; 102: 216–225.

    Article  PubMed  Google Scholar 

  4. Dawson DA . US low-risk drinking guidelines: an examination of four alternatives. Alcohol Clin Exp Res 2000; 24: 1820–1829.

    Article  CAS  PubMed  Google Scholar 

  5. Dawson DA, Grant BF, Li TK . Quantifying the risks associated with exceeding recommended drinking limits. Alcohol Clin Exp Res 2005; 29: 902–908.

    Article  PubMed  Google Scholar 

  6. Willenbring ML, Massey SH, Gardner MB . Helping patients who drink too much: an evidence-based guide for primary care clinicians. Am Fam Physician 2009; 80: 44–50.

    PubMed  Google Scholar 

  7. Irving HM, Samokhvalov AV, Rehm J . Alcohol as a risk factor for pancreatitis. A systematic review and meta-analysis. Jop 2009; 10: 387–392.

    PubMed  Google Scholar 

  8. Lonnroth K, Williams BG, Stadlin S, Jaramillo E, Dye C . Alcohol use as a risk factor for tuberculosis - a systematic review. BMC Public Health 2008; 8: 289.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Nelson DE, Jarman DW, Rehm J, Greenfield TK, Rey G, Kerr WC et al. Alcohol-attributable cancer deaths and years of potential life lost in the United States. Am J Public Health 2013; 103: 641–648.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Patra J, Taylor B, Irving H, Roerecke M, Baliunas D, Mohapatra S et al. Alcohol consumption and the risk of morbidity and mortality for different stroke types—a systematic review and meta-analysis. BMC Public Health 2010; 10: 258.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rehm J, Parry C . Alcohol consumption and infectious diseases in South Africa. Lancet 2009; 374: 2053.

    Article  CAS  PubMed  Google Scholar 

  12. Samokhvalov AV, Irving H, Mohapatra S, Rehm J . Alcohol consumption, unprovoked seizures, and epilepsy: a systematic review and meta-analysis. Epilepsia 2010; 51: 1177–1184.

    Article  PubMed  Google Scholar 

  13. Samokhvalov AV, Irving HM, Rehm J . Alcohol consumption as a risk factor for pneumonia: a systematic review and meta-analysis. Epidemiol Infect 2010; 138: 1789–1795.

    Article  CAS  PubMed  Google Scholar 

  14. Stein E, Cruz-Lemini M, Altamirano J, Ndugga N, Couper D, Abraldes JG et al. Heavy daily alcohol intake at the population level predicts the weight of alcohol in cirrhosis burden worldwide. J Hepatol 2016; 65: 998–1005.

    Article  CAS  PubMed  Google Scholar 

  15. Taylor B, Irving HM, Kanteres F, Room R, Borges G, Cherpitel C et al. The more you drink, the harder you fall: a systematic review and meta-analysis of how acute alcohol consumption and injury or collision risk increase together. Drug Alcohol Depend 2010; 110: 108–116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. WHO Global Status Report on Alcohol and Health. Geneva, 2014.

  17. Korcha RA, Cherpitel CJ, Ye Y, Bond J, Andreuccetti G, Borges G et al. Alcohol use and injury severity among emergency department patients in six countries. J Addict Nurs 2013; 24: 158–165.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Shield KD, Gmel G, Kehoe-Chan T, Dawson DA, Grant BF, Rehm J . Mortality and potential years of life lost attributable to alcohol consumption by race and sex in the United States in 2005. PLoS ONE 2013; 8: e51923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stahre M, Roeber J, Kanny D, Brewer RD, Zhang X . Contribution of excessive alcohol consumption to deaths and years of potential life lost in the United States. Prev Chronic Dis 2014; 11: E109.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kendler KS, Myers J, Dick D, Prescott CA . The relationship between genetic influences on alcohol dependence and on patterns of alcohol consumption. Alcohol Clin Exp Res 2010; 34: 1058–1065.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dick DM, Meyers JL, Rose RJ, Kaprio J, Kendler KS . Measures of current alcohol consumption and problems: two independent twin studies suggest a complex genetic architecture. Alcohol Clin Exp Res 2011; 35: 2152–2161.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hansell NK, Agrawal A, Whitfield JB, Morley KI, Zhu G, Lind PA et al. Long-term stability and heritability of telephone interview measures of alcohol consumption and dependence. Twin Res Hum Genet 2008; 11: 287–305.

    Article  PubMed  Google Scholar 

  23. Agrawal A, Grant JD, Littlefield A, Waldron M, Pergadia ML, Lynskey MT et al. Developing a quantitative measure of alcohol consumption for genomic studies on prospective cohorts. J Stud Alcohol Drugs 2009; 70: 157–168.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Edenberg HJ . The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 2007; 30: 5–13.

    PubMed  PubMed Central  Google Scholar 

  25. Edenberg HJ, Foroud T . Genetics and alcoholism. Nat Rev Gastroenterol Hepatol 2013; 10: 487–494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu K, Kranzler HR, Sherva R, Sartor CE, Almasy L, Koesterer R et al. Genome-wide Association Study for maximum number of alcoholic drinks in European Americans and African Americans. Alcohol Clin Exp Res 2015; 39: 1137–1147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 2011; 108: 7119–7124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pan Y, Luo X, Liu X, Wu LY, Zhang Q, Wang L et al. Genome-wide association studies of maximum number of drinks. J Psychiatr Res 2013; 47: 1717–1724.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B et al. KLB is associated with alcohol drinking, and its gene product beta-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci USA 2016; 113: 14372–14377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mbarek H, Milaneschi Y, Fedko IO, Hottenga JJ, de Moor MH, Jansen R et al. The genetics of alcohol dependence: Twin and SNP-based heritability, and genome-wide association study based on AUDIT scores. Am J Med Genet B Neuropsychiatr Genet 2015; 168: 739–748.

    Article  CAS  PubMed  Google Scholar 

  31. Banda Y, Kvale MN, Hoffmann TJ, Hesselson SE, Ranatunga D, Tang H et al. Characterizing race/ethnicity and genetic ancestry for 100,000 subjects in the genetic epidemiology research on adult health and aging (GERA) cohort. Genetics 2015; 200: 1285–1295.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kvale MN, Hesselson S, Hoffmann TJ, Cao Y, Chan D, Connell S et al. Genotyping informatics and quality control for 100,000 subjects in the genetic epidemiology research on adult health and aging (GERA) cohort. Genetics 2015; 200: 1051–1060.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hoffmann TJ, Kvale MN, Hesselson SE, Zhan Y, Aquino C, Cao Y et al. Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array. Genomics 2011; 98: 79–89.

    Article  CAS  PubMed  Google Scholar 

  34. Hoffmann TJ, Zhan Y, Kvale MN, Hesselson SE, Gollub J, Iribarren C et al. Design and coverage of high throughput genotyping arrays optimized for individuals of East Asian, African American, and Latino race/ethnicity using imputation and a novel hybrid SNP selection algorithm. Genomics 2011; 98: 422–430.

    Article  CAS  PubMed  Google Scholar 

  35. Hoffmann TJ, Van Den Eeden SK, Sakoda LC, Jorgenson E, Habel LA, Graff RE et al. A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer Discov 2015; 5: 878–891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Delaneau O, Marchini J, Zagury JF . A linear complexity phasing method for thousands of genomes. Nat Methods 2012; 9: 179–181.

    Article  CAS  Google Scholar 

  37. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR . Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 2012; 44: 955–959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Howie B, Marchini J, Stephens M . Genotype imputation with thousands of genomes. G3 2011; 1: 457–470.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Howie BN, Donnelly P, Marchini J . A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 2009; 5: e1000529.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Marchini J, Howie B . Genotype imputation for genome-wide association studies. Nat Rev Genet 2010; 11: 499–511.

    Article  CAS  PubMed  Google Scholar 

  41. Baik I, Cho NH, Kim SH, Han BG, Shin C . Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr 2011; 93: 809–816.

    Article  CAS  PubMed  Google Scholar 

  42. Takeuchi F, Isono M, Nabika T, Katsuya T, Sugiyama T, Yamaguchi S 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 2011; 75: 911–918.

    Article  CAS  PubMed  Google Scholar 

  43. Yang X, Lu X, Wang L, Chen S, Li J, Cao J et al. Common variants at 12q24 are associated with drinking behavior in Han Chinese. Am J Clin Nutr 2013; 97: 545–551.

    Article  CAS  PubMed  Google Scholar 

  44. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. R Core Team. R: A Language and Environment for Statistical Computing. The R Foundation for Statistical Computing: Vienna, Austria, 2008.

  46. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26: 2336–2337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jones AW . Pharmacokinetics of ethanol—issues of forensic importance. Forensic Sci Rev 2011; 23: 91–136.

    CAS  PubMed  Google Scholar 

  48. Tahari AK, Chien D, Azadi JR, Wahl RL . Optimum lean body formulation for correction of standardized uptake value in PET imaging. J Nucl Med 2014; 55: 1481–1484.

    Article  PubMed  Google Scholar 

  49. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

    Article  CAS  PubMed  Google Scholar 

  50. Quillen EE, Chen XD, Almasy L, Yang F, He H, Li X et al. ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample. Am J Med Genet B Neuropsychiatr Genet 2014; 165B: 103–110.

    Article  PubMed  Google Scholar 

  51. Bierut LJ, Goate AM, Breslau N, Johnson EO, Bertelsen S, Fox L et al. ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Mol Psychiatry 2012; 17: 445–450.

    Article  CAS  PubMed  Google Scholar 

  52. Li H, Mukherjee N, Soundararajan U, Tarnok Z, Barta C, Khaliq S et al. Geographically separate increases in the frequency of the derived ADH1B*47His allele in eastern and western Asia. Am J Hum Genet 2007; 81: 842–846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Osier MV, Pakstis AJ, Soodyall H, Comas D, Goldman D, Odunsi A et al. A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. Am J Hum Genet 2002; 71: 84–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tsuchihashi-Makaya M, Serizawa M, Yanai K, Katsuya T, Takeuchi F, Fujioka A et al. Gene-environmental interaction regarding alcohol-metabolizing enzymes in the Japanese general population. Hypertens Res 2009; 32: 207–213.

    Article  CAS  PubMed  Google Scholar 

  55. Yokoyama A, Tsutsumi E, Imazeki H, Suwa Y, Nakamura C, Yokoyama T . Contribution of the alcohol dehydrogenase-1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men. Int J Cancer 2007; 121: 1047–1054.

    Article  CAS  PubMed  Google Scholar 

  56. Yokoyama A, Kamada Y, Imazeki H, Hayashi E, Murata S, Kinoshita K et al. Effects of ADH1B and ALDH2 genetic polymorphisms on alcohol elimination rates and salivary acetaldehyde levels in intoxicated Japanese alcoholic men. Alcohol Clin Exp Res 2016; 40: 1241–1250.

    Article  CAS  PubMed  Google Scholar 

  57. Park BL, Kim JW, Cheong HS, Kim LH, Lee BC, Seo CH et al. Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication. Hum Genet 2013; 132: 657–668.

    Article  CAS  PubMed  Google Scholar 

  58. Macgregor S, Lind PA, Bucholz KK, Hansell NK, Madden PA, Richter MM et al. Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis. Hum Mol Genet 2009; 18: 580–593.

    Article  CAS  PubMed  Google Scholar 

  59. Peng GS, Chen YC, Wang MF, Lai CL, Yin SJ . ALDH2*2 but not ADH1B*2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge: correlation of the pharmacokinetic and pharmacodynamic findings. Pharmacogenet Genomics 2014; 24: 607–617.

    Article  CAS  PubMed  Google Scholar 

  60. Crabb DW, Edenberg HJ, Bosron WF, Li TK . Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J Clin Invest 1989; 83: 314–316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK et al. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 1991; 48: 677–681.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK et al. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 1999; 65: 795–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Higuchi S, Matsushita S, Murayama M, Takagi S, Hayashida M . Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism. Am J Psychiatry 1995; 152: 1219–1221.

    Article  CAS  PubMed  Google Scholar 

  64. Li D, Zhao H, Gelernter J . Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biol Psychiatry 2011; 70: 504–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jorgenson E, Witte JS . Coverage and power in genome-wide association studies. Am J Hum Genet 2006; 78: 884–888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jorgenson E, Witte JS . A gene-centric approach to genome-wide association studies. Nat Rev Genet 2006; 7: 885–891.

    Article  CAS  PubMed  Google Scholar 

  67. Lindquist KJ, Jorgenson E, Hoffmann TJ, Witte JS . The impact of improved microarray coverage and larger sample sizes on future genome-wide association studies. Genet Epidemiol 2013; 37: 383–392.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study was supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) R21 No. R21AA021223.

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Authors and Affiliations

  1. Kaiser Permanente Division of Research, Oakland, CA, USA

    E Jorgenson, K K Thai, L C Sakoda, C Schaefer, N Risch, J Mertens, C Weisner & H Choquet

  2. Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA

    T J Hoffmann, Y Banda & N Risch

  3. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    T J Hoffmann, M N Kvale & N Risch

  4. Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    C Weisner

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  1. E Jorgenson
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Jorgenson, E., Thai, K., Hoffmann, T. 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). https://doi.org/10.1038/mp.2017.101

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