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Journal of Molecular Neuroscience

, Volume 51, Issue 2, pp 416–424 | Cite as

Genetic Variants in the Fat Mass- and Obesity-Associated (FTO) Gene are Associated with Alcohol Dependence

  • Liang Wang
  • Xuefeng Liu
  • Xingguang Luo
  • Min Zeng
  • Lingjun Zuo
  • Ke-Sheng WangEmail author
Article

Abstract

Variants (such as rs9939609) in the fat mass- and obesity-associated (FTO) gene have been associated with obesity, type 2 diabetes, some cancers, and alcohol consumption. This study tested the associations of 167 single-nucleotide polymorphisms (SNPs) within FTO gene with alcohol dependence (AD) using two Caucasian samples: the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis of AD as a binary trait was performed using the PLINK software. For the SAGE sample, the top three SNPs showing associations with AD were rs8062891, rs1108086, and rs1420318 (p = 0.00088, 0.00086 and 0.00086, respectively). Two SNPs (rs12597786 and rs7204609) associated with AD in the SAGE sample (p = 0.017 and 0.034, respectively) were replicated in the COGA sample (p = 0.017 and 0.014, respectively). Through meta-analysis of two samples using PLINK, the top three SNPs associated with AD were rs8062891, rs12597786, and rs7204609 (p = 0.00064, 0.00076 and 0.0011, respectively). Haplotype analysis in the SAGE sample further supported the associations with AD in single-marker analysis. In addition, we found association of rs17817449 (which has a strong linkage disequilibrium with rs9939609) with AD in the SAGE sample (p = 0.00339). The findings provide evidence of joint intervention and prevention of AD and obesity.

Keywords

Alcohol dependence FTO Single nucleotide polymorphism Association Meta-analysis Haplotype 

Notes

Acknowledgments

Funding support for the (CIDR-COGA Study) was provided through the Center for Inherited Disease Research (CIDR) and the Collaborative Study on the Genetics of Alcoholism (COGA). The CIDR–COGA Study is a genome-wide association studies funded as part of the COGA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the COGA. Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the COGA (U10 AA008401). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?Db = gap through dbGaP accession number: phs000125.v1.p1. Funding support for the SAGE was provided through the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) grant U01 HG004422. SAGE is one of the GWAS funded as part of the GENEVA under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (grant U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by COGA (grant U10 AA008401), COGEND (grant P01 CA089392), and FSCD (grant R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by NIH GEI grant U01HG004438, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/ study.cgi study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p.1. This study was approved by the Internal Review Board (IRB), East Tennessee State University.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

12031_2013_44_MOESM1_ESM.xls (60 kb)
Table S1 (XLS 60 kb)

References

  1. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (4th ed.) (DSM-IV). APA, Washington, D.CGoogle Scholar
  2. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders: DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, D.C.Google Scholar
  3. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265Google Scholar
  4. Barry D, Clarke M, Petry NM (2009) Obesity and its relationship to addictions: is overeating a form of addictive behavior. Am J Addict 18:439–451PubMedCrossRefGoogle Scholar
  5. Bierut LJ, Agrawal A, Bucholz KK, Doheny KF, Laurie C, Pugh E et al (2010) A genome-wide association study of alcohol dependence. Proc Natl Acad Sci U S A 107:5082–5087PubMedCrossRefGoogle Scholar
  6. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN (2008) An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 359:2558–2566PubMedCrossRefGoogle Scholar
  7. Davis C, Levitan RD, Muglia P, Bewell C, Kennedy JL (2004) Decision-making deficits and overeating: a risk model for obesity. Obes Res 12:929–935PubMedCrossRefGoogle Scholar
  8. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P et al (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39:724–726PubMedCrossRefGoogle Scholar
  9. Dlouhá D, Hubáček JA (2012) FTO gene and his role in genetic determination of obesity. Vnitr Lek 58(3):208–215PubMedGoogle Scholar
  10. Dom G, D’haene P, Hulstijn W, Sabbe B (2006) Impulsivity in abstinent early- and late-onset alcoholics: differences in self-report measures and a discounting task. Addiction 101:50–59PubMedCrossRefGoogle Scholar
  11. Dong C, Sanchez LE, Price RA (2004) Relationship of obesity to depression: a family-based study. Int J Obes Relat Metab Disord 28(6):790–795PubMedCrossRefGoogle Scholar
  12. Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66:87–98Google Scholar
  13. Edenberg HJ, Koller DL, Xuei X, Wetherill L, McClintick JN, Almasy L et al (2010) Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcohol Clin Exp Res 34:840–852PubMedCrossRefGoogle Scholar
  14. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedCrossRefGoogle Scholar
  15. Freathy RM, Timpson NJ, Lawlor DA, Pouta A, Ben-Shlomo Y, Ruokonen A et al (2008) Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI. Diabetes 57(5):1419–1426PubMedCrossRefGoogle Scholar
  16. Fredriksson R, Hägglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM et al (2008) The obesity gene, FTO, is of ancient origin, upregulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology 149(5):2062–2071PubMedCrossRefGoogle Scholar
  17. Galanti K, Gluck ME, Geliebter A (2007) Test meal intake in obese binge eaters in relation to impulsivity and compulsivity. Int J Eat Disord 40:727–732PubMedCrossRefGoogle Scholar
  18. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS et al (2007) The obesity-associated FTO gene encodes a 2 oxoglutarate-dependent nucleic acid demethylase. Science 318:1469–1472PubMedCrossRefGoogle Scholar
  19. Harwood H (2000) Updating estimates of the economic costs of alcohol abuse in the United States: Estimates, update methods, and data. Report prepared by The Lewin Group for the National Institute on Alcohol Abuse and Alcoholism, 2000. Based on estimates, analyses, and data reported in Harwood, H.; Fountain, D.; and Livermore, G. The Economic Costs of Alcohol and Drug Abuse in the United States 1992. Report prepared for the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services. National Institutes of Health, Rockville, MDGoogle Scholar
  20. Hasin DS, Stinson FS, Ogburn E, Grant BF (2007) Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States. Arch Gen Psychiatry 64(7):830PubMedCrossRefGoogle Scholar
  21. Hubacek JA, Adamkova V, Dlouha D, Jirsa M, Šperl J, Tönjes A et al (2012) Fat mass and obesity associated (FTO) gene and alcohol intake. Addiction 107(6):1185–1186PubMedCrossRefGoogle Scholar
  22. James GA, Gold MS, Liu Y (2004) Interaction of satiety and reward response to food stimulation. J Addict Dis 23:23–37PubMedCrossRefGoogle Scholar
  23. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y et al (2011) N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7(12):885–887PubMedCrossRefGoogle Scholar
  24. Johnston E, Johnson S, McLeod P, Johnston M (2004) The relation of body mass index to depressive symptoms. Can J Public Health 95(3):179–183PubMedGoogle Scholar
  25. Kalsi G, Prescott CA, Kendler KS, Riley BP (2009) Unraveling the molecular mechanisms of alcohol dependence. Trends Genet 25:49–55PubMedCrossRefGoogle Scholar
  26. Keller L, Xu W, Wang HX, Winblad B, Fratiglioni L, Graff C (2011) The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimer's Dis 23(3):461–469Google Scholar
  27. Kleiner KD, Gold MS, Frost-Pineda K, Lenz-Brunsman B, Perri MG, Jacobs WS (2004) Body mass index and alcohol use. J Addict Dis 23:105–118PubMedCrossRefGoogle Scholar
  28. Kusinska R, Górniak P, Pastorczak A, Fendler W, Potemski P, Mlynarski W et al (2012) Influence of genomic variation in FTO at 16q12.2, MC4R at 18q22 and NRXN3 at 14q31 genes on breast cancer risk. Mol Biol Rep 39(3):2915–2919PubMedCrossRefGoogle Scholar
  29. McGue M (1999) Phenotyping alcoholism. Alcohol Clin Exp Res 23:757–758PubMedCrossRefGoogle Scholar
  30. Myers A, Rosen JC (1999) Obesity stigmatization and coping: relation to mental health symptoms, body image, and self-esteem. Int J Obes Relat Metab Disord 23(3):221–230PubMedCrossRefGoogle Scholar
  31. Olszewski PK, Fredriksson R, Olszewska AM, Stephansson O, Alsiö J, Radomska KJ et al (2009) Hypothalamic FTO is associated with the regulation of energy intake not feeding reward. BMC Neurosci 10:129PubMedCrossRefGoogle Scholar
  32. Onyike CU, Crum RM, Lee HB, Lyketsos CG, Eaton WW (2003) Is obesity associated with major depression? Results from the Third National Health and Nutrition Examination Survey. Am J Epidemiol 158(12):1139–1147PubMedCrossRefGoogle Scholar
  33. Peters T, Ausmeier K, Dildrop R, Rüther U (2002) The mouse Fused toes (Ft) mutation is the result of a 1.6-Mb deletion including the entire Iroquois B gene cluster. Mamm Genome 13(4):186–188PubMedCrossRefGoogle Scholar
  34. Prescott CA, Kendler KS (1999) Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 156:34–40PubMedGoogle Scholar
  35. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575PubMedCrossRefGoogle Scholar
  36. Qi L, Kang K, Zhang C, van Dam RM, Kraft P, Hunter D, Lee CH et al (2008) Fat mass-and obesity-associated (FTO) gene variant is associated with obesity: longitudinal analyses in two cohort studies and functional test. Diabetes 57(11):3145–3151PubMedCrossRefGoogle Scholar
  37. Roberts RE, Strawbridge WJ, Deleger S, Kaplan GA (2002) Are the fat more jolly? Ann Behav Med 24(3):169–180PubMedCrossRefGoogle Scholar
  38. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J et al (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3(7):e115PubMedCrossRefGoogle Scholar
  39. Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G et al (2006) Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 63(7):824–830PubMedCrossRefGoogle Scholar
  40. Sobczyk-Kopciol A, Broda G, Wojnar M, Kurjata P, Jakubczyk A, Klimkiewicz A et al (2011) Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction 106(4):739–748PubMedCrossRefGoogle Scholar
  41. Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI et al (2008) Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294:R1185–R1196PubMedCrossRefGoogle Scholar
  42. Treutlein J, Rietschel M (2011) Genome-wide association studies of alcohol dependence and substance use disorders. Curr Psychiatry Rep 13:147–155PubMedCrossRefGoogle Scholar
  43. Treutlein J, Cichon S, Ridinger M, Wodarz N, Soyka M, Zill P et al (2009) Genome-wide association study of alcohol dependence. Arch Gen Psychiatry 66:773–784PubMedCrossRefGoogle Scholar
  44. Trinko R, Sears RM, Guarnieri DJ, DiLeone RJ (2007) Neural mechanisms underlying obesity and drug addiction. Physiol Behav 91:499–505PubMedCrossRefGoogle Scholar
  45. Volkow ND, O’Brien CP (2007) Issues for DSM-V: should obesity be included as a brain disorder? Am J Psychiatry 164:708–710PubMedCrossRefGoogle Scholar
  46. Wang KS, Liu X, Zhang Q, Pan Y, Aragam N, Zeng M (2011) A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence. J Psychiatr Res 45:1419–1425PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Liang Wang
    • 1
  • Xuefeng Liu
    • 1
  • Xingguang Luo
    • 2
  • Min Zeng
    • 1
  • Lingjun Zuo
    • 2
  • Ke-Sheng Wang
    • 1
    Email author
  1. 1.Department of Biostatistics and Epidemiology, College of Public HealthEast Tennessee State UniversityJohnson CityUSA
  2. 2.Department of PsychiatryYale University School of MedicineNew HavenUSA

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