Abstract
Much evidence indicates that gene-by-environment interactions (GxE) play a role in alcohol misuse. It has been proposed that interactions between serotonin and stress confer vulnerability for alcohol misuse. The present review examined studies of the interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) genotype and stressful life events and alcohol-related phenotypes, in rhesus monkeys and humans. Ten studies were found that had investigated the interaction of 5-HTTLPR and various measures of stress and alcohol use or misuse, two studies of rhesus monkeys, and eight of humans. The results are contradictory. Important differences were reported in study samples, experimental designs, measures used to assess environmental variables, definitions and measurements of alcohol-related phenotypes, and in the statistical analyses. These differences may explain the contradictory results. Guidelines for future studies are suggested. Results are discussed in light of findings from molecular, non-human animal, and clinical studies. The review highlights the need for future studies examining associations of interactions between the serotonin transporter gene and environmental factors and alcohol misuse, especially in samples followed over time.
Similar content being viewed by others
References
Cases O., Vitalis T., Seif I., De Maeyer E., Sotelo C., Gaspar P., Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period, Neuron, 1996, 16, 297–307
Gaspar P., Cases O., Maroteaux L., The developmental role of serotonin: news from mouse molecular genetics, Nat. Rev. Neurosci., 2003, 4, 1002–1012
Nordquist N., Oreland L., Serotonin, genetic variability, behaviour, and psychiatric disorders — a review, Ups. J. Med. Sci., 2010, 115, 2–10
Amara S.G., Kuhar M.J., Neurotransmitter transporters: recent progress, Ann. Rev. Neurosci., 1993, 16, 73–93
Heils A., Teufel A., Petri S., Stober G., Riederer P., Bengel D., et al., Allelic variation of human serotonin transporter gene expression, J. Neurochem., 1996, 66, 2621–2624
Nakamura M., Ueno S., Sano A., Tanabe H., The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants, Mol. Psychiatry, 2000, 5, 32–38
Hu X.Z., Lipsky R.H., Zhu G., Akhtar L.A., Taubman J., Greenberg B.D., et al., Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder, Am J. Hum. Gen., 2006, 78, 815–826
Lesch K.P., Meyer J., Glatz K., Flugge G., Hinney A., Hebebrand J., et al., The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys, J. Neural Transm., 1997, 104, 1259–1266
Bengel D., Heils A., Petri S., Seemann M., Glatz K., Andrews A., et al., Gene structure and 5’-flanking regulatory region of the murine serotonin transporter, Mol. Brain Res., 1997, 44, 286–292
Dawes M.A., Roache J.D., Javors M.A., Bergeson S.E., Richard D.M., Mathias C.W., et al., Drinking histories in alcohol-use-disordered youth: preliminary findings on relationships to platelet serotonin transporter expression with genotypes of the serotonin transporter, J. Stud. Alcohol Drugs, 2009, 70, 899–907
Buchmann A.F., Schmid B., Blomeyer D., Becker K., Treutlein J., Zimmermann U.S., et al., Impact of age at first drink on vulnerability to alcohol-related problems: testing the marker hypothesis in a prospective study of young adults, J. Psychiatr. Res., 2009, 43, 1205–1212
Pinto E., Reggers J., Gorwood P., Boni C., Scantamburlo G., Pitchot W., et al., The short allele of the serotonin transporter promoter polymorphism influences relapse in alcohol dependence, Alcohol Alcohol., 2008, 43, 398–400
Gokturk C., Schultze S., Nilsson K.W., von Knorring L., Oreland L., Hallman J., Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism, Arch. Womens Ment. Health, 2008, 11, 347–355
van der Zwaluw C.S., Engels R.C., Vermulst A.A., Rose R.J., Verkes R.J., Buitelaar J., et al., A serotonin transporter polymorphism (5-HTTLPR) predicts the development of adolescent alcohol use, Drug Alcohol Depend., 2010, 112, 134–139
Hammoumi S., Payen A., Favre J.D., Balmes J.L., Benard J.Y., Husson M., et al., Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence?, Alcohol, 1999, 17, 107–112
Rasmussen H., Bagger Y., Tanko L.B., Christiansen C., Werge T., Lack of association of the serotonin transporter gene promoter region polymorphism, 5-HTTLPR, including rs25531 with cigarette smoking and alcohol consumption, Am. J. Med. Genet. B Neuropsychiatr. Genet., 2009, 150B, 575–580
Shin S., Stewart R., Ferri C.P., Kim J.M., Shin I.S., Kim S.W., et al., An investigation of associations between alcohol use disorder and polymorphisms on ALDH2, BDNF, 5-HTTLPR, and MTHFR genes in older Korean men, Int. J. Geriatr. Psychiatry, 2010, 25, 441–448
McHugh R.K., Hofmann S.G., Asnaani A., Sawyer A.T., Otto M.W., The serotonin transporter gene and risk for alcohol dependence: a metaanalytic review, Drug Alcohol Depend., 2010, 108, 1–6
Herman A.I., Conner T.S., Anton R.F., Gelernter J., Kranzler H.R., Covault J., Variation in the gene encoding the serotonin transporter is associated with a measure of sociopathy in alcoholics, Addict. Biol., 2011, 16, 124–132
Belsky J., Pluess M., Beyond diathesis stress: differential susceptibility to environmental influences, Psychol. Bull., 2009, 135, 885–908
Boyce W.T., Ellis B.J., Biological sensitivity to context: I. an evolutionary-developmental theory of the origins and functions of stress reactivity, Dev. Psychopathol., 2005, 17, 271–301
Beaver K.M., Belsky J., Gene-environment interaction and the intergenerational transmission of parenting: testing the differential-susceptibility hypothesis, Psychiatr. Q., 2012, 83, 29–40
Caspi A., Sugden K., Moffitt T.E., Taylor A., Craig I.W., Harrington H., et al., Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene, Science, 2003, 301, 386–389
Karg K., Burmeister M., Shedden K., Sen S., The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation, Arch. Gen. Psychiatry, 2011, 68, 444–454
Enoch M.A., The influence of gene-environment interactions on the development of alcoholism and drug dependence, Curr. Psychiatry Rep., 2012, 14, 150–158
Jose B.S., van Oers H.A., van de Mheen H.D., Garretsen H.F., Mackenbach J.P., Stressors and alcohol consumption, Alcohol Alcohol., 2000, 35, 307–312
Ferguson B., Hunter J.E., Luty J., Street S.L., Woodall A., Grant K.A., Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques, Genes Brain Behav., 2012, [Epub ahead of print], doi: 10.1111/j.1601-183X.2012.00856.x
Barr C.S., Newman T.K., Becker M.L., Champoux M., Lesch K.P., Suomi S.J., et al., Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress, Alcohol. Clin. Exp. Res., 2003, 27, 812–817
Nilsson K.W., Sjoberg R.L., Damberg M., Alm P.O., Ohrvik J., Leppert J., et al., Role of the serotonin transporter gene and family function in adolescent alcohol consumption, Alcohol. Clin. Exp. Res., 2005, 29, 564–570
Barr C.S., Newman T.K., Lindell S., Shannon C., Champoux M., Lesch K.P., et al., Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates, Arch. Gen. Psychiatry, 2004, 61, 1146–1152
Vaske J., Newsome J., Wright J.P., Interaction of serotonin transporter linked polymorphic region and childhood neglect on criminal behavior and substance use for males and females, Dev. Psychopathol., 2012, 24, 181–193
Dick D.M., Plunkett J., Hamlin D., Nurnberger J.Jr., Kuperman S., Schuckit M., et al. Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample, Psychiatr. Genet., 2007, 17, 35–38
Laucht M., Treutlein J., Schmid B., Blomeyer D., Becker K., Buchmann A.F., et al., Impact of psychosocial adversity on alcohol intake in young adults: moderation by the LL genotype of the serotonin transporter polymorphism, Biol. Psychiatry, 2009, 66, 102–109
Covault J., Tennen H., Armeli S., Conner T.S., Herman A.I., Cillessen A.H., et al., Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use, Biol. Psychiatry, 2007, 61, 609–616
Olsson C.A., Byrnes G.B., Lotfi-Miri M., Collins V., Williamson R., Patton C., et al., Association between 5-HTTLPR genotypes and persisting patterns of anxiety and alcohol use: results from a 10-year longitudinal study of adolescent mental health, Mol. Psychiatry, 2005, 10, 868–876
Kranzler H.R., Scott D., Tennen H., Feinn R., Williams C., Armeli S., et al., The 5-HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent, Am. J. Med. Genet. B Neuropsychiatr. Genet., 2012, 159B, 484–490
Kaufman J., Yang B.Z., Douglas-Palumberi H., Crouse-Artus M., Lipschitz D., Krystal J.H., et al., Genetic and environmental predictors of early alcohol use, Biol. Psychiatry, 2007, 61, 1228–1234
Dick D.M., Wang J.C., Plunkett J., Aliev F., Hinrichs A., Bertelsen S., et al., Family-based association analyses of alcohol dependence phenotypes across DRD2 and neighboring gene ANKK1, Alcohol. Clin. Exp. Res., 2007, 31, 1645–1653
Suomi S.J., Risk, resilience, and gene x environment interactions in rhesus monkeys, Ann. NY Acad. Sci., 2006, 1094, 52–62
Barr C.S., Newman T.K., Becker M.L., Parker C.C., Champoux M., Lesch K.P., et al., The utility of the non-human primate; model for studying gene by environment interactions in behavioral research, Genes Brain Behav., 2003, 2, 336–340
O’Malley P.M., Johnston L.D., Epidemiology of alcohol and other drug use among American college students, J. Stud. Alcohol Suppl., 2002, 14, 23–39
Philibert R.A., Sandhu H., Hollenbeck N., Gunter T., Adams W., Madan A., The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies, Am. J. Med. Genet. B Neuropsychiatr. Genet., 2008, 147B, 543–549
Nilsson K.W., Comasco E., Aslund C., Nordquist N., Leppert J., Oreland L., MAOA genotype, family relations and sexual abuse in relation to adolescent alcohol consumption, Addict. Biol., 2011, 16, 347–355
Comasco E., Nordquist N., Leppert J., Oreland L., Kronstrand R., Alling C., et al., Adolescent alcohol consumption: biomarkers PEth and FAEE in relation to interview and questionnaire data, J. Stud. Alcohol Drugs, 2009, 70, 797–804
Comasco E., Berglund K., Oreland L., Nilsson K.W., Why do adolescents drink? Motivational patterns related to alcohol consumption and alcohol-related problems, Subst. Use Misuse, 2010, 45, 1589–1604
Wray N.R., James M.R., Gordon S.D., Dumenil T., Ryan L., Coventry W.L., et al., Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures, Biol. Psychiatry, 2009, 66, 468–476
Richardson D.B., Kaufman J.S., Estimation of the relative excess risk due to interaction and associated confidence bounds, Am. J. Epidemiol., 2009, 169, 756–760
Caspi A., Moffitt T.E., Gene-environment interactions in psychiatry: joining forces with neuroscience, Nat. Rev. Neurosci., 2006, 7, 583–590
Altamura C., Dell’Acqua M.L., Moessner R., Murphy D.L., Lesch K.P., Persico A.M., Altered neocortical cell density and layer thickness in serotonin transporter knockout mice: a quantitation study, Cereb. Cortex, 2007, 17, 1394–1401
Persico A.M., Baldi A., Dell’Acqua M.L., Moessner R., Murphy D.L., Lesch K.P., et al., Reduced programmed cell death in brains of serotonin transporter knockout mice, Neuroreport, 2003, 14, 341–344
Carola V., Pascucci T., Puglisi-Allegra S., Cabib S., Gross C., Effect of the interaction between the serotonin transporter gene and maternal environment on developing mouse brain, Behav. Brain Res., 2011, 217, 188–194
Oreland S., Pickering C., Gokturk C., Oreland L., Arborelius L., Nylander I., Two repeated maternal separation procedures differentially affect brain 5-hydroxytryptamine transporter and receptors in young and adult male and female rats, Brain Res., 2009, 1305 Suppl., S37–S49
Kelai S., Aissi F., Lesch K.P., Cohen-Salmon C., Hamon M., Lanfumey L., Alcohol intake after serotonin transporter inactivation in mice, Alcohol Alcohol., 2003, 38, 386–389
Boyce-Rustay J.M., Wiedholz L.M., Millstein R.A., Carroll J., Murphy D.L., Daws L.C., et al., Ethanol-related behaviors in serotonin transporter knockout mice, Alcohol. Clin. Exp. Res., 2006, 30, 1957–1965
Fahlke C., Berggren U., Berglund K.J., Zetterberg H., Blennow K., Engel J.A., et al., Neuroendocrine assessment of serotonergic, dopaminergic, and noradrenergic functions in alcohol-dependent individuals, Alcohol. Clin. Exp. Res., 2012, 36, 97–103
Berggren U., Eriksson M., Fahlke C., Balldin J., Is long-term heavy alcohol consumption toxic for brain serotonergic neurons? Relationship between years of excessive alcohol consumption and serotonergic neurotransmission, Drug Alcohol Depend., 2002, 65, 159–165
Heinz A., Ragan P., Jones D.W., Hommer D., Williams W., Knable M.B., et al., Reduced central serotonin transporters in alcoholism, Am. J. Psychiatry, 1998, 155, 1544–1549
Murphy J.M., McBride W.J., Lumeng L., Li T.K., Regional brain levels of monoamines in alcohol-preferring and -nonpreferring lines of rats, Pharmacol. Biochem. Behav., 1982, 16, 145–149
Berglund K.J., Balldin J., Berggren U., Gerdner A., Fahlke C., Childhood maltreatment affects the serotonergic system in male alcoholdependent individuals, Alcohol. Clin. Exp. Res., 2013, 37, 757–762
Jonsson E.G., Nothen M.M., Gustavsson J.P., Neidt H., Bunzel R., Propping P., et al., Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationships to monoamine metabolite concentrations in CSF of healthy volunteers, Psychiatry Res., 1998, 79, 1–9
Nielsen D.A., Mazzanti C.M., Linnoila M., Goldman D., Serotonin transporter and seasonal variation in serotonin function, Neuropsychopharmacology, 1999, 20, 507–508
Bennett A.J., Lesch K.P., Heils A., Long J.C., Lorenz J.G., Shoaf S.E., et al., Early experience and serotonin transporter gene variation interact to influence primate CNS function, Mol. Psychiatry, 2002, 7, 118–122
Bah J., Lindstrom M., Westberg L., Manneras L., Ryding E., Henningsson S., et al., Serotonin transporter gene polymorphisms: effect on serotonin transporter availability in the brain of suicide attempters, Psychiatry Res., 2008, 162, 221–229
Cirulli E.T., Goldstein D.B., In vitro assays fail to predict in vivo effects of regulatory polymorphisms, Hum. Mol. Genet., 2007, 16, 1931–1939
Balciuniene J., Emilsson L., Oreland L., Pettersson U., Jazin E., Investigation of the functional effect of monoamine oxidase polymorphisms in human brain, Hum. Genet., 2002, 110, 1–7
Cases O., Seif I., Grimsby J., Gaspar P., Chen K., Pournin S., et al., Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA, Science, 1995, 268, 1763–1766
Szyf M., How do environments talk to genes?, Nat. Neurosci., 2013, 16, 2–4
Weaver I.C., Champagne F.A., Brown S.E., Dymov S., Sharma S., Meaney M.J., et al., Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life, J. Neurosci., 2005, 25, 11045–11054
Kim J.S., Shukla S.D., Acute in vivo effect of ethanol (binge drinking) on histone H3 modifications in rat tissues, Alcohol Alcohol., 2006, 41, 126–132
Park B.Y., Lee B.C., Jung K.H., Jung M.H., Park B.L., Chai Y.G., et al., Epigenetic changes of serotonin transporter in the patients with alcohol dependence: methylation of an serotonin transporter promoter CpG island, Psychiatry Investig., 2011, 8, 130–133
Kinnally E.L., Capitanio J.P., Leibel R., Deng L., LeDuc C., Haghighi F., et al., Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques, Genes Brain Behav., 2010, 9, 575–582
Lindell S.G., Yuan Q., Zhou Z., Goldman D., Thompson R.C., Lopez J.F., et al., The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: potential roles in genetic selection and gene x environment interactions, Dev. Psychopathol., 2012, 24, 1391–400
Duncan L.E., Keller M.C., A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry, Am. J. Psychiatry, 2011, 168, 1041–1049
Dunn E.C., Uddin M., Subramanian S.V., Smoller J.W., Galea S., Koenen K.C., Research review: gene-environment interaction research in youth depression — a systematic review with recommendations for future research, J. Child Psychol. Psychiatry, 2011, 52, 1223–1238
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Todkar, A., Nilsson, K.W., Oreland, L. et al. Serotonin transporter genotype by environment: Studies on alcohol use and misuse in non-human and human primates. Translat.Neurosci. 4, 241–250 (2013). https://doi.org/10.2478/s13380-013-0121-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.2478/s13380-013-0121-6