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Genome-wide association study of pathological gambling

Published online by Cambridge University Press:  23 March 2020

M. Lang ,
T. Leménager ,
F. Streit ,
M. Fauth-Bühler ,
J. Frank ,
D. Juraeva ,
S.H. Witt ,
F. Degenhardt ,
A. Hofmann  and
S. Heilmann-Heimbach
...Show all authors
M. Lang*
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany Contributed equally.
T. Leménager
Affiliation:
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany Contributed equally.
F. Streit
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany
M. Fauth-Bühler
Affiliation:
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany
J. Frank
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany
D. Juraeva
Affiliation:
Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
S.H. Witt
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany
F. Degenhardt
Affiliation:
Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
A. Hofmann
Affiliation:
Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
S. Heilmann-Heimbach
Affiliation:
Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
F. Kiefer
Affiliation:
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany
B. Brors
Affiliation:
Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
H.-J. Grabe
Affiliation:
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Helios Hospital Stralsund, Stralsund, Germany German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany
U. John
Affiliation:
Department of Social Medicine and Prevention, University Medicine Greifswald, Greifswald, Germany Partner site Greifswald, (DZHK) German Centre for Cardiovascular Research, Greifswald, Germany
A. Bischof
Affiliation:
Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck, Germany
G. Bischof
Affiliation:
Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck, Germany
U. Völker
Affiliation:
Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany Partner site Greifswald, (DZHK) German Centre for Cardiovascular Research, Greifswald, Germany
G. Homuth
Affiliation:
Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
M. Beutel
Affiliation:
Kraichtal-Kliniken, Kraichtal, Germany
P.A. Lind
Affiliation:
Department of Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
S.E. Medland
Affiliation:
Department of Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
W.S. Slutske
Affiliation:
Department of Psychological Sciences, University of Missouri, Columbia, MO, USA
N.G. Martin
Affiliation:
Department of Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
H. Völzke
Affiliation:
Institute for Community Medicine, University of Greifswald, Center for Dental, Oral and Maxillofacial Medicine, University of Greifswald, Institute of Social Medicine and Prevention, University of Greifswald, Greifswald, Germany Partner site Greifswald, (DZHK) German Centre for Cardiovascular Research, Greifswald, Germany
M.M. Nöthen
Affiliation:
Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
C. Meyer
Affiliation:
Department of Social Medicine and Prevention, University Medicine Greifswald, Greifswald, Germany Partner site Greifswald, (DZHK) German Centre for Cardiovascular Research, Greifswald, Germany
H.-J. Rumpf
Affiliation:
Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck, Germany
F.M. Wurst
Affiliation:
Centre for Interdisciplinary Addiction Research (CIAR), University of Hamburg, Hamburg, Germany Paracelsus Medical University, Salzburg, Austria
M. Rietschel
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany Contributed equally.
K.F. Mann
Affiliation:
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany Contributed equally.
*
⁎Corresponding author. Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health, J5, 68159 Mannheim, Germany. Tel.: +49 621 1703 6093; fax: +49 621 1703 6065. [email protected]
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Abstract

Background

Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence.

Methods

Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence.

Results

No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value = 6.63 × 10−3); 5′-adenosine monophosphate-activated protein kinase signalling (P-value = 9.57 × 10−3); and apoptosis (P-value = 1.75 × 10−2) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status.

Conclusions

The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

Keywords

GamblingGenome-wideAssociationAddictionGenetics
Type
Original article
Information
European Psychiatry , Volume 36 , August 2016 , pp. 38 - 46
Copyright
Copyright © European Psychiatric Association 2016

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References

Lupi, M., Martinotti, G., Acciavatti, T., Pettorruso, M., Brunetti, M., Santacroce, R.Pharmacological treatments in gambling disorder: a qualitative review. BioMed Res Int 2014;2014:537306. http://dx.doi.org/10.1155/2014/537306.CrossRefGoogle Scholar
Sassen, M., Kraus, L., Bühringer, G.Differences in pathological gambling prevalence estimates: facts or artefacts?. Int J Methods Psychiatr Res 2011;20:e83–e99. http://dx.doi.org/10.1002/mpr.354CrossRefGoogle Scholar
Meyer, C., Bischof, A., Westram, A., Jeske, C., de Brito, S., Glorius, S.The “Pathological Gambling and Epidemiology” (PAGE) study program: design and fieldwork. Int J Methods Psychiatr Res 2015;24:11–31. http://dx.doi.org/10.1002/mpr.1458.CrossRefGoogle Scholar
Grant, J.E., Potenza, M.N., Weinstein, A., Gorelick, D.A.Introduction to Behavioral Addictions. Am J Drug Alcohol Abuse 2010;36:233–241. http://dx.doi.org/10.3109/00952990.2010.491884.CrossRefGoogle Scholar
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American Psychiatric Association; 2013.CrossRefGoogle Scholar
Fattore, L., Melis, M., Fadda, P., Fratta, W.Sex differences in addictive disorders. Front Neuroendocrinol 2014;35:272–284. http://dx.doi.org/10.1016/j.yfrne.2014.04.003.CrossRefGoogle Scholar
Barnes, G.M., Welte, J.W., Tidwell M-CO, , Hoffman, J.H.Gambling and substance use: co-occurrence among adults in a recent general population study in the United States. Int Gambl Stud 2015;15:55–71. http://dx.doi.org/10.1080/14459795.2014.990396.CrossRefGoogle Scholar
Kastirke, N., Rumpf, H.-J., John, U., Bischof, A., Meyer, C.Demographic risk factors and gambling preference may not explain the high prevalence of gambling problems among the population with migration background: results from a German Nationwide Survey. J Gambl Stud 2014. http://dx.doi.org/10.1007/s10899-014-9459-0.CrossRefGoogle Scholar
Bagby, R.M., Vachon, D.D., Bulmash, E.L., Toneatto, T., Quilty, L.C., Costa, P.T.Pathological gambling and the five-factor model of personality. Personal Individ Differ 2007;43:873–880. http://dx.doi.org/10.1016/j.paid.2007.02.011CrossRefGoogle Scholar
Lister, J.J., Milosevic, A., Ledgerwood, D.M.Personality traits of problem gamblers with and without alcohol dependence. Addict Behav 2015;47:48–54. http://dx.doi.org/10.1016/j.addbeh.2015.02.021CrossRefGoogle Scholar
Black, D.W., Coryell, W.H., Crowe, R.R., Shaw, M., McCormick, B., Allen, J.Personality disorders, impulsiveness, and novelty seeking in persons with DSM-IV pathological gambling and their first-degree relatives. J Gambl Stud 2014. http://dx.doi.org/10.1007/s10899-014-9505-yCrossRefGoogle Scholar
Bischof, A., Meyer, C., Bischof, G., Kastirke, N., John, U., Rumpf, H.-J.Comorbid Axis I-disorders among subjects with pathological, problem, or at-risk gambling recruited from the general population in Germany: results of the PAGE study. Psychiatry Res 2013;210:1065–1070. http://dx.doi.org/10.1016/j.psychres.2013.07.026CrossRefGoogle Scholar
Blanco, C., Myers, J., Kendler, K.S.Gambling, disordered gambling and their association with major depression and substance use: a web-based cohort and twin-sibling study. Psychol Med 2012;42:497–508. http://dx.doi.org/10.1017/S0033291711001401CrossRefGoogle Scholar
Slutske, W.S., Eisen, S., True, W.R., Lyons, M.J., Goldberg, J., Tsuang, M.Common genetic vulnerability for pathological gambling and alcohol dependence in men. Arch Gen Psychiatry 2000;57:666–673CrossRefGoogle ScholarPubMed
Slutske, W.S., Ellingson, J.M., Richmond-Rakerd, L.S., Zhu, G., Martin, N.G.Shared genetic vulnerability for disordered gambling and alcohol use disorder in men and women: evidence from a National Community-Based Australian Twin Study. Twin Res Hum Genet 2013;16:525–534. http://dx.doi.org/10.1017/thg.2013.11CrossRefGoogle Scholar
Slutske, W.S., Zhu, G., Meier, M.H., Martin, N.G.Genetic and environmental influences on disordered gambling in men and women. Arch Gen Psychiatry 2010;67:624–630. http://dx.doi.org/10.1001/archgenpsychiatry.2010.51CrossRefGoogle Scholar
Slutske, W.S., Meier, M.H., Zhu, G., Statham, D.J., Blaszczynski, A., Martin, N.G.The Australian Twin Study of Gambling (OZ-GAM): rationale, sample description, predictors of participation, and a first look at sources of individual differences in gambling involvement. Twin Res Hum Genet 2009;12:63–78. http://dx.doi.org/10.1375/twin.12.1.63CrossRefGoogle Scholar
Eisen, S.A., Slutske, W.S., Lyons, M.J., Lassman, J., Xian, H., Toomey, R.The genetics of pathological gambling. Semin Clin Neuropsychiatry 2001;6:195–204CrossRefGoogle ScholarPubMed
Slutske, W.S., Richmond-Rakerd, L.S.A closer look at the evidence for sex differences in the genetic and environmental influences on gambling in the National Longitudinal Study of Adolescent health: from disordered to ordered gambling: a twin study of gambling in Add Health redux. Addiction 2014;109:120–127. http://dx.doi.org/10.1111/add.12345CrossRefGoogle Scholar
Lind, P.A., Zhu, G., Montgomery, G.W., Madden, P.A.F., Heath, A.C., Martin, N.G.Genome-wide association study of a quantitative disordered gambling trait. Addict Biol 2013;18:511–522. http://dx.doi.org/10.1111/j.1369-1600.2012.00463.CrossRefGoogle Scholar
Eisenegger, C., Knoch, D., Ebstein, R.P., Gianotti, L.R.R., Sándor, P.S., Fehr, E.Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior. Biol Psychiatry 2010;67:702–706. http://dx.doi.org/10.1016/j.biopsych.2009.09.021CrossRefGoogle Scholar
Lobo, D.S.S., Aleksandrova, L., Knight, J., Casey, D.M., el-Guebaly, N., Nobrega, J.N.Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models. Mol Psychiatry 2015;20:1002–1010. http://dx.doi.org/10.1038/mp.2014.113CrossRefGoogle Scholar
Lobo, D.S.S., Souza, R.P., Tong, R.P., Casey, D.M., Hodgins, D.C., Smith, G.J.Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects. Biol Psychol 2010;85:33–37. http://dx.doi.org/10.1016/j.biopsycho.2010.04.008CrossRefGoogle Scholar
Wilson, D., da Silva Lobo, D.S., Tavares, H., Gentil, V., Vallada, H.Family-based association analysis of serotonin genes in pathological gambling disorder: evidence of vulnerability risk in the 5HT-2A receptor gene. J Mol Neurosci MN 2013;49:550–553. http://dx.doi.org/10.1007/s12031-012-9846-xCrossRefGoogle Scholar
Gyollai, A., Griffiths, M.D., Barta, C., Vereczkei, A., Urbán, R., Kun, B.The genetics of problem and pathological gambling: a systematic review. Curr Pharm Des 2014;20:3993–3999CrossRefGoogle ScholarPubMed
Slutske, W.S., Genetics of Disordered Gambling. Chichester, UK: John Wiley & Sons, Ltd., eLS; 2013.CrossRefGoogle ScholarPubMed
Ibáñez, A., Blanco, C., Perez de Castro, I., Fernandez-Piqueras, J., Sáiz-Ruiz, J.Genetics of pathological gambling. J Gambl Stud 2003;19:11–22CrossRefGoogle ScholarPubMed
Potenza, M.N.Neurobiology of gambling behaviors. Curr Opin Neurobiol 2013;23:660–667. http://dx.doi.org/10.1016/j.conb.2013.03.004CrossRefGoogle Scholar
Fauth-Bühler, M., Mann, K., Potenza, M.N.Pathological gambling: a review of the neurobiological evidence relevant for its classification as an addictive disorder. Addict Biol 2016. http://dx.doi.org/10.1111/adb.12378CrossRefGoogle Scholar
Takeuchi, F., Isono, M., Nabika, T., Katsuya, T., Sugiyama, T., Yamaguchi, S.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;75:911–918CrossRefGoogle Scholar
Lesieur, H.R., Blume, S.B.The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers. Am J Psychiatry 1987;144:1184–1188Google ScholarPubMed
Wittchen, H.-U., Zaudig, M., Fydrich, T.Strukturiertes Klinisches Interview für DSM-IV Göttingen; Hogrefe: 1997.Google Scholar
Volzke, H., Alte, D., Schmidt, C.O., Radke, D., Lorbeer, R., Friedrich, N.Cohort profile: the study of health in pomerania. Int J Epidemiol 2011;40:294–307. http://dx.doi.org/10.1093/ije/dyp394CrossRefGoogle Scholar
Mishra, A., Macgregor, S.VEGAS2: software for more flexible gene-based testing. Twin Res Hum Genet 2015;18:86–91. http://dx.doi.org/10.1017/thg.2014.79CrossRefGoogle Scholar
Deelen, J., Uh, H.-W., Monajemi, R., van Heemst, D., Thijssen, P.E., Böhringer, S.Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways. Age Dordr Neth 2013;35:235–249. http://dx.doi.org/10.1007/s11357-011-9340-3CrossRefGoogle Scholar
Kanehisa, M., Goto, S.KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000;28:27–30CrossRefGoogle ScholarPubMed
http://www.genome.jp/kegg/pathway.html. KEGG n.d.Google Scholar
Croft, D., Mundo, A.F., Haw, R., Milacic, M., Weiser, J., Wu, G.The reactome pathway knowledgebase. Nucleic Acids Res 2014;42:D472–D477. http://dx.doi.org/10.1093/nar/gkt1102CrossRefGoogle Scholar
http://geneontology.org/page/go-database. Reactome n.d.Google Scholar
Gene Ontology Consortium Gene Ontology Consortium: going forward. Nucleic Acids Res 2015;43:D1049–D1056. http://dx.doi.org/10.1093/nar/gku1179CrossRefGoogle Scholar
International Schizophrenia Consortium, , Purcell, S.M., Wray, N.R., Stone, J.L., Visscher, P.M., O’Donovan, M.C.Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748–752. http://dx.doi.org/10.1038/nature08185CrossRefGoogle Scholar
Frank, J., Cichon, S., Treutlein, J., Ridinger, M., Mattheisen, M., Hoffmann, P.Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addict Biol 2012;17:171–180. http://dx.doi.org/10.1111/j.1369-1600.2011.00395.xCrossRefGoogle Scholar
Liinamaa, M.J., Hannuksela, M.L., Kesäniemi, Y.A., Savolainen, M.J.Altered transfer of cholesteryl esters and phospholipids in plasma from alcohol abusers. Arterioscler Thromb Vasc Biol 1997;17:2940–2947CrossRefGoogle ScholarPubMed
Mäkelä, S.M., Jauhiainen, M., Ala-Korpela, M., Metso, J., Lehto, T.M., Savolainen, M.J.HDL2 of heavy alcohol drinkers enhances cholesterol efflux from raw macrophages via phospholipid-rich HDL 2b particles. Alcohol Clin Exp Res 2008;32:991–1000. http://dx.doi.org/10.1111/j.1530-0277.2008.00660.xCrossRefGoogle Scholar
Chasman, D.I., Paré, G., Mora, S., Hopewell, J.C., Peloso, G., Clarke, R.Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet 2009;5:e1000730. http://dx.doi.org/10.1371/journal.pgen.1000730CrossRefGoogle Scholar
Inouye, M., Ripatti, S., Kettunen, J., Lyytikäinen, L.-P., Oksala, N., Laurila, P-P.Novel loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. PLoS Genet 2012;8:e1002907. http://dx.doi.org/10.1371/journal.pgen.1002907CrossRefGoogle Scholar
Lee, A.M., Messing, R.O.Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens. Proc Natl Acad Sci U S A 2011;108:16080–16085. http://dx.doi.org/10.1073/pnas.1106277108CrossRefGoogle Scholar
Kalkhoven, C., Sennef, C., Peeters, A., van den Bos, R.Risk-taking and pathological gambling behavior in Huntington's disease. Front Behav Neurosci 2014;8:103. http://dx.doi.org/10.3389/fnbeh.2014.00103CrossRefGoogle Scholar
Campbell, M.C., Stout, J.C., Finn, P.R.Reduced autonomic responsiveness to gambling task losses in Huntington's disease. J Int Neuropsychol Soc 2004;10:239–245. http://dx.doi.org/10.1017/S1355617704102105CrossRefGoogle Scholar
Busemeyer, J.R., Stout, J.C.A contribution of cognitive decision models to clinical assessment: decomposing performance on the Bechara gambling task. Psychol Assess 2002;14:253–262CrossRefGoogle ScholarPubMed
Brevers, D., Koritzky, G., Bechara, A., Noël, X.Cognitive processes underlying impaired decision-making under uncertainty in gambling disorder. Addict Behav 2014;39:1533–1536. http://dx.doi.org/10.1016/j.addbeh.2014.06.004CrossRefGoogle Scholar
Hardie, D.G.AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 2011;25:1895–1908. http://dx.doi.org/10.1101/gad.17420111CrossRefGoogle Scholar
Tomita, K., Tamiya, G., Ando, S., Kitamura, N., Koizumi, H., Kato, S.AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res 2005;29:240S–245SCrossRefGoogle ScholarPubMed
Ceni, E., Mello, T., Galli, A.Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J Gastroenterol 2014;20:17756–17772. http://dx.doi.org/10.3748/wjg.v20.i47.17756CrossRefGoogle Scholar
Hassan, M., Watari, H., AbuAlmaaty, A., Ohba, Y., Sakuragi, N.Apoptosis and molecular targeting therapy in cancer. BioMed Res Int 2014;2014:150845. http://dx.doi.org/10.1155/2014/150845CrossRefGoogle Scholar
Quintero, G.C.Role of nucleus accumbens glutamatergic plasticity in drug addiction. Neuropsychiatry Dis Treat 2013;9:1499–1512. http://dx.doi.org/10.2147/NDT.S45963CrossRefGoogle Scholar
Slutske, W.S., Zhu, G., Meier, M.H., Martin, N.G.Disordered gambling as defined by the Diagnostic and Statistical Manual of Mental Disorders and the South Oaks Gambling Screen: evidence for a common etiologic structure. J Abnorm Psychol 2011;120:743–751. http://dx.doi.org/10.1037/a0022879CrossRefGoogle Scholar
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