Skip to main content

Advertisement

Log in

Possible involvement of the circadian pathway in alcohol use disorder in a South African adolescent cohort

Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Alcoholism has an estimated heritability of between 40 and 60 % and it is thought that several genes of small effect may contribute to the risk of developing this disorder. Studies of the genetics of alcohol use disorder (AUD) may, however, be confounded by issues of comorbidity. The aim of this investigation was to assess associations between variants in a range of candidate genes and AUD in a unique sample of adolescents without comorbidity. Our cohort consisted of 80 adolescents with an AUD diagnosis and 80 matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 SNPs in 378 candidate genes. Association analysis, gene-based analysis and polygenic scoring were performed. There was no statistical association between any of the investigated SNPs and AUD after correction for multiple testing. However, from the gene-based analysis it was found that the circadian rhythm genes NR1D1 and BHLHE41 are associated with AUD. While preliminary, these data provide some evidence that the circadian pathway may be relevant to the pathophysiology of AUD. Study of early onset non-comorbid populations with AUD may be useful in identifying target genes for study in larger more representative samples.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  • Chawla A, Lazar MA (1993) Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem 268:16265–16269

    PubMed  CAS  Google Scholar 

  • Chen CP, Kuhn P, Advis JP, Sarkar DK (2004) Chronic ethanol consumption impairs the circadian rhythm of pro‐opiomelanocortin and period genes mRNA expression in the hypothalamus of the male rat. J Neurochem 88:1547–1554

    Article  PubMed  CAS  Google Scholar 

  • Duez H, Staels B (2009) Rev-erb-alpha: an integrator of circadian rhythms and metabolism. J Appl Physiol (1985) 107:1972–1980

    Article  CAS  Google Scholar 

  • Enoch MA, Shen PH, Xu K, Hodgkinson C, Goldman D (2006) Using ancestry-informative markers to define populations and detect population stratification. J Psychopharmacol 20:19–26

    Article  PubMed  Google Scholar 

  • Epps C, Holt L (2011) The genetic basis of addiction and relevant cellular mechanisms. Int Anesthesiol Clin 49:3

    Article  PubMed  Google Scholar 

  • Fujimoto K, Hamaguchi H, Hashiba T, Nakamura T, Kawamoto T, Sato F, Noshiro M, Bhawal UK, Suardita K, Kato Y (2007) Transcriptional repression by the basic helix-loop-helix protein Dec2: multiple mechanisms through E-box elements. Int J Mol Med 19:925–932

    PubMed  CAS  Google Scholar 

  • Hatonen T, Forsblom S, Kieseppa T, Lonnqvist J, Partonen T (2008) Circadian phenotype in patients with the co-morbid alcohol use and bipolar disorders. Alcohol Alcohol 43:564–568

    Article  PubMed  Google Scholar 

  • Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K (2002) Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419:841–844

    Article  PubMed  CAS  Google Scholar 

  • Hu M, Lee S, Wang T, Chen S, Chang Y, Chen S, Chu C, Wang C, Lee IH, Yeh TL (2013) Association study of DRD2 and MAOA genes with subtyped alcoholism comorbid with bipolar disorder in Han Chinese. Prog Neuro-Psychopharmacol Biol Psychiatry 40:144–148

    Article  CAS  Google Scholar 

  • Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997) Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatr 36:980–988

    Article  CAS  Google Scholar 

  • Kranzler HR, Gelernter J, Anton RF, Arias AJ, Herman A, Zhao H, Burian L, Covault J (2009) Association of markers in the 3′ region of the GluR5 kainate receptor subunit gene to alcohol dependence. Alcohol Clin Exp Res 33:925–930

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe JR (2009) Circadian polymorphisms associated with affective disorders. J Circadian Rhythms 7:2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu Y, Sato F, Kawamoto T, Fujimoto K, Morohashi S, Akasaka H, Kondo J, Wu Y, Noshiro M, Kato Y (2010) Anti‐apoptotic effect of the basic helix‐loop‐helix (bHLH) transcription factor DEC2 in human breast cancer cells. Gene Cells 15:315–325

    Article  CAS  Google Scholar 

  • Lydall GJ, Bass NJ, McQuillin A, Lawrence J, Anjorin A, Kandaswamy R, Pereira A, Guerrini I, Curtis D, Vine AE, Sklar P, Purcell SM, Gurling HM (2011) Confirmation of prior evidence of genetic susceptibility to alcoholism in a genome-wide association study of comorbid alcoholism and bipolar disorder. Psychiatr Genet 21:294–306

    Article  PubMed  PubMed Central  Google Scholar 

  • Merikangas KR, Swendsen JD (1997) Genetic epidemiology of psychiatric disorders. Epidemiol Rev 19(1):144

    Article  PubMed  CAS  Google Scholar 

  • Merrow M, Spoelstra K, Roenneberg T (2005) The circadian cycle: daily rhythms from behaviour to genes. EMBO Rep 6:930–935

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Preitner N, Damiola F, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260

    Article  PubMed  CAS  Google Scholar 

  • 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 156:34–40

    Article  PubMed  CAS  Google Scholar 

  • Prescott CA, Aggen SH, Kendler KS (2000) Sex-specific genetic influences on the comorbidity of alcoholism and major depression in a population-based sample of US twins. Arch Gen Psychiatry 57:803–811

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, De Bakker PI, Daly MJ (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P, Ruderfer DM, McQuillin A, Morris DW (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–752

    PubMed  CAS  Google Scholar 

  • Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK (1990) Comorbidity of mental disorders with alcohol and other drug abuse. results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264:2511–2518

    Article  PubMed  CAS  Google Scholar 

  • Schumann G, Johann M, Frank J, Preuss U, Dahmen N, Laucht M, Rietschel M, Rujescu D, Lourdusamy A, Clarke T (2008) Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch Gen Psychiatry 65:826–838

    Article  PubMed  CAS  Google Scholar 

  • Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Desrivieres S, Aliev FA, Khan AA, Amin N, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Cauchi S, Cavalcanti-Proenca C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Fernandez-Medarde A, Foroud T, Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Numans ME, Nunez A, Nyholt DR, Onland-Moret CN, Oostra BA, O’Reilly PF, Palkovits M, Penninx BW, Polidoro S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Thorgeirsson TE, Thorsteinsdottir U, Troakes C, Tyrfingsson T, Tonjes A, Uiterwaal CS, Uitterlinden AG, van der Harst P, van der Schouw YT, Staehlin O, Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Whitfield JB, Wichmann EH, Willemsen G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Martin NG, Metspalu A, Doering A, Scott J, Spector TD, Loos RJ, Boomsma DI, Mooser V, Peltonen L, Stefansson K, van Duijn CM, Vineis P, Sommer WH, Kooner JS, Spanagel R, Heberlein UA, Jarvelin MR, Elliott P (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci U S A 108:7119–7124

    Article  PubMed  PubMed Central  Google Scholar 

  • Sobell LC, Sobell MB (1992) Timeline follow-back. In: Measuring alcohol consumption. Springer, pp 41–72

  • Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11:35–42

    Article  PubMed  CAS  Google Scholar 

  • Yasseen B, Kennedy JL, Zawertailo LA, Busto UE (2009) Comorbidity between bipolar disorder and alcohol use disorder: Association of dopamine and serotonin gene polymorphisms. Psychiatr Res

  • Yoon G, Westermeyer J, Kuskowski MA, Nesheim L (2013) Impact of the number of parents with alcohol use disorder on alcohol use disorder in offspring: a population-based study. J Clin Psychiatry 74:795–801

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the assistance of A/Prof. Karestan Koenen and the support of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Research Foundation (NRF), the Medical Research Council of South Africa and the University of Cape Town (UCT). The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shareefa Dalvie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dalvie, S., King, A., Fein, G. et al. Possible involvement of the circadian pathway in alcohol use disorder in a South African adolescent cohort. Metab Brain Dis 31, 75–80 (2016). https://doi.org/10.1007/s11011-015-9744-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-015-9744-3

Keywords

Navigation