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Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations

Molecular Psychiatry volume 11, pages 301–311 (2006)Cite this article

Abstract

The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P=0.001) and Plains Indian (P=0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (⩾ and P<0.0001) and diplotype (P<0.0001) distributions differed between high HA alcoholics, low HA alcoholics and nonalcoholics. Our results from two independent populations suggest that GAL may contribute to vulnerability to alcoholism, perhaps mediated by dimensional anxiety.

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References

  1. Jacobowitz DM, Kresse A, Skofitsch G . Galanin in the brain: chemoarchitectonics and brain cartography – a historical review. Peptides 2004; 25: 433–464.

    Article  CAS  Google Scholar 

  2. Wrenn CC, Crawley JN . Pharmacological evidence supporting a role for galanin in cognition and affect. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 283–299.

    Article  CAS  Google Scholar 

  3. Crawley JN . Biological actions of galanin. Regul Pept 1995; 59: 1–16.

    Article  CAS  Google Scholar 

  4. Hokfelt T, Broberger C, Diez M, Xu ZQ, Shi T, Kopp J et al. Galanin and NPY, two peptides with multiple putative roles in the nervous system. Horm Metab Res 1999; 31: 330–334.

    Article  CAS  Google Scholar 

  5. Yoshitake T, Wang FH, Kuteeva E, Holmberg K, Yamaguchi M, Crawley JN et al. Enhanced hippocampal noradrenaline and serotonin release in galanin-overexpressing mice after repeated forced swimming test. Proc Natl Acad Sci USA 2004; 101: 354–359.

    Article  CAS  Google Scholar 

  6. Yoshitake T, Reenila I, Ogren SO, Hokfelt T, Kehr J . Galanin attenuates basal and antidepressant drug-induced increase of extracellular serotonin and noradrenaline levels in the rat hippocampus. Neurosci Lett 2003; 339: 239–242.

    Article  CAS  Google Scholar 

  7. Charney DS . Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 2004; 161: 195–216.

    Article  Google Scholar 

  8. Hokfelt T, Xu ZQ, Shi TJ, Holmberg K, Zhang X . Galanin in ascending systems. Focus on coexistence with 5-hydroxytryptamine and noradrenaline. Ann NY Acad Sci 1998; 863: 252–263.

    Article  CAS  Google Scholar 

  9. Ma X, Tong YG, Schmidt R, Brown W, Payza K, Hodzic L et al. Effects of galanin receptor agonists on locus coeruleus neurons. Brain Res 2001; 919: 169–174.

    Article  CAS  Google Scholar 

  10. Sevcik J, Finta EP, Illes P . Galanin receptors inhibit the spontaneous firing of locus coeruleus neurones and interact with mu-opioid receptors. Eur J Pharmacol 1993; 230: 223–230.

    Article  CAS  Google Scholar 

  11. Khoshbouei H, Cecchi M, Morilak DA . Modulatory effects of galanin in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuropsychopharmacology 2002; 27: 25–34.

    Article  CAS  Google Scholar 

  12. Bing O, Moller C, Engel JA, Soderpalm B, Heilig M . Anxiolytic-like action of centrally administered galanin. Neurosci Lett 1993; 164: 17–20.

    Article  CAS  Google Scholar 

  13. Holmes A, Yang RJ, Crawley JN . Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice. J Mol Neurosci 2002; 18: 151–165.

    Article  CAS  Google Scholar 

  14. Kuteeva E, Hokfelt T, Ogren SO . Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter. Regul Pept 2005; 125: 67–78.

    Article  CAS  Google Scholar 

  15. Khoshbouei H, Cecchi M, Dove S, Javors M, Morilak DA . Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol Biochem Behav 2002; 71: 407–417.

    Article  CAS  Google Scholar 

  16. Brady KT, Sonne SC . The role of stress in alcohol use, alcoholism treatment, and relapse. Alcohol Res Health 1999; 23: 263–271.

    CAS  PubMed  Google Scholar 

  17. Breese GR, Chu K, Dayas CV, Funk D, Knapp DJ, Koob GF et al. Stress enhancement of craving during sobriety: a risk for relapse. Alcohol Clin Exp Res 2005; 29: 185–195.

    Article  Google Scholar 

  18. Rada P, Mark GP, Hoebel BG . Galanin in the hypothalamus raises dopamine and lowers acetylcholine release in the nucleus accumbens: a possible mechanism for hypothalamic initiation of feeding behavior. Brain Res 1998; 798: 1–6.

    Article  CAS  Google Scholar 

  19. Leibowitz SF, Avena NM, Chang GQ, Karatayev O, Chau DT, Hoebel BG . Ethanol intake increases galanin mRNA in the hypothalamus and withdrawal decreases it. Physiol Behav 2003; 79: 103–111.

    Article  CAS  Google Scholar 

  20. Lewis MJ, Johnson DF, Waldman D, Leibowitz SF, Hoebel BG . Galanin microinjection in the third ventricle increases voluntary ethanol intake. Alcohol Clin Exp Res 2004; 28: 1822–1828.

    Article  CAS  Google Scholar 

  21. Rada P, Avena NM, Leibowitz SF, Hoebel BG . Ethanol intake is increased by injection of galanin in the paraventricular nucleus and reduced by a galanin antagonist. Alcohol 2004; 33: 91–97.

    Article  CAS  Google Scholar 

  22. Thiele TE, Stewart RB, Badia-Elder NE, Geary N, Massi M, Leibowitz SF et al. Overlapping peptide control of alcohol self-administration and feeding. Alcohol Clin Exp Res 2004; 28: 288–294.

    Article  CAS  Google Scholar 

  23. Evans H, Baumgartner M, Shine J, Herzog H . Genomic organization and localization of the gene encoding human preprogalanin. Genomics 1993; 18: 473–477.

    Article  CAS  Google Scholar 

  24. Kofler B, Lapsys N, Furler SM, Klaus C, Shine J, Iismaa TP . A polymorphism in the 3′ region of the human preprogalanin gene. Mol Cell Probes 1998; 12: 431–432.

    Article  CAS  Google Scholar 

  25. Eckenrode S, Marron MP, Nicholls R, Yang MC, Yang JJ, Guida Fonseca LC et al. Fine-mapping of the type 1 diabetes locus (IDDM4) on chromosome 11q and evaluation of two candidate genes (FADD and GALN) by affected sibpair and linkage-disequilibrium analyses. Hum Genet 2000; 106: 14–18.

    Article  CAS  Google Scholar 

  26. Vrontakis ME, Torsello A, Friesen HG . Galanin. J Endocrinol Invest 1991; 14: 785–794.

    Article  CAS  Google Scholar 

  27. Association AP . Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association Press: Washington DC, revised, 1987.

    Google Scholar 

  28. Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35: 837–844.

    Article  CAS  Google Scholar 

  29. Skinner HA, Sheu WJ . Reliability of alcohol use indices. The Lifetime Drinking History and the MAST. J Stud Alcohol 1982; 43: 1157–1170.

    Article  CAS  Google Scholar 

  30. Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 1998; 55: 989–994.

    Article  CAS  Google Scholar 

  31. Enoch MA, Albaugh B, Virkkunen M, Goldman D . Anxious temperament mediates linkage of GABRA2 haplotypes with alcoholism (submitted).

  32. Spitzer RL, Williams JB, Gibbon M, First MB . The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale, and description. Arch Gen Psychiatry 1992; 49: 624–629.

    Article  CAS  Google Scholar 

  33. Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J et al. The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test–retest reliability. Arch Gen Psychiatry 1992; 49: 630–636.

    Article  CAS  Google Scholar 

  34. Cloninger CR . A systematic method for clinical description and classification of personality variants. A proposal. Arch Gen Psychiatry 1987; 44: 573–588.

    Article  CAS  Google Scholar 

  35. Heath AC, Cloninger CR, Martin NG . Testing a model for the genetic structure of personality: a comparison of the personality systems of Cloninger and Eysenck. J Pers Soc Psychol 1994; 66: 762–775.

    Article  CAS  Google Scholar 

  36. Shi MM, Myrand SP, Bleavins MR, de la Iglesia FA . High throughput genotyping for the detection of a single nucleotide polymorphism in NAD(P)H quinone oxidoreductase (DT diaphorase) using TaqMan probes. Mol Pathol 1999; 52: 295–299.

    Article  CAS  Google Scholar 

  37. Mulligan CJ, Hunley K, Cole S, Long JC . Population genetics, history, and health patterns in native Americans. Annu Rev Genomics Hum Genet 2004; 5: 295–315.

    Article  CAS  Google Scholar 

  38. Stephens M, Donnelly P . A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.

    Article  CAS  Google Scholar 

  39. Long JC, Williams RC, Urbanek M . An E–M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 1995; 56: 799–810.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Clamp M, Cuff J, Searle SM, Barton GJ . The Jalview Java alignment editor. Bioinformatics 2004; 20: 426–427.

    Article  CAS  Google Scholar 

  41. Ke X, Cardon LR . Efficient selective screening of haplotype tag SNPs. Bioinformatics 2003; 19: 287–288.

    Article  CAS  Google Scholar 

  42. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

  43. Shen ES, Meade EH, Perez MC, Deecher DC, Negro-Vilar A, Lopez FJ . Expression of functional estrogen receptors and galanin messenger ribonucleic acid in immortalized luteinizing hormone-releasing hormone neurons: estrogenic control of galanin gene expression. Endocrinology 1998; 139: 939–948.

    Article  CAS  Google Scholar 

  44. Ponchon M, Lause P, Maiter D . In vitro effects of oestradiol on galanin gene expression in rat anterior pituitary cells. J Neuroendocrinol 2000; 12: 559–564.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr Alec Roy for permitting the use of a subset of his African American data set, and to Longina Akhtar and Lori Schwartz for technical assistance. This research was supported in part by the Office of Research on Minority Health and the Intramural Research Programs of the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism, NIH.

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Authors and Affiliations

  1. Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA

    I Belfer, H Hipp, C McKnight, C Evans, B Buzas, A Bollettino & M B Max

  2. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    I Belfer, H Hipp, C McKnight, C Evans, B Buzas, A Bollettino, Q Yuan, D Goldman & M A Enoch

  3. Center for Human Behavior Studies Inc., Weatherford, OK, USA

    B Albaugh

  4. Department of Psychiatry, University of Helsinki, Helsinki, Finland

    M Virkkunen

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  1. I Belfer
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Correspondence to I Belfer.

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Belfer, I., Hipp, H., McKnight, C. et al. Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations. Mol Psychiatry 11, 301–311 (2006). https://doi.org/10.1038/sj.mp.4001768

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