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Association study between the corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar disorder

Published online by Cambridge University Press:  16 April 2020

Vincenzo De Luca ,
Subi Tharmalingam  and
James L. Kennedy
Vincenzo De Luca*
Affiliation:
Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street, R-30, Toronto, Ontario, M5T 1R8, Canada Department of Neuroscience, University of Naples, Federico II, Italy
Subi Tharmalingam
Affiliation:
Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street, R-30, Toronto, Ontario, M5T 1R8, Canada
James L. Kennedy
Affiliation:
Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street, R-30, Toronto, Ontario, M5T 1R8, Canada
*
*Corresponding author. Neurogenetics Section, CAMH, Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8, Canada. Tel.: +1 416 5358501x4421; fax: +1 416 979 4666. E-mail address: vincenzo_deluca@camh.net (V. De Luca).
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Abstract

Family, adoption and twin studies show that genetics influences suicidal behavior, but does not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic–pituitary–adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, that are common features in Bipolar Disorder (BD). CRH is a hypothalamic factor that stimulates the pituitary gland. Two CRH receptors are known, CRHR1 and CRHR2. To search for markers conferring genetic susceptibility to suicide, we typed three polymorphisms of the CRHR2 gene, CRHR2(CA), CRHR2(GT), and CRHR2(GAT), in 312 families where at least one subject had DSM-IV bipolar disorder. Family based association analyses in the suicide attempters using FBAT yielded no difference in the distribution of the alleles for all three markers. HBAT analysis for quantitative measures on suicide-related traits showed association between haplotype 5-2-3 and higher severity. The current results show that haplotype variation at the CRHR2 locus is associated with suicidal behaviour. This is to our knowledge the first investigation on suicidal behavior and genetic variation at the CRHR2 locus, an important regulator of the HPA axis.

Keywords

Corticotropin-releasing hormoneCRHR2SuicideHaplotypeLinkage
Type
Original article
Information
European Psychiatry , Volume 22 , Issue 5 , July 2007 , pp. 282 - 287
Copyright
Copyright © Elsevier Masson SAS 2007

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References

Austin, M.C., Janosky, J.E., Murphy, H.A.Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men. Mol Psychiatry 2003;8(3):324–332.CrossRefGoogle ScholarPubMed
Baldessarini, R.J., Hennen, J.Genetics of suicide: an overview. Harv Rev Psychiatry 2004;12(1):1–13.Google ScholarPubMed
Bale, T.L., Contarino, A., Smith, G.W., Chan, R., Gold, L.H., Sawchenko, P.E.et al.Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 2000;24(4):410–414.CrossRefGoogle ScholarPubMed
Bissette, G., Klimek, V., Pan, J., Stockmeier, C., Ordway, G.Elevated concentrations of CRF in the locus coeruleus of depressed subjects. Neuropsychopharmacology 2003;28(7):1328–1335.CrossRefGoogle ScholarPubMed
Chen, Y.W., Dilsaver, S.C.Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other axis I disorders. Biol Psychiatry 1996;39(10):896–899.CrossRefGoogle ScholarPubMed
Coste, S.C., Kesterson, R.A., Heldwein, K.A., Stevens, S.L., Heard, A.D., Hollis, J.H.et al.Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 2000;24(4):403–409.CrossRefGoogle ScholarPubMed
Curtis, D., Sham, P.C.Model-free linkage analysis using likelihoods. Am J Hum Genet 1995;57(3):703–716.Google ScholarPubMed
Horvath, S., Xu, X., Lake, S.L., Silverman, E.K., Weiss, S.T., Laird, N.M.Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004;26(1):61–69.CrossRefGoogle ScholarPubMed
Hucks, D., Lowther, S., Crompton, M.R., Katona, C.L., Horton, R.W.Corticotropin-releasing factor binding sites in cortex of depressed suicides. Psychopharmacology (Berl) 1997;134(2):174–178.CrossRefGoogle ScholarPubMed
Jamison, K.R.Suicide and bipolar disorder. J Clin Psychiatry 2000;61(Suppl. 9):47–51.Google ScholarPubMed
Lahiri, D.K., Nurnberger, J.I. Jr.A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991;19(19):5444.CrossRefGoogle ScholarPubMed
Liaw, C.W., Lovenberg, T.W., Barry, G., Oltersdorf, T., Grigoriadis, D.E., de Souza, E.B.Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 1996;137(1):72–77.CrossRefGoogle ScholarPubMed
Merali, Z., Du, L., Hrdina, P., Palkovits, M., Faludi, G., Poulter, M.O.et al.Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004;24(6):1478–1485.CrossRefGoogle ScholarPubMed
Meyer, A.H., Ullmer, C., Schmuck, K., Morel, C., Wishart, W., Lubbert, H.et al.Localization of the human CRF2 receptor to 7p21-p15 by radiation hybrid mapping and FISH analysis. Genomics 1997;40(1):189–190.CrossRefGoogle ScholarPubMed
Mitchell, A.J.The role of corticotropin releasing factor in depressive illness: a critical review. Neurosci Biobehav Rev 1998;22(5):635–651.CrossRefGoogle ScholarPubMed
Nemeroff, C.B.The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1996;1(4):336–342.Google ScholarPubMed
Nemeroff, C.B., Owens, M.J., Bissette, G., Andorn, A.C., Stanley, M.Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 1988;45(6):577–579.CrossRefGoogle ScholarPubMed
Pfennig, A., Kunzel, H.E., Kern, N., Ising, M., Majer, M., Fuchs, B.et al.Hypothalamus–pituitary–adrenal system regulation and suicidal behavior in depression. Biol Psychiatry 2005;57(4):336–342.CrossRefGoogle ScholarPubMed
Raadsheer, F.C., Hoogendijk, W.J., Stam, F.C., Tilders, F.J., Swaab, D.F.Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60(4):436–444.CrossRefGoogle ScholarPubMed
Roy, A., Segal, N.L., Sarchiapone, M.Attempted suicide among living co-twins of twin suicide victims. Am J Psychiatry 1995;152(7):1075–1076.Google ScholarPubMed
Rydin, E., Asberg, M., Edman, G., Schalling, D.Violent and nonviolent suicide attempts – a controlled Rorschach study. Acta Psychiatr Scand 1990;82(1):30–39.CrossRefGoogle ScholarPubMed
Slatkin, M., Excoffier, L.Testing for linkage disequilibrium in genotypic data using the expectation–maximization algorithm. Heredity 1996;76(Pt 4):377–383.CrossRefGoogle ScholarPubMed
Smith, G.W., Aubry, J.M., Dellu, F., Contarino, A., Bilezikjian, L.M., Gold, L.H.et al.Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 1998;20(6):1093–1102.CrossRefGoogle ScholarPubMed
Timpl, P., Spanagel, R., Sillaber, I., Kresse, A., Reul, J.M., Stalla, G.K.et al.Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 1998;19(2):162–166.CrossRefGoogle ScholarPubMed
Villafuerte, S.M., Del-Favero, J., Adolfsson, R., Souery, D., Massat, I., Mendlewicz, J.et al.Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression. Am J Med Genet 2002;114(2):222–226.CrossRefGoogle Scholar
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