Progress in Neuro-Psychopharmacology and Biological Psychiatry
Association of FKBP5 gene haplotypes with completed suicide in the Japanese population
Research Highlights
► Support for association of FKBP5 gene haplotypes with suicide. ► The hypothalamus–pituitary–adrenal (HPA) axis may have a role in suicidal behavior genetically. ► Support for the genetic component of suicidal behavior.
Introduction
Genetic factors have been shown to be involved in suicide attempts and completed suicide by family, twin and adoption studies (Roy et al., 1997). Both genetic and environmental factors likely play a crucial role in the pathogenesis of suicide (Brent and Mann, 2005, World Health Organization, 2005).
The hypothalamus–pituitary–adrenal (HPA) axis has been associated with suicidal behaviors in patients with affective disorders (Dorovini-Zis and Zis, 1987, Coryell, 1990, Roy, 1992, Westrin et al., 1999, Westrin, 2000, Mann, 2003, Pfennig et al., 2005, Mann et al., 2006, Lindqvist et al., 2008a, Lindqvist et al., 2008b) and other psychiatric disorders such as schizophrenia (De Luca et al., 2010). Suicidal patients in diagnostically heterogeneous populations exhibit HPA axis abnormalities, most commonly resistance to the dexamethasone suppression test (DST) (Inder et al., 1997, Van Heeringen et al., 2000, Coryell and Schlesser, 2001). Abnormal DST results predict higher suicide risk in affective disorder patients (Targum et al., 1983, Mann et al., 2006, Jokinen et al., 2007, Jokinen and Nordstrom, 2008, Jokinen and Nordstrom, 2009).
Although most suicide victims and suicide attempters have a diagnosable psychiatric illness (Robins et al., 1959, Beautrais et al., 1996, Shaffer et al., 1996, Van Heeringen, 2003), most patients never attempt suicide, indicating a predisposition to suicidal behaviors that is independent of the main psychiatric disorder (Mann, 1998, Mann, 2003, Rujescu et al., 2007, Ernst et al., 2009, Van Heeringen et al., 2000) including affective disorders. Suicidal depressive patients might represent a distinct subgroup with a different genetic background. The overlapping of genes thought to contribute to suicidal behaviors and affective disorders is incomplete, suggesting that separate genetic factors are involved in each disorder (Pfeffer et al., 1991, Mann, 2003, Jokinen et al., 2007). Studies have shown that HPA axis abnormalities may contribute to suicidal behaviors independently from the main psychiatric disorders (Szigethy et al., 1994, Dumser et al., 1998).
The involvement of the HPA axis in suicidal behaviors is thought to be mediated by stress response mechanisms (Westrin et al., 1999). Although environmental factors such as stressful life events are important components of suicidal behaviors, genetic components might also play a role in modifying suicide risk. HPA axis reactivity is regulated by feedback mechanisms mediated by the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Functional polymorphisms in genes encoding these receptors most likely will affect the HPA axis reactivity, and thus the stress response (De Kloet et al., 2005, De Rijk and De Kloet, 2005, De Rijk and De Kloet, 2008, De Rijk et al., 2008, Claes, 2009, De Rijk, 2009, Van Leeuwen et al., 2010). GR is a nuclear receptor regulated by co-chaperone immunophilin FK506 binding protein 5 (encoded by FKBP5). Given FKBP5 role as a GR regulator, polymorphisms in FKBP5 might also affect HPA axis reactivity.
These findings suggested that polymorphisms in GR, MR (encoded by NR3C1 and NR3C2, respectively), and FKBP5 genes might underlie the contribution of the HPA axis to suicidal behaviors. To confirm this hypothesis, we conducted an association study on these genes in 219 completed suicide victims and 228 age- and gender-matched healthy control subjects. Out of the selected SNPs, rs1360780 and rs3800373 had been reported to affect FKBP5 expression levels by affecting the translation or protein stability (Binder et al., 2004, Tatro et al., 2009a). The rs5525, rs2070951, and rs10052957 have been associated with abnormal DST results (De Rijk et al., 2006, De Rijk, 2009, Van Leeuwen et al., 2010) which might be due to their effect on the receptors expression or affinity.
Section snippets
Subjects
The study population consisted of 219 completed suicide victims (144 males: mean age ± SD, 48.7 ± 16.5; 75 females: 46.1 ± 18.9) on whom autopsies were conducted at the Department of Legal Medicine, Kobe University Graduate School of Medicine. The verdict of “completed suicide” was made through the discussion with the Hyogo Medical Examiner's Office and Department of Legal Medicine, Kobe University Graduate School of Medicine. Because accurate information about the clinical backgrounds of the
Results
No statistically significant differences were observed between the completed suicide and control groups for the mean values of age (t = 1.84, d.f. = 439.0, p = 0.07). The distributions of all eight SNPs in the suicide group and seven of the SNPs (all but rs6196 of the NR3C1 gene) in the control group did not differ from HWE. The one exception might have occurred because our sample selection was too small and did not adequately cover the general population.
We found no significant difference in either
Discussion
Here we report an association between haplotypes of the FKBP5 gene and completed suicide. Polymorphisms in the FKBP5 gene have been reported to be associated with suicidal behaviors (Brent et al., 2010, Roy et al., 2010) and psychiatric disorders closely related to suicide (Binder et al., 2004, Lekman et al., 2008, Sarginson et al., 2009, De Luca et al., 2010). However we failed to detect any association between single polymorphisms and completed suicide. Our findings raise the possibility that
Acknowledgement
This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan.
References (52)
The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders
Psychoneuroendocrynology
(2009)DST abnormality as a predictor of course in major depression
J Affect Disord
(1990)- et al.
Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience
Eur J Pharmacol
(2008) - et al.
Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health
Eur J Pharmacol
(2008) - et al.
Power and sample size calculations for studies involving linear regression
Control Clin Trials
(1998) - et al.
Suicide neurobiology
Prog Neurobiol
(2009) - et al.
Personality and attempted suicide. Analysis of aggression and impulsivity
J Psychiatry Res
(2009) - et al.
Arginine vasopressin is associated with hypercortisolemia and suicide attempts in depression
Biol Psychiatry
(1997) - et al.
HPA axis hyperactivity as suicide predictor in elderly mood disorder inpatients
Psychoneuroendocrinology
(2008) - et al.
HPA axis hyperactivity and attempted suicide in young adult mood disorder inpatients
J Affect Disord
(2009)
DST non-suppression predicts suicide after attempted suicide
Psychiatry Res
The FKBP5-gene in depression and treatment response—an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) cohort
Biol Psychiatry
Salivary cortisol and suicidal behavior—a follow-up study
Psychoneuroendocrin
Suicidal behavior and hypothalamic–pituitary–adrenocortical axis indices in child psychiatric inpatients
Biol Psychiatry
Hypothalamus–pituitary–adrenal system regulation and suicidal behavior in depression
Biol Psychiatry
Hypothalamic–pituitary–adrenal axis function and suicidal behavior in depression
Biol Psychiatry
Adrenal weight and morphology in victims of completed suicide
Biol Psychiatry
Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder
Brain Res
Cortisol in violent suicidal behaviour: association with personality and monoaminergic activity
J Affect Disord
Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone
Psychoneuroendocrin
Stress system alterations and mood disorders in suicidal patients. A review
Biomed Pharmacother
Alterations of corticotrophin releasing hormone (CRH) and neuropeptide Y (NPY) plasma levels in mood disorder patients with a recent suicide attempt
Eur Neuropsychopharmacol
Haploview: analysis and visualization of LD and haplotype maps
Bioinformatics
Prevalence and comorbidity of mental disorders in persons making serious suicide attempts: a case–control study
Am J Psychiatry
Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment
Nat Gen
Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults
JAMA
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2021, Brain Research BulletinCitation Excerpt :Due to the function of FKBP51 protein, there is an increasing interest of the possible association between single-nucleotide polymorphisms (SNP’s) in FKBP5 gene and suicide (Hernandez-Diaz et al., 2019). Several genetic association studies have suggested that SNP’s in FKBP5 gene are associated with suicide attempt, including rs4713916, rs4713902, rs1360780, rs9296158 and rs3800373, as well as their haplotypes in populations of different origins (Brent et al., 2010; Leszczynska-Rodziewicz et al., 2014; Supriyanto et al., 2011). In this idea, the rs1360780 T allele has been associated with a greater induction of FKBP5 mRNA, which is mediated by allele-specific differences observed in the three-dimensional DNA conformation.
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2019, Psychiatry ResearchCitation Excerpt :The cases were confirmed using DMS-IV, SCID-I, ICD-10 and BDI scales and 6 studies adopted Real-time PCR as the detection method. For suicidal behavior we included three cases-control studies (Supriyanto et al., 2011; Fudalej et al., 2015; Yeo et al., 2017); the which were confirmed using DMS-IV and ICD-10 scales; Real-time PCR as the detection method was used in the three studies. Tables 1 and 2 list the essential features of the studies included in this meta-analysis.
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2017, Behavioural Brain ResearchCitation Excerpt :Likewise, Roy et al. [46] analyzed an African-American population and found that carriers of polymorphism rs3800373 had high suicide attempt rate (0.35), in comparison with patients exposed to life adversities [46]. On the other hand, Supriyanto et al. [45] found a significant association between the haplotypes rs3800373TT and rs1360780TC in FKBP5 with suicidal behavior in Japanese population (p < 0.05 for each haplotype) [45]. The number of cases (sample size) for studies that associated the FKBP5 gene with suicidal behavior ranged from 18 to 563.
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