GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations.

BACKGROUND: Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism. METHODS: This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag single nucleotide polymorphisms were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs. RESULTS: We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism, whereas carriers of the IND allele and either rs29220 homozygote were more resilient. CONCLUSIONS: Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist.

Comparisons of prisoners who make or do not make suicide attempts and further who make one or multiple attempts.

Suicidal behavior among prisoners is a major problem. The objective of this study was to compare prisoners who have made an attempt at suicide vs non-attempters and further to compare single vs multiple suicide attempts. Among 1,537 prisoners, 200 (13%) had a lifetime history of attempting suicide and 92 (6%) had made multiple attempts. Those who had made multiple or single attempts were compared on socio-demographic, developmental, personality, forensic, and psychiatric variables. In a re-analysis we also compared non-attempters with attempters in this larger sample. The comparison showed that prisoners who had made multiple attempts had experienced significantly more childhood trauma, were more introverted, less resilient, had a history of self-mutilation, and had more suicidal ideation. Anger and hostility scores and criminal and violence histories significantly differentiated prisoners who had attempted from those who had never attempted but they did not differentiate multiple from single attempters. Having a history of multiple attempts may be indicative of more severe psychopathology in prisoners, as found in other populations. These findings may be helpful in predicting which prisoner is at increased risk of exhibiting suicidal behavior while incarcerated and after release.

Trait-aggressiveness and impulsivity: role of psychological resilience and childhood trauma in a sample of male prisoners.

BACKGROUND: One of the major challenges for research in the field of human aggression is the need to define the role of personality and trait-like dimensions, such as impulsivity and aggressiveness, in predisposing to violent behavior. AIMS: 1) To determine whether trait- aggressiveness and impulsivity may be associated with socio-demographic, clinical and crime history variables in a sample of male prisoners; 2) to detect any association of those traits with measures of early traumatic experiences and current resilience traits. METHODS: A sample of male prisoners (n = 1356) underwent the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and the Barratt Impulsivity Scale (BIS). Axis I psychiatric disorders were also assessed. Early traumatic experiences and psychological resilience were detected respectively by the Childhood Trauma Questionnaire (CTQ) and the Connor-Davidson Resilience Scale (CD-RISC). Two non-linear logistic regression models were performed to test for the best predictors of trait-aggressiveness and impulsivity. RESULTS: Subjects with a history of substance use disorders and self-mutilation reported both higher BGLHA and BIS scores. Axis I disorders and suicide attempts were associated with aggressiveness, but not to impulsivity. A consistent correlation was found between BGLHA scores and early traumatic experiences. Resilience was positively correlated to impulsivity but not to aggressiveness scores. CONCLUSIONS: Our results support the view that aggressiveness and impulsivity are two different, albeit related trait-like dimensions of personality, having a different relationship with resilience, and, inferentially, a different impact over the development of psychiatric disorders.

Independent effects of 5' and 3' functional variants in the serotonin transporter gene on suicidal behavior in the context of childhood trauma.

The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT). DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers. There were independent G × E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034-rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034-rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12-0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant. Our findings suggest that the 5' and 3'SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals.

Interaction between FKBP5 and childhood trauma and risk of aggressive behavior.

CONTEXT: Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation. OBJECTIVE: To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. DESIGN: Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity. SETTING: Penitentiary District of Abruzzo-Molise in central Italy. PARTICIPANTS: A population of 583 male Italian prisoners recruited between 2005 and 2008. MAIN OUTCOME MEASURES: A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed. RESULTS: Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed. CONCLUSION: These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior.

Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Corticotropin releasing hormone (CRH) regulates the HPA axis and its actions are moderated by a high-affinity binding protein (CRHBP). We hypothesized that CRHBP variation and interaction with childhood trauma might influence suicidal behavior. Moreover, there might be an additive effect with FKPB5, another HPA axis gene previously associated with suicidality in this dataset. African Americans were recruited: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). A total of 474 participants (112 suicide attempters) completed the Childhood Trauma Questionnaire (CTQ). Haplotype-tagging SNPs were genotyped across CRHBP and, for completeness, across CRH, CRHR1 and CRHR2. FKBP5 genotypes were available. Three CRHBP SNPs rs6453267, rs7728378 and rs10474485 showed a nominally significant interaction with the continuous CTQ score to predict suicide attempt; rs7728378 remained significant after FDR correction. There was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 0.35-0.30 in carriers of either the FKBP5 rs3800373 major homozygote or the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes. Individuals without either major homozygote were resilient to the effects of childhood trauma (suicide attempt prevalence 0.24). Main effects of CRHBP rs6453267 and CRHR1 rs9900679, both unique to African ancestry, were detected. CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced childhood trauma.

Medical and psychological risk factors for incident hypertension in type 1 diabetic african-americans.

Objective. To determine risk factors for the development of hypertension among African-Americans living with type 1 diabetes. Methods. African-Americans with type 1 diabetes (n = 483) participated in a 6-year followup. At both baseline and followup blood pressure was measured twice in both sitting and standing positions using a standard protocol. Patients had a structured clinical interview, ocular examination, retinal photographs, and blood and urine assays and completed the Hostility and Direction of Hostility Questionnaire (HDHQ) and the Beck Depression Inventory (BDI). Results. Of the 280 diabetic patients with no hypertension at baseline, 82 (29.3%) subsequently developed hypertension over the 6-year followup. Baseline older age, longer duration of diabetes, family history of hypertension, greater mean arterial blood pressure, overt proteinuria, increasing retinopathy severity, peripheral neuropathy, smoking, and higher hostility scores were significantly associated with the development of hypertension. Multivariate analyses showed that higher hostility scores and overt proteinuria were significantly and independently associated with the development of hypertension in this population. Conclusions. The development of hypertension in African-Americans living with type 1 diabetes appears to be multifactorial and includes both medical (overt proteinuria) as well as psychological (high hostility) risk factors.

Resilience mitigates the suicide risk associated with childhood trauma.

OBJECTIVE: We wished to examine whether resilience might be a protective factor in relation to suicidal behavior. METHOD: To do this resilience was examined in relation to childhood trauma, a well established risk factor for suicidal behavior, in two samples. In a preliminary sample 20 abstinent substance abuse patients who had attempted suicide were matched for age and their score on the Childhood Trauma Questionnaire (CTQ) with 20 substance abuse patients who had never attempted suicide. The two age and CTQ matched attempter (N=20) and non-attempter (N=20) groups were then compared for their scores on the Connor-Davidson Resilience Scale (CD-RISC). In the second sample 166 prisoners who had attempted suicide were matched for age and their scores on the CTQ with 166 prisoners who had never attempted suicide. These two age and CTQ matched attempter (N=166)and non-attempter (N=166) groups were similarly compared for their CD-RISC resilience scores. RESULTS: In the preliminary substance abuse sample, patients who had never attempted suicide (N=20) had significantly higher mean CD-RISC resilience scores than the age and CTQ matched patients who had attempted suicide (N=20). Similarly in the prisoner sample, those who had never attempted suicide (N=166) had significantly higher CD-RISC resilience scores than the age and CTQ matched prisoners who had attempted suicide (N=166). CONCLUSIONS: The results from these two studies suggest that resilience may be a protective factor mitigating the risk of suicidal behavior associated with childhood trauma.

Combination of family history of suicidal behavior and childhood trauma may represent correlate of increased suicide risk.

BACKGROUND: There is a need to try to identify patients at highest risk for suicidal behavior. A family history of suicidal behavior (FHS) and childhood trauma are two important risk factors for suicidal behavior. It was therefore decided to combine them and examine if the combination would identify patients at even increased risk for suicidal behavior. METHODS: Two hundred and eighty one substance dependent patients with a FHS completed the Childhood Trauma Questionnaire (CTQ) and were interviewed about their lifetime history of suicidal behavior. Patients with the combination of a FHS and CTQ score above the mean were examined and compared with FHS patients with a CTQ score below the mean. RESULTS: One hundred and two of the 129 (79.1%) FHS patients with a CTQ score above the mean had attempted suicide. Thirty five of the 40 female (87.5%) FHS patients with a CTQ score above the mean had attempted suicide .Patients with a CTQ score above the mean were found significantly more among FHS patients who had attempted suicide than among FHS patients who had never attempted. FHS attempters with a CTQ score above the mean had a significantly earlier age of first attempting and had made more attempts than FHS attempters with a CTQ score below the mean. LIMITATIONS: Childhood trauma data derived from self-report questionnaire. No consistent collateral information about FHS. CONCLUSION: The combination of a FHS and childhood trauma may represent a correlate of increased risk of attempting suicide, attempting earlier, and making more attempts.

Insomnia and suicidal behaviour in prisoners.

Insomnia has been associated with suicidality. Prisoners have an increased risk of both insomnia and suicidal behaviour. Therefore, it was decided to examine for a relationship between insomnia and suicidal behaviour in a large group of 1420 prisoners. Prisoners had a semi-structured psychiatric interview, which included the Hamilton Depression Rating Scale (HDRS), and completed the Childhood Trauma Questionnaire, Eysenck Personality Questionnaire, Spielberg Anger Expression Inventory and Connor-Davidson Resilience Scale. It was found that 568 (61.2%) of the prisoners scored in the insomnia cluster of the HDRS and that 183 (12.8%) had attempted suicide. Regression analyses showed that insomnia was significantly and independently associated with a lifetime history of attempting suicide. Insomnia was also significantly related to actual suicidality. After controlling for confounders, axis 1 psychiatric disorder, childhood trauma, neuroticism, low resilience, and anger were significantly associated with insomnia in male prisoners. These data suggest the possibility of a relationship between insomnia and suicidality in prisoners. Assessing insomnia may be helpful when evaluating the risk of suicidality in prisoners.

Childhood trauma and depressive symptoms in type 1 diabetes.

BACKGROUND: To examine the relationship of childhood trauma to depressive symptoms in type 1 diabetes, a chronic disease in which the frequency of depression is increased. METHOD: One hundred fifty African American patients with type 1 diabetes seen between August 1993 and January 1998 completed the Beck Depression Inventory and Childhood Trauma Questionnaire. They were also genotyped for a functional serotonin transporter promoter polymorphism (5-HTTLPR) that modulates resiliency. Patients who had Beck Depression Inventory scores above and below 14 were compared. RESULTS: Diabetic patients who had Beck Depression Inventory scores ≥ 14 had experienced significantly more different types of childhood trauma than those with Beck Depression Inventory scores < 14 (P < .001), independent of potential interaction with 5-HTTLPR genotype. CONCLUSIONS: Childhood trauma appears to be a determinant of depressive symptoms in type 1 diabetes, independently of genotype of a functional locus modulating resiliency.

Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations.

BACKGROUND: Ethanol is metabolized by 2 rate-limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation. METHODS: Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case control sample sizes were the following: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; and Southwestern American (SW) Indians: 317, 72. RESULTS: In all four populations, as well as HapMap populations, 5 haplotype blocks were identified across the ADH gene cluster: (i) ADH5-ADH4; (ii) ADH6-ADH1A-ADH1B; (iii) ADH1C; (iv) intergenic; (v) ADH7. The ALDH1A1 gene was defined by 4 blocks and ALDH2 by 1 block. No haplotype or SNP association results were significant after correction for multiple comparisons; however, several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3' UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317, respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. CONCLUSIONS: The systematic evaluation of alcohol-metabolizing genes in four non-East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study.

Controlling access to suicide means.

BACKGROUND: Restricting access to common means of suicide, such as firearms, toxic gas, pesticides and other, has been shown to be effective in reducing rates of death in suicide. In the present review we aimed to summarize the empirical and clinical literature on controlling the access to means of suicide. METHODS: This review made use of both MEDLINE, ISI Web of Science and the Cochrane library databases, identifying all English articles with the keywords "suicide means", "suicide method", "suicide prediction" or "suicide prevention" and other relevant keywords. RESULTS: A number of factors may influence an individual's decision regarding method in a suicide act, but there is substantial support that easy access influences the choice of method. In many countries, restrictions of access to common means of suicide has lead to lower overall suicide rates, particularly regarding suicide by firearms in USA, detoxification of domestic and motor vehicle gas in England and other countries, toxic pesticides in rural areas, barriers at jumping sites and hanging, by introducing "safe rooms" in prisons and hospitals. Moreover, decline in prescription of barbiturates and tricyclic antidepressants (TCAs), as well as limitation of drugs pack size for paracetamol and salicylate has reduced suicides by overdose, while increased prescription of SSRIs seems to have lowered suicidal rates. CONCLUSIONS: Restriction to means of suicide may be particularly effective in contexts where the method is popular, highly lethal, widely available, and/or not easily substituted by other similar methods. However, since there is some risk of means substitution, restriction of access should be implemented in conjunction with other suicide prevention strategies.

The influence of childhood trauma on the onset and repetition of suicidal behavior: an investigation in a high risk sample of male prisoners.

BACKGROUND AND AIMS: Childhood trauma is a well recognized risk factor for attempting suicide. However, its relationship to the age of onset of first suicide attempt and the repetition of attempts has been little studied. METHODS: One thousand five hundred and fifty-three prisoners underwent a psychiatric interview which included the Brown-Goodwin Lifetime History of Aggression (BGHA) interview. The prisoners completed the Childhood Trauma Questionnaire (CTQ) and the Buss-Durkee Hostility Inventory (BDHI). RESULTS: Two hundred prisoners (12.9%) had a history of attempting suicide. Subjects who had attempted suicide had significantly higher CTQ scores than subjects who had never attempted. Childhood traumas were also significantly associated with the early onset of suicidal behavior, while repeated attempts were predicted by sexual abuse only. Early suicidal behavior was further associated with young age, psychiatric disease, aggressive traits and violent behavior. Early age at onset of suicidal behavior was also associated with repetition of suicide attempts. Repetition of suicide attempt was further associated with other self-injurious behaviors (self-harm). CONCLUSIONS: These results confirm that a history of attempting suicide is frequent among prisoners. Childhood trauma is a risk factor not only for suicidal behavior but also for its early onset as is having a psychiatric disorder and aggressive traits. Sexual abuse may increase the risk for multiple attempts, which strongly correlated with age at onset and other self-harm behaviors.

Self-harm in prisoners.

UNLABELLED: IntroductionSelf-harm is a direct, socially unacceptable,repetitive behavior that causes minor to moderate physical injury without suicidal intent. It is also a significant and growing concern among prison inmates, although it has been rarely studied. In the present study, we aimed to investigate demographic, psychosocial, and clinical variables associated to this critical bahaviour in a high risk sample of 1,555 male prisoners. METHODS: Prisoners were interviewed about their history of self-mutilation, psychiatric history,and forensic history. The prisoners completed the Barratt Impulsivity Scale, Buss-Durkee Hostility Inventory, Eysenck Personality Questionnaire, and Childhood Trauma Questionnaire. RESULTS: Eighteen percent of prisoners had a history of self-harm. They more frequently reported childhood traumas, were more likely to be unmarried, previously imprisoned, tested positive for substance abuse, had a history of suicide attempt, and more likely showed violent tendencies.DiscussionSelf-harm among prisoners is common, being found in almost 20% of the subjects in our sample. Self-mutilation among prisoners appears to be multi-factorial with developmental, socio-demographic, psychiatric, and personality determinants. CONCLUSION: Self-harm is associated with critical behaviors such as violence, substance abuse and suicide attempts, which represent major critical problems in contention environments.

Risk factors for attempting suicide in heroin addicts.

In order to examine risk factors for attempting suicide in heroin dependent patients, a group of 527 abstinent opiate dependent patients had a psychiatric interview and completed the Childhood Trauma Questionnaire. Patients who had or had never attempted suicide were compared on putative suicide risk factors. It was found that 207 of the 527 heroin abusers (39.3%) had attempted suicide. Attempters were younger; more were female, reported childhood trauma, a family history of suicidal behavior, a history of aggression, treatment with antidepressant medication, and alcohol and cocaine dependence. Logistic regression revealed that a family history of suicidal behavior, alcohol dependence, cocaine dependence, and treatment with antidepressant medication were significant predictors of attempting suicide. These results suggest that attempting suicide is common among opiate dependent patients and that both distal and proximal risk factors may play a role.

Childhood trauma and prevalence of cardiovascular disease in patients with type 1 diabetes.

OBJECTIVE: To examine the relationship between childhood trauma and prevalence of cardiovascular disease (CVD) (either coronary disease or stroke) in Type 1 diabetes (DM). METHODS: From an original cohort of 725 African Americana with Type 1 DM, 444 (61.2%) were reexamined as part of a 6-year follow-up. In both examinations, patients underwent a structured clinical interview to determine their medical history and a detailed ocular examination. At follow-up, patients completed the Childhood Trauma Questionnaire, Hostility and Direction of Hostility Questionnaire, and Beck Depression Inventory. Diabetic patients who had CVD and those had not developed CVD at the 6-year follow-up were compared for their experience of childhood trauma at the same time controlling for the presence of known risk factors for CVD. RESULTS: Of the 393 patients at risk, 60 (15.3%) had developed any CVD, 52 (12.9%) had coronary disease, and 16 (3.8%) had a stroke at the 6-year follow-up. On univariate analysis, childhood trauma was significantly associated with 6-year incidence of any CVD (p < .01), coronary disease (p < .05), and stroke (p < .01). Childhood trauma scores were also significantly associated with depression (p < .001) and hostility (p < .001) scores, age (p < .05), and renal disease (p < .05). In primary multivariate analyses, childhood trauma predicted CVD independent of age, body mass index, blood pressure, and proteinuria. Secondary analyses suggested that association between the 6-year incidence of CVD and childhood trauma was also independent of depression ratings. CONCLUSION: Childhood seems to be an independent risk factor for the incidence of CVD in Type 1 DM.

Suicide attempts and ideation in African-American type 1 diabetic patients.

In order to examine suicidality and its correlates in type 1 diabetics 412 African-American type 1 diabetics and 404 African-American controls underwent a semi-structured interview that asked if they had ever attempted suicide. Patients completed the Childhood Trauma Questionnaire (CTQ), Hostility and Direction of Hostility Questionnaire (HDHQ), and Beck Depression Inventory (BDI). Diabetics and controls were compared for their rate of suicide attempt. Diabetic patients who had or had never attempted suicide were compared on socio-demographic and clinical data. It was found that diabetics were 3 to 4 times more likely to attempt suicide than controls (13.3% vs 3.5%, respectively, P<0.001). Diabetic attempters were significantly more likely to be female, depressed and hostile, and to report a history of childhood trauma, smoking, alcohol abuse, and drug abuse than diabetic non-attempters. Multivariate analyses showed that female sex, severity of childhood abuse, history of alcohol abuse, and depression were significantly and independently associated with having attempted suicide. These results suggest that African-Americans with type 1 diabetes have a raised risk of attempting suicide. Suicide risk in diabetics appears to be multifactorial and includes gender, developmental, personality, psychiatric, and substance abuse determinants.

Increased BDNF promoter methylation in the Wernicke area of suicide subjects.

CONTEXT: Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. OBJECTIVES: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. DESIGN: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. SETTING: Academic medical center. PATIENTS OR OTHER PARTICIPANTS: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. MAIN OUTCOME MEASURES: The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area. RESULTS: Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). Most of the CpG sites lying in the -300/+500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels. CONCLUSIONS: BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.