Dataset Information

Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.

ABSTRACT: A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported.To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci.Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design.Inpatients and screened control subjects.The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively.Blood or saliva samples were collected from each participant for DNA extraction and genotyping.Associations of SNPs in BDNF and NTRK2 with SA and MDD.Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10(-7) for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes.Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.

SUBMITTER: Kohli MA

PROVIDER: S-EPMC3696349 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.

Kohli Martin A MA Salyakina Daria D Pfennig Andrea A Lucae Susanne S Horstmann Sonja S Menke Andreas A Kloiber Stefan S Hennings Johannes J Bradley Bekh B BB Ressler Kerry J KJ Uhr Manfred M Müller-Myhsok Bertram B Holsboer Florian F Binder Elisabeth B EB

Archives of general psychiatry 20100201 4

<h4>Context</h4>A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported.<h4>Objective</h4>To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for sui ...[more]

PMID: 20124106

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Project description:Suicidal behavior (SB) has a complex etiology of genes, environment or both. One of the genetic components in SB could be copy number variations (CNVs), since CNVs are implicated in a range of neurodevelopmental disorders. However, a recently published genome-wide and case-control study failed to observe a significant role of CNVs in SB (see E-MTAB-3519). Here we complement those initial observations by conducting a brief CNV-association study, for the first time in a family-based trio-sample with severe suicide attempt (SA) outcome in offspring (n=660 trios; the \GISS\ sample, see http://www.ncbi.nlm.nih.gov/pubmed/23422793 and refs therein). For association testing, we here used the FBAT-CNV methodology (http://www.ncbi.nlm.nih.gov/pubmed/18228561), which allows for CNV association testing directly on the raw intensity values (Illumina \log R ratio\), evaluating any type of CNVs (e.g. de novo or inherited) without reliance on CNV calling algorithms and robust to control selection biases. Here we have deposited these raw logR-values for 88,450 on-chip CNV-loci of the HumanOmni1-Quad_v1 chip, arranged in a standard pedigree format used as input for FBAT-CNV analysis in SVS software (goldenhelix.com): column 1 is the family ID, column 2 is the Subject type (1 = offspring, 2 = mother, 3 = father), column 3 is the father ID (? for missing), column 4 is the mother ID (? for missing), column 5 is the sex (1 = female, 0 = male), column 6 is the affection status (1 = suicide attempt, 0 = not affected) and columns 7 and onward are the logR-values for each CNV-loci as is listed in the header row. We observed experiment-wide significant association (P ≤ 5.6 x 10-7) of two proximal CNVs at chromosome 14 (Illumina markers cnvi0108946 and cnvi0118308, with NCBI 36.3 start positions 22794779 and 22582820). However, these CNV-associations mapped to T-cell receptor regions, and therefore most likely reflect inter-individual variation in somatic rearrangements occurring in white blood cells (as our source of DNA was blood), rather than association with SA. In conclusion, our results did not suggest any major role of CNVs in SA etiology, in line with the results of the recent case-control study (see E-MTAB-3519).

Project description:BackgroundRates of suicide are increasing in the US. Although psychiatric disorders are associated with suicide risk, there is a dearth of epidemiological research on the relationship between suicide attempts (SAs) and eating disorders (EDs). The study therefore aimed to examine prevalence and correlates of SAs in DSM-5 EDs-anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED)-in a nationally representative sample of US adults. In addition, prevalence and correlates of SAs were examined in the two subtypes of AN-restricting (AN-R) and binge/purge (AN-BP) types.MethodsThe study included 36,171 respondents in the Third National Epidemiological Survey on Alcohol and Related Conditions (NESARC-III) who completed structured diagnostic interviews (AUDADIS-5) and answered questions regarding SA histories and psychosocial impairment associated with EDs. We evaluated lifetime prevalence of SA, psychosocial impairment, clinical profiles, and psychiatric comorbidity in adults with EDs with and without SA histories, and temporal relationships between age onset of SA and EDs.ResultsPrevalence estimates of suicide attempts were 24.9% (for AN), 15.7% (for AN-R), 44.1% (for AN-BP), 31.4% (for BN), and 22.9% (for BED). Relative to respondents without specific EDs, adjusted odds ratios (AORs) of SAs were significantly greater in all EDs: AN = 5.40 (95% confidence intervals [CIs] = 3.80-7.67), AN-R = 3.16 (95% CIs = 1.82-5.42), AN-BP = 12.09 (95% CIs = 6.29-23.24), BN = 6.33 (95% CIs = 3.39-11.81), and BED = 4.83 (95% CIs = 3.54-6.60). Among those with SA history, mean age at first SA and number of SAs were not significantly different across the specific EDs. SA was associated with significantly earlier ED onset in BN and BED, longer duration of AN but shorter duration of BN, greater psychosocial impairment in AN and BN, and with significantly increased risk for psychiatric disorder comorbidity across EDs. Onset of BED was significantly more likely to precede SA (71.2%) but onsets of AN (50.4%) and BN (47.6%) were not.ConclusionsUS adults with lifetime DSM-5 EDs have significantly elevated risk of SA history. Even after adjusting for sociodemographic factors, those with lifetime EDs had a roughly 5-to-6-fold risk of SAs relative to those without specific EDs; the AN binge/purge type had an especially elevated risk of SAs. SA history was associated with distinctively different clinical profiles including greater risk for psychosocial impairment and psychiatric comorbidity. These findings highlight the importance of improving screening for EDs and for suicide histories.

Project description:ImportanceMental health of soldiers is adversely affected by the death and injury of other unit members, but whether risk of suicide attempt is influenced by previous suicide attempts in a soldier's unit is unknown.ObjectiveTo examine whether a soldier's risk of suicide attempt is influenced by previous suicide attempts in that soldier's unit.Design, setting, and participantsUsing administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (STARRS), this study identified person-month records for all active-duty, regular US Army, enlisted soldiers who attempted suicide from January 1, 2004, through December 31, 2009 (n = 9650), and an equal-probability sample of control person-months (n = 153 528). Data analysis was performed from August 8, 2016, to April 10, 2017.Main outcomes and measuresLogistic regression analyses examined the number of past-year suicide attempts in a soldier's unit as a predictor of subsequent suicide attempt, controlling for sociodemographic features, service-related characteristics, prior mental health diagnosis, and other unit variables, including suicide-, combat-, and unintentional injury-related unit deaths. The study also examined whether the influence of previous unit suicide attempts varied by military occupational specialty (MOS) and unit size.ResultsOf the final analytic sample of 9512 enlisted soldiers who attempted suicide and 151 526 control person-months, most were male (86.4%), 29 years or younger (68.4%), younger than 21 years when entering the army (62.2%), white (59.8%), high school educated (76.6%), and currently married (54.8%). In adjusted models, soldiers were more likely to attempt suicide if 1 or more suicide attempts occurred in their unit during the past year (odds ratios [ORs], 1.4-2.3; P < .001), with odds increasing as the number of unit attempts increased. The odds of suicide attempt among soldiers in a unit with 5 or more past-year attempts was more than twice that of soldiers in a unit with no previous attempts (OR, 2.3; 95% CI, 2.1-2.6). The association of previous unit suicide attempts with subsequent risk was significant whether soldiers had a combat arms MOS or other MOS (ORs, 1.4-2.3; P < .001) and regardless of unit size, with the highest risk among those in smaller units (1-40 soldiers) (ORs, 2.1-5.9; P < .001). The population-attributable risk proportion for 1 or more unit suicide attempts in the past year indicated that, if this risk could be reduced to no unit attempts, 18.2% of attempts would not occur.Conclusions and relevanceRisk of suicide attempt among soldiers increased as the number of past-year suicide attempts within their unit increased for combat arms and other MOSs and for units of any size but particularly for smaller units. Units with a history of suicide attempts may be important targets for preventive interventions.

Project description:ImportancePatients with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk of attempting suicide. Stimulants, such as methylphenidate hydrochloride, are the most common treatment for ADHD, but the association between their therapeutic use and suicide is unclear.ObjectiveTo investigate the association between methylphenidate and the risk of suicide attempts.Design, setting, and participantsA population-based, electronic medical records database from the Hong Kong Clinical Data Analysis & Reporting System was used to identify 25 629 individuals aged 6 to 25 years who were treated with methylphenidate between January 1, 2001, and December 31, 2015. Those who had attempted suicide were included in the analysis. A self-controlled case series design was used to control for time-invariant characteristics of the patients.Main outcomes and measuresRelative incidence of suicide attempt during periods when patients were exposed to methylphenidate compared with nonexposed periods.ResultsAmong 25 629 patients with methylphenidate prescriptions, 154 had their first recorded suicide attempt within the study period; of these individuals, 111 (72.1%) were male; mean (SD) age at baseline was 7.15 (2.19) years. The overall incidence of suicide attempts during methylphenidate treatment was 9.27 per 10 000 patient-years. An increased risk of suicide attempts was detected during the 90-day period before methylphenidate was initiated, with an incidence rate ratio (IRR) of 6.55 (95% CI, 3.37-12.72). The IRR remained elevated during the first 90 days of treatment (IRR, 3.91; 95% CI, 1.62-9.42) before returning to baseline levels during ongoing treatment (IRR, 1.35; 95% CI, 0.77-2.38). When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of suicide attempts was not elevated (IRR, 0.78; 95% CI, 0.26-2.35).Conclusions and relevanceThe incidence of suicide attempts was higher in the period immediately before the start of methylphenidate treatment. The risk remained elevated immediately after the start of methylphenidate treatment and returned to baseline levels during continuation of methylphenidate treatment. The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment. Therefore, this study's results do not support a causal association between methylphenidate treatment and suicide attempts.

Project description:Importance:Previous studies have shown an inverse association between offspring religiosity and suicidal ideation/attempts, but the association of parent religiosity on offspring suicidal ideation/attempts has not been examined. Objective:To examine associations of parent and offspring religiosity with suicide ideation and attempts in offspring. Design, Setting, and Participants:The study is based on offspring (generation 3) from a 3-generation family study at New York State Psychiatric Institute and Columbia University, in which generations 2 and 3 were defined as being at high risk or low risk for major depressive disorder because of the presence or absence of major depressive disorder in generation 1. The association between suicidal behaviors (ideation/attempts) and parent and offspring religiosity in generation 3 offspring aged 6 to 18 years (214 offspring from 112 nuclear families) was examined. Main Outcomes and Measures:Parents' psychiatric diagnoses and suicidal behaviors were assessed with the Schedule for Affective Disorders and Schizophrenia, and offspring were independently assessed using the child version. Two measures of religiosity were assessed: religious importance and religious attendance. Logistic regressions in the framework of generalized estimation equations were performed to analyze offspring suicidal behaviors while adjusting for sibling correlation and offspring age, sex, and familial depression risk status. Results:Of 214 offspring, 112 (52.3%) were girls. Offspring religious importance was associated with a lower risk for suicidal behavior in girls (odds ratio [OR], 0.48; 95% CI, 0.33-0.70) but not in boys (OR, 1.15; 95% CI, 0.74-1.80) (religiosity by sex interaction, P = .05). Religious attendance was associated with a lower risk for suicidal behavior in girls (OR, 0.64; 95% CI, 0.49-0.84) but not boys (OR, 0.94; 95% CI, 0.69-1.27) (religiosity by sex interaction, P = .17). Parent religious importance was associated with a lower risk for offspring suicidal behavior (OR, 0.61; 95% CI, 0.41-0.91) but not parent religious attendance. When parent and offspring religious importance were considered simultaneously, we found a lower risk associated with parental religious importance (OR, 0.61; 95% CI, 0.39-0.96) independent of offspring importance. These associations were independent of parental depression, marital status, and parental suicide ideation. Conclusions and Relevance:In this study, parental belief in religious importance was associated with lower risk for suicidal behavior in offspring independent of an offspring's own belief about religious importance and other known parental factors, such as parental depression, suicidal behavior, and divorce.

Dataset Information

Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.

Publications

Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.

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