Genetic associations with suicide attempt severity and genetic overlap with major depression.
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ABSTRACT:
SUBMITTER: Levey DF
PROVIDER: S-EPMC6336846 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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Project description:Background: Major Depressive Disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for MDD suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesized that regulatory genomic processes are involved in the pathology of both MDD and suicidality. Methods: Genome-wide patterns of DNA methylation were assessed in depressed MDD suicide completers (n=20) and compared to non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focussed on identifying differentially methylated regions (DMRs) associated with suicidal depression, and epigenetic variation was explored in the context of polygenic risk scores for major depression and MDD suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed MDD suicide completers and polygenic burden for MDD and MDD suicide attempt. Results: We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite-pyrosequencing and replicated in a second set of MDD suicide samples, which is characterized by significant hypomethylation in both cortical brain regions in MDD MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for MDD suicide attempt, but not major depression. MDD suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Conclusions: Our data suggest there are coordinated changes in DNA methylation associated with MDD suicide that may offer novel insights into the molecular pathology associated with depressed MDD suicide completers.
2016-11-01 | GSE88890 | GEO
Project description:Importance:Predicting suicidal behavior continues to be among the most challenging tasks in psychiatry. Objectives:To examine the trajectories of clinical predictors of suicide attempt (specifically, depression symptoms, hopelessness, impulsivity, aggression, impulsive aggression, and irritability) for their ability to predict suicide attempt and to compute a risk score for suicide attempts. Design, Setting, and Participants:This is a longitudinal study of the offspring of parents (or probands) with mood disorders who were recruited from inpatient units at Western Psychiatric Institute and Clinic (Pittsburgh) and New York State Psychiatric Institute. Participants were recruited from July 15, 1997, to September 6, 2005, and were followed up through January 21, 2014. Probands and offspring (n = 663) were interviewed at baseline and at yearly follow-ups for 12 years. Lifetime and current psychiatric disorders were assessed, and self-reported questionnaires were administered. Model evaluation used 10-fold cross-validation, which split the entire data set into 10 equal parts, fit the model to 90% of the data (training set), and assessed it on the remaining 10% (test set) and repeated that process 10 times. Preliminary analyses were performed from July 20, 2015, to October 5, 2016. Additional analyses were conducted from July 26, 2017, to July 24, 2018. Main Outcomes and Measures:The broad definition of suicide attempt included actual, interrupted, and aborted attempts as well as suicidal ideation that prompted emergency referrals during the study. The narrow definition referred to actual attempt only. Results:The sample of offspring (n = 663) was almost equally distributed by sex (316 female [47.7%]) and had a mean (SD) age of 23.8 (8.5) years at the time of censored observations. Among the 663 offspring, 71 (10.7%) had suicide attempts over the course of the study. The trajectory of depression symptoms with the highest mean scores and variability over time was the only trajectory to predict suicide attempt (odds ratio [OR], 4.72; 95% CI, 1.47-15.21; P = .01). In addition, we identified the following predictors: younger age (OR, 0.82; 95% CI, 0.74-0.90; P < .001), lifetime history of unipolar disorder (OR, 4.71; 95% CI, 1.63-13.58; P = .004), lifetime history of bipolar disorder (OR, 3.4; 95% CI, 0.96-12.04; P = .06), history of childhood abuse (OR, 2.98; 95% CI, 1.40-6.38; P = .01), and proband actual attempt (OR, 2.24; 95% CI, 1.06-4.75; P = .04). Endorsing a score of 3 or higher on the risk score tool resulted in high sensitivity (87.3%) and moderate specificity (63%; area under the curve = 0.80). Conclusions and Relevance:The specific predictors of suicide attempt identified are those that clinicians already assess during routine psychiatric evaluations; monitoring and treating depression symptoms to reduce their severity and fluctuation may attenuate the risk for suicidal behavior.
| S-EPMC6551844 | biostudies-literature
Project description:Depression is a multifactorial disorder representing a significant public health burden. Previous studies have linked multiple single nucleotide polymorphisms with depressive phenotypes and suicidal behavior. MAD1L1 is a mitosis metaphase checkpoint protein that has been linked to depression in GWAS. Using a longitudinal EWAS approach in an adolescent cohort at two time points (n = 216 and n = 154), we identified differentially methylated sites that were associated with depression-related genetic variants in MAD1L1. Three methylation loci (cg02825527, cg18302629, and cg19624444) were consistently hypomethylated in the minor allele carriers, being cross-dependent on several SNPs. We further investigated whether DNA methylation at these CpGs is associated with depressive psychiatric phenotypes in independent cohorts. The first site (cg02825527) was hypomethylated in blood (exp(β) = 84.521, p value ~ 0.003) in participants with severe suicide attempts (n = 88). The same locus showed increased methylation in glial cells (exp(β) = 0.041, p value ~ 0.004) in the validation cohort, involving 29 depressed patients and 29 controls, and showed a trend for association with suicide (n = 40, p value ~ 0.089) and trend for association with depression treatment (n = 377, p value ~ 0.075). The second CpG (cg18302629) was significantly hypomethylated in depressed participants (exp(β) = 56.374, p value ~ 0.023) in glial cells, but did not show associations in the discovery cohorts. The last methylation site (cg19624444) was hypomethylated in the whole blood of severe suicide attempters; however, this association was at the borderline for statistical significance (p value ~ 0.061). This locus, however, showed a strong association with depression treatment in the validation cohort (exp(β) = 2.237, p value ~ 0.003) with 377 participants. The direction of associations between psychiatric phenotypes appeared to be different in the whole blood in comparison with brain samples for cg02825527 and cg19624444. The association analysis between methylation at cg18302629 and cg19624444 and MAD1L1 transcript levels in CD14+ cells shows a potential link between methylation at these CpGs and MAD1L1 expression. This study suggests evidence that methylation at MAD1L1 is important for psychiatric health as supported by several independent cohorts.
| S-EPMC9811786 | biostudies-literature
Project description:BACKGROUND:Suicide is major public health concern. It is imperative to find robust biomarkers so that at-risk individuals can be identified in a timely and reliable manner. Previous work suggests mechanistic links between increased cytokines and risk for suicide, but questions remain regarding the etiology of this association, as well as the roles of sex and BMI. METHODS:Analyses were conducted using a randomly-ascertained extended-pedigree sample of 1882 Mexican-American individuals (60% female, mean age?=?42.04, range?=?18-97). Genetic correlations were calculated using a variance components approach between the cytokines TNF-?, IL-6 and IL-8, and Lifetime Suicide Attempt and Current Suicidal Ideation. The potentially confounding effects of sex and BMI were considered. RESULTS:159 individuals endorse a Lifetime Suicide Attempt. IL-8 and IL-6 shared significant genetic overlap with risk for suicide attempt (?g?=?0.49, pFDR?=?7.67?×?10-03; ?g?=?0.53, pFDR?=?0.01), but for IL-6 this was attenuated when BMI was included as a covariate (?g?=?0.37, se?=?0.23, pFDR?=?0.12). Suicide attempts were significantly more common in females (pFDR?=?0.01) and the genetic overlap between IL-8 and risk for suicide attempt was significant in females (?g?=?0.56, pFDR?=?0.01), but not in males (?g?=?0.44, pFDR?=?0.30). DISCUSSION:These results demonstrate that: IL-8 shares genetic influences with risk for suicide attempt; females drove this effect; and BMI should be considered when assessing the association between IL-6 and suicide. This finding represents a significant advancement in knowledge by demonstrating that cytokine alterations are not simply a secondary manifestation of suicidal behavior, but rather, the pathophysiology of suicide attempts is, at least partly, underpinned by the same biological mechanisms responsible for regulating inflammatory response.
| S-EPMC7168352 | biostudies-literature
Project description:ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
| S-EPMC6675659 | biostudies-literature
Project description:BackgroundThis study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion.MethodsTwenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score.ResultsKetamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness.LimitationsLimitations include a small sample size of attempters.ConclusionsThe findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history.
| S-EPMC9262873 | biostudies-literature
Project description:ImportanceSuicide rates have been increasing among youth in the US. While the heritability of suicide risk is well established, there is limited understanding of how genetic risk is associated with suicidal thoughts and behaviors in young children.ObjectiveTo examine whether genetic susceptibility to suicide attempts (SAs) is associated with suicidal thoughts and behaviors in children.Design, setting, and participantsThis case-control study examined data from the Adolescent Brain Cognitive Development (ABCD) study, a population-based longitudinal study of 11 878 US children enrolled at age 9 and 10 years from September 2016 to November 2018. Youth reports of suicidal ideation (SI) and SAs were obtained from the Kiddie Schedule for Affective Disorder and Schizophrenia at baseline and 2 subsequent years. After conservative quality control of genotype data, this analysis focused on 4344 unrelated individuals of European ancestry. Data analysis was conducted from November 2020 to February 2022.Main outcomes and measuresChildren's lifetime experiences of SI and SAs were assessed each year from ages 9 to 10 years to ages 11 to 12 years. Polygenic risk scores (PRSs) for SAs were calculated for ABCD study participants based on the largest genome-wide association study of SA cases and controls of European ancestry (total sample n = 518 612).ResultsOf 4344 children of European ancestry (2045 [47.08%] female; mean [SD] age, 9.93 [0.62] years), significant associations were found between children's SA PRSs and their lifetime SAs with the most robust association in the follow-up year 2 (odds ratio, 1.43 [95% CI, 1.18-1.75]; corrected P = 1.85 × 10-3; Nagelkerke pseudo R2 = 1.51%). These associations remained significant after accounting for children's sociodemographic backgrounds, psychopathology symptoms, parental histories of suicide and mental health, and PRSs for major depression and attention-deficit/hyperactivity disorder (likelihood ratio test P < .05). Children's depressive mood and aggressive behavior were the most significant partial mediators of SA genetic risk on SAs (mediation analysis P < 1 × 10-16). Children's behavioral problems, such as attention problems, rule-breaking behavior, and social problems, also partially mediated the association of SA PRSs with SAs (mediation analysis false discover rate < 0.05).Conclusions and relevanceThis study's findings indicate that there may be genetic factors associated with SA risk across the life span and suggest behaviors and conditions through which the risk could be mediated in childhood. Further research is warranted to examine whether incorporating genetic data could improve the identification of children at risk for suicide.
| S-EPMC9434482 | biostudies-literature
Project description:BackgroundHow does genetic liability to suicide attempt (SA), suicide death (SD), major depression (MD), bipolar disorder (BD), schizophrenia (SZ), alcohol use disorder (AUD), and drug use disorder (DUD) impact on risk for SA and SD?MethodsIn the Swedish general population born 1932-1995 and followed through 2017 (n = 7 661 519), we calculate family genetic risk scores (FGRS) for SA, SD, MD, BD, SZ, AUD, and DUD. Registration for SA and SD was assessed from Swedish national registers.ResultsIn univariate and multivariate models predicting SA, FGRS were highest for SA, AUD, DUD, and MD. In univariate models predicting SD, the strongest FGRS were AUD, DUD, SA, and SD. In multivariate models, the FGRS for SA and AUD were higher in predicting SA while the FGRS for SD, BD, and SZ were higher in predicting SD. Higher FGRS for all disorders significantly predicted both younger age at first SA and frequency of attempts. For SD, higher FGRS for MD, AUD, and SD predicted later age at SD. Mediation of FGRS effects on SA and SD was more pronounced for SD than SA, strongest for AUD, DUD, and SZ FGRS and weakest for MD.ConclusionsFGRS for both SA and SD and for our five psychiatric disorders impact on risk for SA and SD in a complex manner. While some of the impact of genetic risk factors for psychiatric disorders on risk for SA and SD is mediated through developing the disorders, these risks also predispose directly to suicidal behaviors.
| S-EPMC10916711 | biostudies-literature
Project description:Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co-occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio-metabolic traits/diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta-analyzed across samples, including a total of 688 patients with SA (Neff = 2,258) and 214 with TWESI (Neff = 785). Stratified genetic covariance analyses were performed to investigate functionally cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11-1.38; p = 1.73 × 10-4 ). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 × 10-3 ), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.
| S-EPMC9305542 | biostudies-literature
Project description:RNAs were extracted from entorhinal cortex of human suicide patients with major depression and matched control subjects. The transcription profile was investigated by Agilent microarray platform and quantitative real-time PCR to reveal alterations in neuronal functions in this brain region.
2010-12-31 | E-MEXP-2607 | biostudies-arrayexpress