Search

With regard to suicidal behavior (SB) genetics, many novel genes have been implicated over the years, in particular by a variety of hypothesis-free genomic methods (e.g. GWAS and exome sequencing). In addition, many novel SB gene findings appear enigmatic in their biological relevance and have weak statistical support, e.g. lack direct replications. Adding to this is the comorbidity between psychiatric disorders and SB. Here we provide a synopsis of SB genes, by prioritization of 106 (out of ~2500) genes based on their highest level of evidence diversity across mainly five genetic evidence types (candidate/GWAS SNP, CNV, linkage and whole exome sequencing), supplemented by three functional categories. This is a representative set of both old and new SB gene candidates, implicated by all kinds of evidence. Furthermore, we define a subset of 40 SB "specific" genes, which are not found among ~3900 genes implicated in other neuropsychiatric disorders, e.g. Autism spectrum disorders (ASD) or Schizophrenia. Biological research of suicidality contains a major developmental focus, e.g. with regard to the gene-environment interactions and epigenetic effects during childhood. Less is known about early (fetal) development and SB genes. Inspired by huge efforts to understand the role early (fetal) neurodevelopment in e.g. ASD by using brain transcriptomic data, we here also characterize the 106 SB genes. We find interesting spatiotemporal expression differences and similarities between SB specific and non-specific genes during brain neurodevelopment. These aspects are of interest to investigate further, to better understand and counteract the genetic origins suicidality., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Suicidal behavior (SB) has a complex etiology involving different polygenic and environmental components. Here we used an excess of significant markers (ESM) test to study gene-level associations in previous genome-wide association studies (GWAS) SNP data from a family-based sample, having medically severe suicide attempt (SA) as main outcome in the offspring. In SA without major psychiatric disorders (N = 498), a screening of 5,316 genes across the genome suggested association 17 genes (at fdr < 0.05). Genes RETREG1 (a.k.a. FAM134B), GSN, GNAS, and CACNA1D were particularly robust to different methodological variations. Comparison with the more widely used Multi-marker Analysis of GenoMic Annotation (MAGMA) methods, mainly supported RETREG1, GSN, RNASEH2B, UBE2H, and CACNA1D by using the "mean" model, and ranked 13 of the same genes as ESM among its top-17. Complementing the ESM screen by using MAGMA to analyze 17,899 genes, we observed excess of genes with p < .05 by using the "top" model, and the "mean" model suggested additional genes with genome-wide fdr < 0.25. Overrepresentation analysis of 10 selected gene sets using all genes with p < .05, showed significant results for synaptic genes, genes differentially expressed in brain development and for ~12% of the SA polygenic association genes identified previously in this sample. Exploratory analysis linked some of the ESM top-17 genes to psychotropic drugs and we examined the allelic heterogeneity in the previous SA candidate GRIN2B. This study complemented previous GWAS on SB outcomes, implicating both previous candidate (e.g., GRIN2B and GNAS) and novel genes in SA outcomes, as well as synaptic functions and brain development., (© 2018 Wiley Periodicals, Inc.)

Suicidal behavior (SB) has a complex etiology involving genes and environment. One of the genetic components in SB could be copy number variations (CNVs), as CNVs are implicated in neurodevelopmental disorders. However, a recently published genome-wide and case-control study did not observe any significant role of CNVs in SB. Here we complemented these initial observations by instead using a family-based trio-sample that is robust to control biases, having severe suicide attempt (SA) in offspring as main outcome (n = 660 trios). We first tested for CNV associations on the genome-wide Illumina 1M SNP-array by using FBAT-CNV methodology, which allows for evaluating CNVs without reliance on CNV calling algorithms, analogous to a common SNP-based GWAS. We observed association of certain T-cell receptor markers, but this likely reflected inter-individual variation in somatic rearrangements rather than association with SA outcome. Next, we used the PennCNV software to call 385 putative rare (<1%) and large (>100 kb) CNVs, observed in n = 225 SA offspring. Nine SA offspring had rare CNV calls in a set of previously schizophrenia-associated loci, indicating the importance of such CNVs in certain SA subjects. Several additional, very large (>1MB) sized CNV calls in 15 other SA offspring also spanned pathogenic regions or other neural genes of interest. Overall, 45 SA had CNVs enriched for 65 medically relevant genes previously shown to be affected by CNVs, which were characterized by a neurodevelopmental biology. A neurodevelopmental implication was partly congruent with our previous SNP-based GWAS, but follow-up analysis here indicated that carriers of rare CNVs had a decreased burden of common SNP risk-alleles compared to non-carriers. In conclusion, while CNVs did not show genome-wide association by the FBAT-CNV methodology, our preliminary observations indicate rare pathogenic CNVs affecting neurodevelopmental functions in a subset of SA, who were distinct from SA having increased SNP risk-allele burden. These observations may open up new avenues in the genetic etiology of SB., Competing Interests: The authors have declared that no competing interests exist.

The cortisol response to psychosocial stress may become dysregulated in stress-related disorders. It is potentiated by pituitary secretion of adrenocorticotropic hormone (ACTH), which is, in part, regulated by arginine vasopressin receptor-1B (AVPR1B). AVPR1B variants were previously reported to associate with mood and anxiety disorders. This study aims, for the first time, to investigate association of AVPR1B genetic variants with mood and anxiety outcomes in suicidal behavior.Using a family-based study design of 660 complete nuclear family trios with offspring who have made a suicide attempt (SA), we tested the direct association and linkage of AVPR1B single nucleotide polymorphisms (SNPs) with SA, as well as with depression and anxiety in SA. Main findings were the association and linkage of AVPR1B exon 1 SNP rs33990840 and a major 6-SNP haplotype representative of all common AVPR1B-SNPs, on the outcome of high Beck Depression Inventory scores in SA. By contrast, genetic associations with lifetime diagnoses of depression and anxiety in SA or gene-environment interactions between AVPR1B variants and stressful life events (SLEs) were not significant. An exploratory screen of interactions between AVPR1B and CRHR1 (corticotropin-releasing hormone receptor-1), the principal pituitary regulator of ACTH secretion, showed no support for gene-gene interactions on the studied outcomes. The results suggest that AVPR1B genetic variation, eg, non-synonymous SNP rs33990840 mediating putative consequences on ligand binding, has a role in SA etiology characterized by elevated depression symptoms, without involving AVPR1B-moderation of SLEs.

Unlabelled: Suicide is a major public health problem in the WHO European Region accounting for over 150,000 deaths per year. Suicidal crisis: Acute intervention should start immediately in order to keep the patient alive., Diagnosis: An underlying psychiatric disorder is present in up to 90% of people who completed suicide. Comorbidity with depression, anxiety, substance abuse and personality disorders is high. In order to achieve successful prevention of suicidality, adequate diagnostic procedures and appropriate treatment for the underlying disorder are essential., Treatment: Existing evidence supports the efficacy of pharmacological treatment and cognitive behavioural therapy (CBT) in preventing suicidal behaviour. Some other psychological treatments are promising, but the supporting evidence is currently insufficient. Studies show that antidepressant treatment decreases the risk for suicidality among depressed patients. However, the risk of suicidal behaviour in depressed patients treated with antidepressants exists during the first 10-14 days of treatment, which requires careful monitoring. Short-term supplementary medication with anxiolytics and hypnotics in the case of anxiety and insomnia is recommended. TREATMENT with antidepressants of children and adolescents should only be given under supervision of a specialist. Long-term treatment with lithium has been shown to be effective in preventing both suicide and attempted suicide in patients with unipolar and bipolar depression. TREATMENT with clozapine is effective in reducing suicidal behaviour in patients with schizophrenia. Other atypical antipsychotics are promising but more evidence is required. TREATMENT team: Multidisciplinary treatment teams including psychiatrist and other professionals such as psychologist, social worker, and occupational therapist are always preferable, as integration of pharmacological, psychological and social rehabilitation is recommended especially for patients with chronic suicidality. Family: The suicidal person independently of age should always be motivated to involve family in the treatment. Social support: Psychosocial treatment and support is recommended, as the majority of suicidal patients have problems with relationships, work, school and lack functioning social networks., Safety: A secure home, public and hospital environment, without access to suicidal means is a necessary strategy in suicide prevention. Each treatment option, prescription of medication and discharge of the patient from hospital should be carefully evaluated against the involved risks. Training of personnel: Training of general practitioners (GPs) is effective in the prevention of suicide. It improves treatment of depression and anxiety, quality of the provided care and attitudes towards suicide. Continuous training including discussions about ethical and legal issues is necessary for psychiatrists and other mental health professionals.

Suicide affects about one million people each year, a phenomenon characterized by heterogeneous and complex causes. Often environmental factors such as negative life events may act as a significant contributor to suicidal behavior. However, in many cases the exposure to the same environmental stress does not result in increased suicidality. It is now well established that there is also a substantial genetic contribution to suicidal behavior. Here, functional and association studies which implicate specific genes in psychological traits and environmental factors are discussed, interactions which are related to completed suicide or suicide attempt, and our novel findings which need replication are presented. We found that genetic variation in the noradrenergic tyrosine hydroxylase gene was associated with the angry/hostility personality trait and vulnerability to stress. Similarly, we recently discovered that genetic variation in components of the stress-related hypothalamic pituitary adrenocortical axis, T-box 19 and corticotropin releasing hormone receptor 1, showed association and linkage to high anger/hostility in and male depression the suicidal offspring, respectively. Further results from our studies have revealed that genetic variation in genes with roles in basal mechanisms of neural conduction, voltage-gated sodium channel type VIII alpha and vesicle-associated membrane 4 protein, showed association and linkage among suicide attempters. Additionally, we have results which give support to the findings of others, implicating the serotonin transporter and serotonin receptor 1A in suicidal behavior. Our future studies aim at identifying and resolving complex patterns and mechanisms of neurobiological gene-environment interactions, which may contribute to suicide.

Serotonergic neurotransmission has been implicated in suicidal behavior, including inconsistent results concerning the serotonin transporter promoter polymorphism (5-HTTLPR). Here, we analyzed the 5-HTTLPR in suicide attempters (n=85). Comparing the presence of SS with SL+LL genotypes showed a significantly higher prevalence of the SS genotype in suicide attempters with high medical damage scores (chi2=9.054, df=1, p=0.0026). The results suggest that the S-allele may predispose for suicidal behavior characterized by high determination.