Suicide Related Phenotypes in a Bipolar Sample: Genetic Underpinnings

Abstract

Suicide in Bipolar Disorder (BD) is a relevant clinical concern. Genetics may shape the individual risk for suicide behavior in BD, together with known clinical factors. The lack of consistent replication in BD may be associated with its multigenetic component. In the present contribution we analyzed a sample of BD individuals (from STEP-BD database) to identify the genetic variants potentially associated with three different suicide-related phenotypes: 1) a feeling that the life was not worth living; 2) fantasies about committing a violent suicide; 3) previous attempted suicide. The sample under analysis included 1115 BD individuals. None of the SNPs reached genome-wide significance. However, a trend of association was evidenced for rs2767403, an intron variant of AOPEP gene, in association with phenotype #1 (p = 5.977 × 10−6). The molecular pathway analysis showed a significant enrichment in all the investigated phenotypes on pathways related to post synaptic signaling, neurotransmission and neurodevelopment. Further, NOTCH signaling or the γ-aminobutyric acid (GABA) -ergic signaling were found to be associated with specific suicide-related phenotypes. The present investigation contributes to the hypothesis that the genetic architecture of suicide behaviors in BD is related to alteration of entire pathways rather than single genes. In particular, our molecular pathway analysis points on some specific molecular events that could be the focus of further research in this field.

Unlocking the Secrets: Exploring the Biochemical Correlates of Suicidal Thoughts and Behaviors in Adults with Autism Spectrum Conditions

“…This evidence is in line with previous items of research that have reported an increased suicidality risk in ASD populations [ 58 , 95 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. The association between ASD and suicidality has long been discussed, and a number of factors contributing to the correlation have been identified.…”

“…On the other hand, as reported by multiple twin and family studies, genetics may be one of the variables influencing the risk of suicide [ 58 ]. In particular, the genetic component for suicide also appears to be shared with the inheritance of psychiatric disorders [ 59 , 60 ], and a recent genome-wide association study revealed an intriguing correlation between suicide attempts and depressive symptoms, neuroticism, schizophrenia, insomnia, and major depressive disorder [ 61 , 62 ].…”

Genetics and epigenetics of self‐injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations

“…Our search revealed thirty‐one GWAS studies for SITB (Table 1), of which nineteen were focused exclusively on suicidal behavior (SA/SD). Some studies which included SI did so by considering continuous suicidality scales ranging from no suicidality to SI to SA (i.e., no reference group; Lybech et al, 2021; Schosser et al, 2011; Strawbridge et al, 2019; Zai et al, 2015; Zai et al, 2021), and only six studies assessed SI independently of suicidal behavior (Brick et al, 2019; Campos et al, 2020; Kimbrel et al, 2018; Mullins et al, 2014; Polimanti et al, 2021; Shen et al, 2020). In most cases, the large sample size needed for GWAS required a combination of multiple cohorts for analysis.…”

“…Of all identified GWAS published to date, nine (Bani‐Fatemi et al, 2016; Lybech et al, 2021; Mullins et al, 2019; Perlis et al, 2010; Rao et al, 2020; Schosser et al, 2011; Willour et al, 2012; Zai et al, 2015; Zai et al, 2021) focused on specific diagnostic groups, such as bipolar disorder (BD) and major depressive disorder (MDD), with some including multiple psychiatric disorder groups assessed separately. There was one GWAS focused on SI in youth (Brick et al, 2019), with no GWAS reports on suicidal behavior in youth.…”

“…In addition to the specific SNPs, gene‐based analyses have identified RETREG1 ( FAM134B ), GSN , GNAS , CACNA1D (SA; Sokolowski, Wasserman, & Wasserman, 2018), HGF (SI; Polimanti et al, 2021), HEPACAM , CNTN5 , PSMD14 , and HEPN1 (ordinal suicidality; Wendt et al, 2021), and BTN2A1 (SA/SD; Mullins et al, 2022) in association with SITB. Pathway analyses performed with significant genes have also implicated multiple biological processes in SITB, including growth hormone secretion, immune processes (SA; González‐Castro et al, 2019), caspase pathway (SA severity; Levey et al, 2019), neurocircuitry (ordinal suicidality; Strawbridge et al, 2019), synaptic function and brain development (ordinal suicidality and SA, respectively; Lybech et al, 2021; Sokolowski et al, 2018), cellular assembly and organization, nervous system development, cell death and survival, immunological disease, infectious disease, inflammatory response (SA/SD; Galfalvy et al, 2015), CNS development, homophilic cell adhesion, regulation of cell proliferation, transmission of nerve impulse (SD; Galfalvy et al, 2013), oxytocin signaling, glutamatergic synapse, axon guidance, calcium signaling, circadian entrainment, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm (SA; Kimbrel et al, 2022). A recent analysis on SD by Sokolowski and Wasserman (2021) pooled information from published GWAS and whole exome studies to group identified genes together, finding evidence for contributions from chromosome 19 as well as a set of 54 “core” genes involved in synaptic and nervous system development.…”