Rare protein‐coding variants implicate genes involved in risk of suicide death

DiBlasi, Emily; Shabalin, Andrey A.; Monson, Eric; Keeshin, Brooks; Bakian, Amanda V.; Kirby, Anne V.; Ferris, Elliott; Chen, Danli; William, Nancy; Gaj, Eoin; Klein, Michael; Jerominski, Leslie; Callor, W. Brandon; Christensen, Erik Damgaard; Smith, Ken R.; Fraser, Alison; Yu, Zhe; Gray, Douglas; Camp, Nicola J.; Stahl, Eli A.; Li, Qingqin; Docherty, Anna R.; Coon, Hilary

doi:10.1002/ajmg.b.32861

Cited by 15 publications

(10 citation statements)

References 61 publications

(78 reference statements)

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“…Four studies have assessed rare variants (Coon et al, 2013; DiBlasi et al, 2021; Monson et al, 2017; Tombácz et al, 2017), all focused on suicidal behaviors. The most recent rare variant approach identified five high‐impact rare variants associated with SD in the following genes: SNAPC1 , TNKS1BP1 , ADGRF5 , PER1 , and ESS2 (DiBlasi, Kang, & Docherty, 2021). SNAPC1 and PER1 had previously been implicated in SITB.…”

Section: Resultsmentioning

confidence: 99%

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

Mirza

Docherty

Bakian

et al. 2022

American J of Med Genetics Pt B

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Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.

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Section: Resultsmentioning

confidence: 99%

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

Mirza

Docherty

Bakian

et al. 2022

American J of Med Genetics Pt B

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“…This gene is not found in the discovered network, or in PEC Network Modules, or in relevant KEGG pathways ( Table S7 and Table 4 ). There are no previously reported associations with addiction or psychiatric traits, except one report of an association of the rare missense variant rs149197213 in exon 6 of this gene with suicide [ 66 ]. Despite this, although we did not consider ADGRF5 among the best functional candidate genes in the present study, further investigations are needed before the role of ADGRF5 in the pathogenesis of AD can be completely ruled out.…”

Section: Resultsmentioning

confidence: 99%

A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures

et al. 2022

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At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33 × 10−8 calculated with the Yates-corrected χ2 test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWASs of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network, where BDNF is the most significant hub gene. This study indicates that several genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The study also reveals a central role of BDNF in the pathogenesis of AD.

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“…Data from the Utah Suicide Genetic Risk Study (USGRS) biobank showed that among the sample of 2,672 suicide deaths, compared to non-suicide deaths, both PER1 (Period Circadian Regulator 1) and SNAPC1 (Small Nuclear RNA Activating Complex Polypeptide 1) genes show evidence of suicide risk in bipolar disorder and schizophrenia [ 37 ]. The PER1 protein is important for the maintenance of circadian rhythms in cells, and its deficiency in mice causes loss of rhythmic telomerase activities, TERT mRNA oscillation, and shortened telomere length [ 11 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Shorter telomere length and suicidal ideation in familial bipolar disorder

et al. 2022

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Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.

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Rare protein‐coding variants implicate genes involved in risk of suicide death

Cited by 15 publications

References 61 publications

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

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

A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures

Shorter telomere length and suicidal ideation in familial bipolar disorder

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