What is the future of suicide genetics?

Mirza, Salahudeen; Fries, Gabriel R.

doi:10.47626/1516-4446-2022-2812

Cited by 3 publications

(2 citation statements)

References 5 publications

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“…Therefore, elucidating the genomic architecture of SB as a transdiagnostic phenotype across major psychopathologies, including depression and other disorders, alongside the psychological constructs underpinning SA, offers insight into SB mechanisms, especially given the fact that vulnerability–stress can be an endophenotype of both SB and mental disorders. As research into the genetics of suicide employing GWAS strategies progresses and evolves, with advancements in analysis methods, accumulation of genomic data, and the integration of multi-omics data (epigenomics, proteomics, metabolomics, microbiomics) [ 68 ], the issue of summarizing these findings within the context of suicide pathogenesis remains paramount.…”

Section: Discussionmentioning

confidence: 99%

Using the Strategy of Genome-Wide Association Studies to Identify Genetic Markers of Suicidal Behavior: A Narrative Review

Rozanov,

Mazo

2024

Consortium Psychiatricum

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BACKGROUND: Several studies involving various suicidal phenotypes based on the strategy of the search of genome-wide associations with single nucleotide polymorphisms have been performed recently. These studies need to be generalized. AIM: To systematize the findings of a number of genome-wide association studies (GWAS) for suicidal phenotypes, annotate the identified markers, analyze their functionality, and possibly substantiate the hypothesis holding that these phenotypes reflect a nonspecific set of gene variants that are relevant as relates to stress-vulnerability as a key endophenotype of suicidal behavior (SB). METHODS: A search on the PubMed and related resources using the combinations “suicide AND GWAS” and “suicidal behavior AND GWAS” was performed. It yielded a total of 34 independent studies and meta-analyses. RESULTS: For the 10 years since such studies emerged, they have undergone significant progress. Estimates of the SNP heritability of SB in some cases are comparable with estimates of heritability based on the twin method. Many studies show a high genetic correlation with the genomic markers of the most common mental disorders (depression, bipolar disorder, schizophrenia, post-traumatic stress disorder). At the same time, a genomic architecture specific to SB is also encountered. Studies utilizing the GWAS strategy have not revealed any associations of SB with candidate genes that had been previously studied in detail (different neurotransmitters, stress response system, polyamines, etc.). Frequently reported findings from various studies belong in three main groups: 1) genes involved in cell interactions, neurogenesis, the development of brain structures, inflammation, and the immune responses; 2) genes encoding receptors for neurotrophins and various components of the intracellular signaling systems involved in synaptic plasticity, embryonic development, and carcinogenesis; and 3) genes encoding various neuro-specific proteins and regulators. CONCLUSION: In general, GWAS in the field of suicidology mainly serve the purpose of a deeper understanding of the pathophysiology of suicidal behavior. However, they also demonstrate growing capability in terms of predicting and preventing suicide, especially when calculating the polygenic risk score among certain populations (psychiatric patients) and in combination with tests of different modalities. From our point of view, there exists a set of markers revealed by the GWAS strategy that seems to point to a leading role played by stress vulnerability, an endophenotype that is formed during early development and which subsequently comes to play the role of key pathogenetic mechanism in SB.

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Section: Discussionmentioning

confidence: 99%

Using the Strategy of Genome-Wide Association Studies to Identify Genetic Markers of Suicidal Behavior: A Narrative Review

Rozanov,

Mazo

2024

Consortium Psychiatricum

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“…Applying a multiple-levels-of-analysis approach may be key to understanding the aetiology of SA [ 4 , 5 ] and identifying signs of risk in vulnerable populations. Integration of information across the biological and clinical domains, when taken together, could illuminate novel pathways and opportunities for intervention.…”

Section: Introductionmentioning

confidence: 99%

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder

Mirza,

Lima,

Del Favero-Campbell

et al. 2024

Transl Psychiatry

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Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort’s significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8–93.8%) and 82.1% (CI = 73.6–90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

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Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder

Mirza¹,

Lima²,

Favero-Campbell³

et al. 2023

Preprint

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Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

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What is the future of suicide genetics?

Cited by 3 publications

References 5 publications

Using the Strategy of Genome-Wide Association Studies to Identify Genetic Markers of Suicidal Behavior: A Narrative Review

Using the Strategy of Genome-Wide Association Studies to Identify Genetic Markers of Suicidal Behavior: A Narrative Review

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder

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