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

Abstract

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.