We read with interest the meta-analysis by Sokolov, Lafta et al. [1] investigating transcriptomic alterations in confirmed suicide cases, primarily in the dorsolateral prefrontal cortex (DLPFC). We commend the authors for their effort integrating 16 cohorts to identify differentially expressed genes, among which were the markers P2RY12 and CX3CR1 in all brain regions and in the DLPFC.
We wish to expand on the authors’ citation of our work [2]. While Sokolov, Lafta et al. graciously reference our study among those reporting P2RY12 associations with suicide, we would like to offer the following observations. Our dataset is not included in their meta-analysis; thus, their findings independently replicate our earlier results. Notably, our study identified the same genes (P2RY12, CX3CR1, and GPR34) emerging from the present meta-analysis in a signature specific to patients who died by suicide by violent method.
In our transcriptomic study of postmortem bulk brain tissue (N = 329 total: 103 neurotypical controls, 99 non-suicide psychiatric patients, 50 non-violent suicide decedents, and 77 violent suicide decedents, with means of suicide carefully classified), we found FDR-corrected upregulation of these genes in the DLPFC only among suicide decedents by violent method, with no significant differences observed in non-violent suicide patients compared to non-suicide patients.
These convergent findings stress a critical point: phenotype matters. Suicide is inherently heterogeneous, and method of suicide may index distinct underlying neurobiology. Violent methods, associated with greater lethality and intent, may reflect a more biologically penetrant form of suicidal behavior. In other words, stratifying by violent method may enrich for individuals with a stronger underlying biological signature. In this regard, we also observed lower genetic liability for various psychiatric disorders among suicide decedents by violent method [2], a pattern recently echoed by Coon et al. [3] in suicide deaths with no prior suicidality. While recent reviews have rightly called for larger studies to detect specific signatures of suicide [4], our data suggest that phenotypic refinement may be equally critical. The consistent identification of these genes across independent datasets (one [1] employing large-scale meta-analysis on 300 suicide decedents by mixed methods, the other [2] focusing on a smaller but phenotypically refined sample with 77 suicides by violent method) strengthens confidence in their relevance to suicide. Transcriptomic studies may benefit from stratification by method or other features that reduce heterogeneity, complementing the essential approach of aggregating samples through meta-analysis.
Author contributions
The author confirms sole responsibility for all contributions to this manuscript.
Funding
Open access funding provided by Università degli Studi di Torino within the CRUI-CARE Agreement.
Competing interests
The author declares no competing interests.
Footnotes
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References
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