Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125, Contesse, Messina, Italy.
Unit for Psychiatric Research, Psychiatry, Aalborg University Hospital, 9100, Aalborg, Denmark.
Eur Arch Psychiatry Clin Neurosci. 2024 Oct;274(7):1527-1541. doi: 10.1007/s00406-024-01836-6. Epub 2024 Jun 15.
Suicide is a leading cause of death worldwide. Suicide ideation (SI) is a known risk factor for suicide behaviour (SB). The current psychobiology and genetic predisposition to SI and SB are poorly defined. Despite convincing relevance of a genetic background for SI, there is no current implementable knowledge about the genetic makeup that identifies subjects at risk for it. One of the possible reasons for the absence of a clear-cut evidence is the polygenetic nature of SI along with the very large sample sizes that are needed to observe significant genetic association result. The CATIE sample was instrumental to the analysis. SI was retrieved as measured by the Calgary test. Clinical possible covariates were identified by a nested regression model. A principal component analysis helped in defining the possible genetic stratification factors. A GWAS analysis, polygenic risk score associated with a random forest analysis and a molecular pathway analysis were undertaken to identify the genetic contribution to SI. As a result, 741 Schizophrenic individuals from the CATIE were available for the genetic analysis, including 166,325 SNPs after quality control and pruning. No GWAS significant result was found. The random forest analysis conducted by combining the polygenic risk score and several clinical variables resulted in a possibly overfitting model (OOB error rate < 1%). The molecular pathway analysis revealed several molecular pathways possibly involved in SI, of which those involved in microglia functioning were of particular interest. A medium-small sample of SKZ individuals was analyzed to shed a light on the genetic of SI. As an expected result from the underpowered sample, no GWAS positive result was retrieved, but the molecular pathway analysis indicated a possible role of microglia and neurodevelopment in SI.
自杀是全球范围内的主要死亡原因之一。自杀意念（SI）是自杀行为（SB）的已知风险因素。目前对 SI 和 SB 的心理生物学和遗传易感性了解甚少。尽管遗传背景对 SI 具有令人信服的相关性，但目前尚无关于确定易患 SI 的遗传构成的可实施知识。缺乏明确证据的原因之一可能是 SI 的多基因性质以及需要观察到显著遗传关联结果的非常大的样本量。CATIE 样本对分析至关重要。通过卡尔加里测试检索到 SI。通过嵌套回归模型确定临床可能的协变量。主成分分析有助于定义可能的遗传分层因素。进行全基因组关联分析、与随机森林分析相关的多基因风险评分和分子途径分析，以确定 SI 的遗传贡献。结果，来自 CATIE 的 741 名精神分裂症个体可用于遗传分析，包括质量控制和修剪后 166,325 个 SNP。未发现全基因组关联分析显著结果。通过结合多基因风险评分和几个临床变量进行的随机森林分析导致可能的过拟合模型（OOB 错误率<1%）。分子途径分析揭示了几个可能与 SI 相关的分子途径，其中涉及小胶质细胞功能的途径特别有趣。对一小部分 SKZ 个体进行了分析，以阐明 SI 的遗传情况。由于样本功率不足，预计不会检索到 GWAS 阳性结果，但分子途径分析表明小胶质细胞和神经发育在 SI 中可能发挥作用。
