Defo Joel, Ramesar Raj
MRC Research Unit for Precision and Genomic Medicine, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
Acta Neuropsychiatr. 2025 Mar 31;37:e58. doi: 10.1017/neu.2025.12.
Suicidality is a significant public health concern, with neuroimaging studies revealing abnormalities in the brains of suicidal individuals and post-mortem samples. However, the genetic architecture between suicidality and subcortical brain volumes remains poorly characterized. Using genome-wide association studies (GWAS), we investigated the genetic overlap between suicidality and subcortical brain volume. GWAS summary statistics for suicidal behaviours, including Suicide Attempts, Ever Self-Harmed, and Thoughts of Life Not Worth Living, from the UK Biobank, Suicide from the FinnGen Biobank, and data on seven subcortical brain volumes and Intracranial Volume from the ENIGMA2 study, were used to investigate the genetic correlation between phenotypes as well as potential genetic factors. A common genetic factor was identified, comprising two categories: Suicide Attempt, Ever Self-Harmed, and Thoughts of Life Not Worth Living from the UK Biobank, and Suicide from FinnGen, Intracranial Volume, and subcortical brain volumes. Cross-phenotype GWAS meta-analysis of each category at variant, gene and subnetwork levels unveils a list of significant variants (P-value <5 × 10), and potential hub genes (P-value <0.05) of consideration. Network, pathway, and Gene Ontology analyses of these joint categories highlighted enriched pathways and biological processes related to blood-brain barrier permeability suggesting that the presence and severity of suicidality are associated with an inflammatory signature detectable in both blood and brain tissues. This study underscores the role of brain and peripheral blood inflammation in suicide risk and holds promise for developing targeted interventions and personalized treatment strategies to reduce suicidality in at-risk populations.
自杀行为是一个重大的公共卫生问题，神经影像学研究揭示了自杀个体大脑及尸检样本存在异常。然而，自杀行为与皮层下脑容量之间的遗传结构仍未得到充分表征。我们利用全基因组关联研究（GWAS）来探究自杀行为与皮层下脑容量之间的遗传重叠。我们使用了来自英国生物银行的自杀行为（包括自杀未遂、曾有过自我伤害行为以及认为生命不值得活下去的想法）、芬兰基因库的自杀数据，以及ENIGMA2研究中关于七种皮层下脑容量和颅内容量的数据的GWAS汇总统计信息，来研究表型之间的遗传相关性以及潜在的遗传因素。我们确定了一个共同的遗传因素，它包括两类：来自英国生物银行的自杀未遂、曾有过自我伤害行为以及认为生命不值得活下去的想法，以及来自芬兰基因库的自杀、颅内容量和皮层下脑容量。在变异体、基因和子网水平上对每个类别进行跨表型GWAS荟萃分析，揭示了一系列显著变异体（P值<5×10）以及值得考虑的潜在枢纽基因（P值<0.05）。对这些联合类别的网络、通路和基因本体分析突出了与血脑屏障通透性相关的富集通路和生物学过程，这表明自杀行为的存在和严重程度与在血液和脑组织中均可检测到的炎症特征相关。这项研究强调了大脑和外周血炎症在自杀风险中的作用，并为开发有针对性的干预措施和个性化治疗策略以降低高危人群的自杀行为带来了希望。
