Radenković Lana, Karanović Jelena, Pantović-Stefanović Maja, Lazić Dušan, Brajušković Goran, Ivković Maja, Pešović Jovan, Savić-Pavićević Dušanka
University of Belgrade-Faculty of Biology, Centre for Human Molecular Genetics, Studentski trg 16, 11000 Belgrade, Serbia.
Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444A, 11042 Belgrade, Serbia.
Int J Mol Sci. 2025 Apr 25;26(9):4085. doi: 10.3390/ijms26094085.
Suicide attempts are prevalent among patients with bipolar disorder (BD). Impaired serotonin (5-HT) system in the pathogenesis of suicide attempt is partially heritable. To quantify the combined effects of multiple genetic variants, we developed a dynamic model of the 5-HT presynapse with functionally integrated individual genetic variants. The model includes five genetic variants in 5-HT system genes (, , ) and quantitatively assesses their influence on 5-HT synthesis, reuptake, and degradation. The model was validated on 140 unaffected individuals and tested on 101 BD patients. Predicted mean concentrations of 5-HT, 5-HT precursor, and degradation product were compared between BD patients with and without a history of attempted suicide, and unaffected individuals. The model consists of eight differential equations that describe the temporal concentration change of model outputs. Calculated concentrations in unaffected control individuals aligned with published experimentally measured values, validating our model. BD patients with a history of suicide attempt showed lower calculated concentrations of 5-HT degradation product 5-hydroxy-3-indolacetic acid (5-HIAA) compared to unaffected individuals ( = 0.044). Additionally, higher calculated concentrations of free cellular 5-HT ( = 0.048) and stored 5-HT ( = 0.047), with the effect size d = 0.35, were observed when comparing suicide attempters to non-attempters.. Our approach illuminated a complex interplay of genetic variants in 5-HT system genes that contributes to the risk of suicide attempt, with quantitative and personalized outputs unattainable through genetic association studies.
自杀未遂在双相情感障碍（BD）患者中很普遍。血清素（5-HT）系统功能受损在自杀未遂的发病机制中具有部分遗传性。为了量化多个基因变异的综合影响，我们开发了一个5-HT突触前膜的动态模型，该模型整合了具有功能的个体基因变异。该模型包括5-HT系统基因中的五个基因变异，并定量评估它们对5-HT合成、再摄取和降解的影响。该模型在140名未受影响的个体上进行了验证，并在101名BD患者上进行了测试。比较了有和没有自杀未遂史的BD患者以及未受影响个体之间5-HT、5-HT前体和降解产物的预测平均浓度。该模型由八个微分方程组成，描述了模型输出的时间浓度变化。未受影响的对照个体中计算出的浓度与已发表的实验测量值一致，验证了我们的模型。与未受影响的个体相比，有自杀未遂史的BD患者计算出的5-HT降解产物5-羟色胺酸（5-HIAA）浓度较低（P = 0.044）。此外，将自杀未遂者与非自杀未遂者进行比较时，观察到游离细胞5-HT（P = 0.048）和储存的5-HT（P = 0.047）的计算浓度较高，效应大小d = 0.35。我们的方法揭示了5-HT系统基因中基因变异的复杂相互作用，这导致了自杀未遂的风险，而通过基因关联研究无法获得定量和个性化的结果。
