Genetically informed disassortative brain morphometric similarities revealing suicide risk in bipolar disorder.

Biological psychiatry. Cognitive neuroscience and neuroimaging Pub Date : 2025-04-25 DOI:10.1016/j.bpsc.2025.04.011

Ting Wang, Li Xue, Zhongpeng Dai, Junneng Shao, Wei Zhang, Yan Rui, Zhilu Chen, Tingting Xiong, Zhijian Yao, Qing Lu

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Abstract

Background: Cortical structure alterations in bipolar disorder (BD) have consistently been reported in association with suicide with high heritability. Currently, multifaceted genetic landscape responsible for replicable neuroanatomical alterations with suicidal effects is poorly explored to develop personalized risk assessments in clinic.

Methods: Anatomically informed suicidal effects quantified with morphometric similarity network (MSN) upon structural MRI was evaluated in two independent BD cohorts consisted of patients with or without suicide attempt (SA and NSA) (discovery: 63 BD-SAs\72 BD-NSAs with 6 potential suicide-related SNPs examined in 46 BD-SAs\55 BD-NSAs; replication: 23 BD-SAs\23 BD-NSAs) and 119 healthy controls. In discovery study, transcriptomic and neurotransmitter correlates of suicide-relevant MSN deficits were examined by partial least squares regression on Allen Human Brain Atlas and dominance analysis on 9 distinct neurotransmitter systems. Molecularly informed MSN deficits were orthogonally validated by estimating genetic risks from targeted SNP genotyping utilizing a multi-level mediation analysis. Reproducible pattern of genetically decoding suicide-relevant MSN changes was validated in replication study.

Results: Opioid receptor was consistently suggested to be responsible for the reproducible suicide-relevant MSN alterations identified in entorhinal and left lateral occipital cortices. MSN deficits of entorhinal cortex positively mediated the effects of genetic risks of OPRM1 on suicide attempted (portion of mediated = 61.3%, β=6.99e-2, p=.02, 95% CI = [3.34e-2, 0.11]).

Conclusion: Abnormal cytoarchitecture communities, especially maladaptive changes in neuronal communication between entorhinal cortex and reward circuit regulated by opioid receptors reflected by enhanced morphometric similarities could mediate the effect on increased suicidal tendencies involved in OPRM1 gene variants in BD.

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遗传信息的非分类脑形态相似性揭示了双相情感障碍的自杀风险。

背景：双相情感障碍（BD）的皮质结构改变一直被报道与自杀有关，且具有高遗传性。目前，负责可复制的神经解剖改变与自杀影响的多方面基因景观很少被探索，以开发个性化的临床风险评估。方法：在结构MRI上用形态学相似网络（MSN）量化的解剖信息自杀效应在两个独立的BD队列中进行评估，该队列由有或没有自杀企图的患者（SA和NSA）组成(发现：63个BD- sas \72个BD- nsas，在46个BD- sas \55个BD- nsas中检测了6个潜在的自杀相关snp；复制：23个BD-SAs / 23个bd - nsa)和119个健康对照。在发现研究中，通过Allen人脑图谱的偏最小二乘回归和9种不同神经递质系统的优势分析，研究了自杀相关MSN缺陷的转录组学和神经递质相关性。利用多层次中介分析，通过估计靶向SNP基因分型的遗传风险，对分子知情的MSN缺陷进行正交验证。在重复研究中证实了基因解码自杀相关MSN变化的可重复性模式。结果：阿片受体一直被认为是在嗅内皮层和左外侧枕皮质中发现的可重复的自杀相关MSN改变的原因。内嗅皮质MSN缺失正介导OPRM1遗传风险对自杀企图的影响(部分介导= 61.3%,β=6.99e-2, p=。02, 95% CI = [3.34e-2, 0.11])。结论：细胞结构群落的异常，尤其是阿片受体调控的内鼻皮层与奖赏回路之间神经元通讯的不适应变化，通过形态相似性增强反映，可能介导了BD中OPRM1基因变异所涉及的自杀倾向的增加。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Biological psychiatry. Cognitive neuroscience and neuroimaging

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