Integration of Metabolomic and Brain Imaging Data Highlights Pleiotropy Among Posttraumatic Stress Disorder, Glycoprotein Acetyls, and Pallidum Structure

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science Pub Date : 2025-03-17 DOI:10.1016/j.bpsgos.2025.100482

Solveig Løkhammer , Markos Tesfaye , Brenda Cabrera-Mendoza , Kristoffer Sandås , Gita A. Pathak , Eleni Friligkou , Stéphanie Le Hellard , Renato Polimanti

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Abstract

Background

The development of posttraumatic stress disorder (PTSD) is attributable to the interplay between exposure to severe traumatic events, environmental factors, and biological characteristics. Blood and brain imaging markers have been associated with PTSD. However, to our knowledge, no study has systematically investigated the genetic relationship between PTSD, metabolic biomarkers, and brainwide imaging.

Methods

We integrated genome-wide data informative of PTSD, 233 metabolic biomarkers, and 3935 brain imaging-derived phenotypes (IDPs). Pleiotropy was assessed by applying global and local genetic correlation, colocalization, and genetically inferred causality.

Results

We observed significant genetic overlap between PTSD and glycoprotein acetyls (GlycA) (a stable inflammatory biomarker) in 2 independent cohorts (discovery r_g = 0.26, p = 1.00 × 10⁻⁴; replication r_g = 0.23, p = 5.99 × 10⁻¹⁹). Interestingly, there was no genetic correlation between anxiety and GlycA (p = .33). PTSD and GlycA were both genetically correlated with median T2∗ in the left pallidum (IDP-1444: r_g = 0.14, p = 1.39 × 10⁻⁵; r_g = −0.38, p = 2.50 × 10⁻³, respectively). Local genetic correlation between PTSD and GlycA was observed in 7 genetic regions (p < 2.0 × 10⁻⁵), mapping genes related to immune and stress response, inflammation, and metabolic processes. Furthermore, we identified 1 variant, rs12048743, with evidence of horizontal pleiotropy linking GlycA and IDP-1444 (z_IDP-1444 = 17.14, z_GlycA = −6.07, theta p = 2.06 × 10⁻⁸). Regional colocalization was observed among GlycA, IDP-1444, and tissue-specific transcriptomic regulation for brain frontal cortex and testis (rs12048743—chr1q32.1; posterior probability > 0.8). While we also tested causality between PTSD, metabolomic biomarkers, and brain IDPs, these were not consistent across different genetically informed causal inference methods.

Conclusions

Our findings highlight a new putative pleiotropic mechanism that links systemic inflammation and pallidum structure to PTSD.

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代谢组学和脑成像数据的整合突出了创伤后应激障碍、糖蛋白乙酰和苍白质结构中的多效性

创伤后应激障碍（PTSD）的发展可归因于暴露于严重创伤事件、环境因素和生物学特征之间的相互作用。血液和脑成像标记与创伤后应激障碍有关。然而，据我们所知，还没有研究系统地调查了创伤后应激障碍、代谢生物标志物和全脑成像之间的遗传关系。方法整合创伤后应激障碍、233种代谢生物标志物和3935种脑成像衍生表型（IDPs）的全基因组数据。通过应用全局和局部遗传相关性、共定位和遗传推断因果关系来评估多效性。结果在2个独立队列中，我们发现PTSD与糖蛋白乙酰（GlycA）（一种稳定的炎症生物标志物）之间存在显著的遗传重叠(发现rg = 0.26, p = 1.00 × 10−4；rg = 0.23, p = 5.99 × 10−19)。有趣的是，焦虑和GlycA之间没有遗传相关性（p = 0.33）。PTSD和GlycA均与左侧苍白质中位T2 *基因相关(IDP-1444: rg = 0.14, p = 1.39 × 10−5；Rg =−0.38,p = 2.50 × 10−3)。PTSD与GlycA在7个遗传区域存在局部遗传相关性(p <；2.0 × 10−5)，绘制与免疫和应激反应、炎症和代谢过程相关的基因。此外，我们鉴定出1个变异rs12048743，证明GlycA和IDP-1444之间存在水平多效性（zIDP-1444 = 17.14, zGlycA = - 6.07, theta p = 2.06 × 10 - 8）。GlycA、IDP-1444以及脑额叶皮质和睾丸的组织特异性转录组调控(rs12048743-chr1q32.1；后验概率>；0.8)。虽然我们也测试了PTSD、代谢组学生物标志物和脑IDPs之间的因果关系，但这些因果关系在不同的遗传信息因果推理方法中并不一致。结论我们的研究结果强调了一种新的假定的多效性机制，将全身性炎症和白质结构与PTSD联系起来。

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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