Shen Jie, Valentim Wander, Friligkou Eleni, Overstreet Cassie, Choi Karmel, Koller Dora, O'Donnell Christopher J, Stein Murray B, Gelernter Joel, Lv Haitao, Sun Ling, Falcone Guido J, Polimanti Renato, Pathak Gita A
Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
medRxiv. 2024 Aug 21:2024.08.20.24312181. doi: 10.1101/2024.08.20.24312181.
Patients with post-traumatic stress disorder (PTSD) experience higher risk of adverse cardiovascular (CV) outcomes. This study explores shared loci, and genes between PTSD and CV conditions from three major domains: CV diagnoses from electronic health records (CV-EHR), cardiac and aortic imaging, and CV health behaviors defined in Life's Essential 8 (LE8).
We used genome-wide association study (GWAS) of PTSD (N=1,222,882), 246 CV diagnoses based on EHR data from Million Veteran Program (MVP; N=458,061), UK Biobank (UKBB; N=420,531), 82 cardiac and aortic imaging traits (N=26,893), and GWAS of traits defined in the LE8 (N = 282,271 ~ 1,320,016). Shared loci between PTSD and CV conditions were identified using local genetic correlations (rg), and colocalization (shared causal variants). Overlapping genes between PTSD and CV conditions were identified from genetically regulated proteome expression in brain and blood tissues, and subsequently tested to identify functional pathways and gene-drug targets. Epidemiological replication of EHR-CV diagnoses was performed in AllofUS cohort (AoU; N=249,906).
Among the 76 PTSD-susceptibility risk loci, 33 loci exhibited local rg with 45 CV-EHR traits (|rg|≥0.4), four loci with eight heart imaging traits(|rg|≥0.5), and 44 loci with LE8 factors (|rg|≥0.36) in MVP. Among significantly correlated loci, we found shared causal variants (colocalization probability > 80%) between PTSD and 17 CV-EHR (in MVP) at 11 loci in MVP, that also replicated in UKBB and/or other cohorts. Of the 17 traits, the observational analysis in the AoU showed PTSD was associated with 13 CV-EHR traits after accounting for socioeconomic factors and depression diagnosis. PTSD colocalized with eight heart imaging traits on 2 loci and with LE8 factors on 31 loci. Leveraging blood and brain proteome expression, we found 33 and 122 genes, respectively, shared between PTSD and CVD. Blood proteome genes were related to neuronal and immune processes, while the brain proteome genes converged on metabolic and calcium-modulating pathways (FDR p <0.05). Drug repurposing analysis highlighted as common targets of psychiatric and CV drugs.
PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms.
创伤后应激障碍（PTSD）患者发生不良心血管（CV）结局的风险更高。本研究从三个主要领域探索PTSD与CV疾病之间的共享基因座和基因：电子健康记录中的CV诊断（CV-EHR）、心脏和主动脉成像，以及生命基本八项（LE8）中定义的CV健康行为。
我们对PTSD（N = 1,222,882）、基于百万退伍军人计划（MVP；N = 458,061）、英国生物银行（UKBB；N = 420,531）的电子健康记录数据的246种CV诊断、82种心脏和主动脉成像特征（N = 26,893）以及LE8中定义的特征（N = 282,271~1,320,016）进行了全基因组关联研究（GWAS）。使用局部遗传相关性（rg）和共定位（共享因果变异）确定PTSD与CV疾病之间的共享基因座。从大脑和血液组织中的基因调控蛋白质组表达中确定PTSD与CV疾病之间重叠的基因，随后进行测试以确定功能途径和基因药物靶点。在全美国队列（AoU；N = 249,906）中对EHR-CV诊断进行了流行病学重复研究。
在76个PTSD易感性风险基因座中，33个基因座在MVP中与45种CV-EHR特征表现出局部rg（|rg|≥0.4），4个基因座与8种心脏成像特征（|rg|≥0.5），44个基因座与LE8因素（|rg|≥0.36）。在显著相关的基因座中，我们在MVP的11个基因座上发现PTSD与17种CV-EHR（在MVP中）之间存在共享因果变异（共定位概率>80%），这也在UKBB和/或其他队列中得到了重复。在这17种特征中，AoU中的观察性分析表明，在考虑社会经济因素和抑郁症诊断后，PTSD与13种CV-EHR特征相关。PTSD在2个基因座上与8种心脏成像特征共定位，在31个基因座上与LE8因素共定位。利用血液和大脑蛋白质组表达，我们分别发现PTSD和心血管疾病（CVD）之间共享33个和122个基因。血液蛋白质组基因与神经元和免疫过程相关，而大脑蛋白质组基因集中在代谢和钙调节途径上（FDR p<0.05）。药物重新利用分析突出显示[此处原文似乎缺失内容]为精神科和CV药物的共同靶点。
PTSD-CV共病表现出共享的风险基因座，以及参与组织特异性调节机制的基因。
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