探究创伤后应激障碍和胃肠道疾病的共享遗传结构：全基因组跨表型分析。

Investigating the shared genetic architecture of post-traumatic stress disorder and gastrointestinal tract disorders: a genome-wide cross-trait analysis.

机构信息

West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center, Sichuan University, Chengdu, China.

Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.

出版信息

Psychol Med. 2023 Dec;53(16):7627-7635. doi: 10.1017/S0033291723001423. Epub 2023 May 23.

DOI:10.1017/S0033291723001423

PMID:37218628

Abstract

BACKGROUND

Observational studies suggest a correlation between post-traumatic stress disorder (PTSD) and gastrointestinal tract (GIT) disorders. However, the genetic overlap, causal relationships, and underlining mechanisms between PTSD and GIT disorders were absent.

METHODS

We obtained genome-wide association study statistics for PTSD (23 212 cases, 151 447 controls), peptic ulcer disease (PUD; 16 666 cases, 439 661 controls), gastroesophageal reflux disease (GORD; 54 854 cases, 401 473 controls), PUD and/or GORD and/or medications (PGM; 90 175 cases, 366 152 controls), irritable bowel syndrome (IBS; 28 518 cases, 426 803 controls), and inflammatory bowel disease (IBD; 7045 cases, 449 282 controls). We quantified genetic correlations, identified pleiotropic loci, and performed multi-marker analysis of genomic annotation, fast gene-based association analysis, transcriptome-wide association study analysis, and bidirectional Mendelian randomization analysis.

RESULTS

PTSD globally correlates with PUD ( = 0.526, = 9.355 × 10), GORD ( = 0.398, = 5.223 × 10), PGM ( = 0.524, = 1.251 × 10), and IBS ( = 0.419, = 8.825 × 10). Cross-trait meta-analyses identify seven genome-wide significant loci between PTSD and PGM (rs13107325, rs1632855, rs1800628, rs2188100, rs3129953, rs6973700, and rs73154693); three between PTSD and GORD (rs13107325, rs1632855, and rs3132450); one between PTSD and IBS/IBD (rs4937872 and rs114969413, respectively). Proximal pleiotropic genes are mainly enriched in immune response regulatory pathways, and in brain, digestive, and immune systems. Gene-level analyses identify five candidates: , , , , and . We found significant causal effects of GORD, PGM, IBS, and IBD on PTSD. We observed no reverse causality of PTSD with GIT disorders, except for GORD.

CONCLUSIONS

PTSD and GIT disorders share common genetic architectures. Our work offers insights into the biological mechanisms, and provides genetic basis for translational research studies.

摘要

背景

观察性研究表明创伤后应激障碍（PTSD）与胃肠道（GIT）疾病之间存在相关性。然而，PTSD 和 GIT 疾病之间的遗传重叠、因果关系和潜在机制尚不清楚。

方法

我们获得了 PTSD（23212 例病例，151447 例对照）、消化性溃疡病（PUD；16666 例病例，439661 例对照）、胃食管反流病（GORD；54854 例病例，401473 例对照）、PUD 和/或 GORD 和/或药物治疗（PGM；90175 例病例，366152 例对照）、肠易激综合征（IBS；28518 例病例，426803 例对照）和炎症性肠病（IBD；7045 例病例，449282 例对照）的全基因组关联研究统计数据。我们量化了遗传相关性，确定了多效性位点，并进行了基因组注释的多标记分析、快速基因关联分析、全转录组关联研究分析以及双向孟德尔随机化分析。

结果

PTSD 与 PUD（ = 0.526， = 9.355×10）、GORD（ = 0.398， = 5.223×10）、PGM（ = 0.524， = 1.251×10）和 IBS（ = 0.419， = 8.825×10）整体相关。跨特征荟萃分析确定了 PTSD 和 PGM 之间的七个全基因组显著位点（rs13107325、rs1632855、rs1800628、rs2188100、rs3129953、rs6973700 和 rs73154693）；三个在 PTSD 和 GORD 之间（rs13107325、rs1632855 和 rs3132450）；一个在 PTSD 和 IBS/IBD 之间（rs4937872 和 rs114969413）。近端多效性基因主要富集在免疫反应调节途径中，以及在大脑、消化和免疫系统中。基因水平分析确定了五个候选基因：、、、、。我们发现 GORD、PGM、IBS 和 IBD 对 PTSD 有显著的因果影响。我们没有观察到 PTSD 对 GIT 疾病的反向因果关系，除了 GORD。