A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for erectile dysfunction.

IF 3.2 2区 医学 Q1 ANDROLOGY
Andrology Pub Date : 2025-03-27 DOI:10.1111/andr.70034
Tianle Zhu, Yukuai Ma, Peng Yang, Zhi Cao, Jingjing Gao, Junhua Du, Pan Gao, Hui Jiang, Xiansheng Zhang
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Abstract

Background: Erectile dysfunction (ED) is a common condition affecting millions of men worldwide. While genome-wide association studies (GWAS) have identified genetic loci associated with ED risk, the potential causative genes and their biological mechanisms leading to ED remain largely unexplored.

Objectives: This study aimed to conduct a comprehensive cross-tissue transcriptome-wide association study (TWAS) to identify susceptibility genes associated with ED risk.

Materials and methods: We conducted a cross-tissue TWAS analysis integrating GWAS data for ED with eQTL files from Genotype-Tissue Expression Project (GTEx) V8. We used the unified test for molecular signatures (UTMOST) for cross-tissue analysis and functional summary-based imputation (FUSION) for single-tissue validation. Candidate genes were further validated through multi-marker analysis of genomic annotation (MAGMA), conditional and joint (COJO) analysis, and colocalization analysis.

Results: The cross-tissue TWAS analysis identified 118 significant genes associated with ED, while the single-tissue TWAS validation revealed 3804 significant genes. Nine candidate genes (CPT1B, CSF2RB, DNAH7, EHD3, L3MBTL2, LCLAT1, MDH1B, REEP1, and SLC30A6) were consistently identified across the TWAS and MAGMA analyses. COJO analysis revealed that LCLAT1 accounted for most of the signals at their respective loci. Colocalization analysis confirmed LCLAT1 as the primary candidate gene, showing strong colocalization with ED in testis, brain cortex, and heart left ventricle.

Discussion and conclusion: This comprehensive cross-tissue TWAS analysis identified LCLAT1 as a primary susceptibility gene for ED, highlighting its potential role in the mitochondrial function and lipid metabolism. The study also revealed several secondary candidate genes that may contribute to ED through pathways related to mitochondrial dynamics, neurotransmission, and cardiovascular function. These findings provide new perspectives on the genetic architecture of ED and suggest potential targets for future research and treatment.

一项跨组织转录组关联研究揭示了勃起功能障碍的新型易感基因。
背景:勃起功能障碍(ED)是影响全世界数百万男性的常见疾病。虽然全基因组关联研究(GWAS)已经确定了与ED风险相关的遗传位点,但导致ED的潜在致病基因及其生物学机制在很大程度上仍未被探索。目的:本研究旨在开展一项全面的跨组织转录组关联研究(TWAS),以确定与ED风险相关的易感基因。材料和方法:我们将ED的GWAS数据与来自Genotype-Tissue Expression Project (GTEx) V8的eQTL文件进行了跨组织TWAS分析。我们使用统一的分子特征测试(most)进行跨组织分析,使用基于功能汇总的归算(FUSION)进行单组织验证。候选基因通过基因组注释多标记分析(MAGMA)、条件联合分析(COJO)和共定位分析进一步验证。结果:跨组织TWAS分析鉴定出118个与ED相关的显著基因,而单组织TWAS验证发现3804个显著基因。9个候选基因(CPT1B、CSF2RB、DNAH7、EHD3、L3MBTL2、LCLAT1、MDH1B、REEP1和SLC30A6)在TWAS和MAGMA分析中一致地被鉴定出来。COJO分析显示LCLAT1占据了它们各自位点上的大部分信号。共定位分析证实LCLAT1为主要候选基因,在睾丸、大脑皮层和心脏左心室显示与ED强共定位。讨论和结论:这项全面的跨组织TWAS分析确定LCLAT1是ED的主要易感基因,突出了其在线粒体功能和脂质代谢中的潜在作用。该研究还揭示了几个次要的候选基因,这些基因可能通过与线粒体动力学、神经传递和心血管功能相关的途径导致ED。这些发现为ED的遗传结构提供了新的视角,并为未来的研究和治疗提供了潜在的靶点。
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来源期刊
Andrology
Andrology ANDROLOGY-
CiteScore
9.10
自引率
6.70%
发文量
200
期刊介绍: Andrology is the study of the male reproductive system and other male gender related health issues. Andrology deals with basic and clinical aspects of the male reproductive system (gonads, endocrine and accessory organs) in all species, including the diagnosis and treatment of medical problems associated with sexual development, infertility, sexual dysfunction, sex hormone action and other urological problems. In medicine, Andrology as a specialty is a recent development, as it had previously been considered a subspecialty of urology or endocrinology
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