A multi-ancestry genome-wide association study of dry eye disease and systemic comorbidities.

IF 11.2 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2026-10-01 Epub Date: 2026-09-25 DOI:10.1016/j.ebiom.2026.106490

Bryan R Gorman, Jaxon J Huang, Peter B Barr, Christopher W Halladay, Cari L Nealon, Chris Chatzinakos, Michael Francis, Chen Jiang, Paul B Greenberg, Wen-Chih Wu, Saiju Pyarajan, Hélène Choquet, Tim B Bigdeli, Sudha K Iyengar, Neal S Peachey, Anat Galor

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引用次数: 0

Abstract

Background: Dry eye disease (DED) affects up to 25% of the adult population, with chronic symptoms of pain and dryness often negatively impacting quality of life. Twin studies indicate a substantial heritability. However, the genetic architecture of DED is largely unknown.

Methods: We devised a case-control algorithm using a combination of ICD-9/10 codes and prescription records and validated its performance through manual chart review, identifying 132,637 DED cases and 352,201 controls across four ancestry groups in the Million Veteran Program biobank. We then performed multi-ancestry genome-wide and phenome-wide association scans. A replication analysis was performed in the Genetic Epidemiology Research on Adult Health and Aging biobank (up to 16,025 cases and 54,818 controls). Genetic correlations were assessed using linkage disequilibrium score regression and multivariate relationships were modelled using genomic structural equation modelling (genomicSEM).

Findings: We identify ten significant loci in nine susceptibility regions with largely consistent effects across ancestries, including loci linked to synapse maintenance (EFNA5, GRIA1, and SYNGAP1) and autoimmunity (BLK). Phenome-wide scans for genetic pleiotropy indicate substantial genetic correlations of DED with numerous comorbidities, including fibromyalgia (r_G = 0.69, 95% confidence interval, CI: [0.58, 0.81]), post-traumatic stress disorder (r_G = 0.58, 95% CI: [0.42, 0.75]), and Sjögren's disease (r_G = 0.40, 95% CI: [0.23, 0.57]). GenomicSEM identified a latent factor underlying DED and other chronic pain traits which accounted for 51% of the genetic variance of DED.

Interpretation: The observed genetic correlations are consistent with shared genetic liability between DED and chronic pain, autoimmune, and psychiatric traits, but do not establish causal direction.

Funding: This work was supported by the US Department of Veterans Affairs, the Department of Defense, the National Eye Institute/NIH, and Research to Prevent Blindness. Full funding details are provided in the Acknowledgements.

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干眼病和全身合并症的多祖先全基因组关联研究

背景：干眼病（DED）影响多达25%的成年人，伴有疼痛和干燥的慢性症状，通常对生活质量产生负面影响。双胞胎研究表明有很大的遗传性。然而，DED的遗传结构在很大程度上是未知的。方法：我们设计了一种结合ICD-9/10代码和处方记录的病例对照算法，并通过人工图表审查验证其性能，在百万退伍军人计划生物库中确定了四个祖先群体的132,637例DED病例和352,201例对照。然后，我们进行了多祖先全基因组和全现象关联扫描。在成人健康和衰老生物库遗传流行病学研究（多达16025例和54818例对照）中进行了复制分析。使用连锁不平衡评分回归评估遗传相关性，使用基因组结构方程建模（genomicSEM）对多变量关系进行建模。研究结果：我们在9个易感区域中发现了10个重要的基因座，这些基因座在整个祖先中具有基本一致的作用，包括与突触维持（EFNA5、GRIA1和SYNGAP1）和自身免疫（BLK）相关的基因座。遗传多效性的全现象扫描显示，DED与许多合并症存在显著的遗传相关性，包括纤维肌痛（rG = 0.69, 95%可信区间，CI:[0.58, 0.81]）、创伤后应激障碍（rG = 0.58, 95% CI:[0.42, 0.75]）和Sjögren病（rG = 0.40, 95% CI:[0.23, 0.57]）。GenomicSEM发现了DED和其他慢性疼痛特征的潜在因素，占DED遗传变异的51%。解释：观察到的遗传相关性与DED与慢性疼痛、自身免疫和精神特征之间的共同遗传倾向是一致的，但不能确定因果关系。资助：这项工作得到了美国退伍军人事务部、国防部、国家眼科研究所/美国国立卫生研究院和预防失明研究机构的支持。在致谢中提供了完整的资金细节。

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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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.