Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Transl Vis Sci Technol. 2023 Aug 1;12(8):8. doi: 10.1167/tvst.12.8.8.
The genetic architecture of corneal dysfunction remains poorly understood. Epidemiological and clinical evidence suggests a relationship between corneal structural features and anthropometric measures. We used global and local genetic similarity analysis to identify genomic features that may underlie structural corneal dysfunction.
We assembled genome-wide association study summary statistics for corneal features (central corneal thickness, corneal hysteresis [CH], corneal resistance factor [CRF], and the 3 mm index of keratometry) and anthropometric traits (body mass index, weight, and height) in Europeans. We calculated global genetic correlations (rg) between traits using linkage disequilibrium (LD) score regression and local genetic covariance using ρ-HESS, which partitions the genome and performs regression with LD regions. Finally, we identified genes located within regions of significant genetic covariance and analyzed patterns of tissue expression and pathway enrichment.
Global LD score regression revealed significant negative correlations between height and both CH (rg = -0.12; P = 2.0 × 10-7) and CRF (rg = -0.11; P = 6.9 × 10-7). Local analysis revealed 68 genomic regions exhibiting significant local genetic covariance between CRF and height, containing 2874 unique genes. Pathway analysis of genes in regions with significant local rg revealed enrichment among signaling pathways with known keratoconus associations, including cadherin and Wnt signaling, as well as enrichment of genes modulated by copper and zinc ions.
Corneal biophysical parameters and height share a common genomic architecture, which may facilitate identification of disease-associated genes and therapies for corneal ectasias.
Local genetic covariance analysis enables the identification of associated genes and therapeutic targets for corneal ectatic disease.
角膜功能障碍的遗传结构仍知之甚少。流行病学和临床证据表明，角膜结构特征与人体测量学指标之间存在关系。我们使用全局和局部遗传相似性分析来确定可能导致结构角膜功能障碍的基因组特征。
我们汇总了欧洲人群角膜特征（中央角膜厚度、角膜滞后量[CH]、角膜阻力因子[CRF]和 3 毫米角膜曲率指数）和人体测量学特征（体重指数、体重和身高）的全基因组关联研究汇总统计数据。我们使用连锁不平衡（LD）得分回归计算性状之间的全局遗传相关性（rg），并使用 ρ-HESS 计算局部遗传协方差，ρ-HESS 对基因组进行分区并使用 LD 区域进行回归。最后，我们确定了位于显著遗传协方差区域内的基因，并分析了组织表达和途径富集的模式。
全局 LD 得分回归显示身高与 CH（rg = -0.12；P = 2.0×10-7）和 CRF（rg = -0.11；P = 6.9×10-7）之间存在显著负相关。局部分析显示 CRF 与身高之间存在 68 个具有显著局部遗传协方差的基因组区域，包含 2874 个独特基因。具有显著局部 rg 区域的基因通路分析显示，已知与圆锥角膜相关的信号通路，包括钙粘蛋白和 Wnt 信号通路，以及受铜和锌离子调节的基因通路存在富集。
角膜生物物理参数和身高具有共同的遗传结构，这可能有助于鉴定角膜扩张相关的疾病相关基因和治疗方法。
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