Genome-wide association study of Fuchs' endothelial corneal dystrophy in the German population.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2025-06-01 Epub Date: 2025-05-12 DOI:10.1007/s00439-025-02749-7
Juliane Fechner, Guilherme B Neumann, Fabia Murza, Leonard Matthias, Marcus Walckling, Claudia Brockmann, Thomas A Fuchsluger, Tobias Brockmann
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引用次数: 0

Abstract

The genetic etiology of Fuchs Endothelial Corneal Dystrophy (FECD) is not yet fully elucidated. While the disease is widespread and the leading indication for corneal transplantation in the Western world, the concurrent shortage of corneal transplants underscores the urgent need for further research into the underlying mechanisms. Such investigations could enable the development of innovative therapeutic strategies. Therefore, we aimed to verify candidate genes previously identified and sought after novel variants in the German population. Undertaking a genome wide association study (GWAS) using the Axiom™ Precision Medicine Diversity Array on 157 FECD cases and 309 controls, followed by pathway enrichment analysis, we were able to confirm the significance of the TCF4 locus (rs613872, p = 8.0 × 10- 23, OR = 8.60, h2 = 0.72) and identified a range of novel variants. Further fine-mapping highlighted novel candidate SNPs, such as on chromosome 5 in the SEMA6A gene (rs153643, p = 3.1 × 10- 9, OR = 2.75, h2 = 0.30), and on chromosome 19 in the DNAJC19P3 gene (rs62117964, p = 3.3 × 10- 8, OR = 3.61, h2 = 0.29). SEMA6A gene is involved in apoptotic pathways and cytoskeletal remodeling, making it an interesting candidate gene for further investigations as a potential therapeutic target. Furthermore, several variants were identified in lncRNAs, which presumably influence the expression of nearby protein-coding genes. For example, LOC105372130, which is associated with corneal hysteresis and corneal resistance factor, may influence the expression of TCF4.

德国人群中Fuchs角膜内皮营养不良的全基因组关联研究。
富克斯内皮性角膜营养不良(FECD)的遗传病因尚未完全阐明。虽然该疾病在西方世界广泛存在,并且是角膜移植的主要适应症,但同时角膜移植的短缺强调了对其潜在机制的进一步研究的迫切需要。这样的研究可以促进创新治疗策略的发展。因此,我们的目标是验证先前在德国人群中发现的候选基因并寻找新的变异。使用Axiom™精密医学多样性阵列对157例FECD病例和309例对照进行了基因组全关联研究(GWAS),随后进行了途径富集分析,我们能够确认TCF4位点(rs613872, p = 8.0 × 10- 23, OR = 8.60, h2 = 0.72)的重要性,并确定了一系列新的变异。进一步的精细定位突出了新的候选snp,例如SEMA6A基因5号染色体上的snp (rs153643, p = 3.1 × 10- 9, OR = 2.75, h2 = 0.30)和DNAJC19P3基因19号染色体上的snp (rs62117964, p = 3.3 × 10- 8, OR = 3.61, h2 = 0.29)。SEMA6A基因参与凋亡途径和细胞骨架重塑,使其成为一个值得进一步研究的潜在治疗靶点的候选基因。此外,在lncrna中发现了一些变异,这些变异可能会影响附近蛋白质编码基因的表达。例如,与角膜迟滞和角膜阻力因子相关的LOC105372130可能会影响TCF4的表达。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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