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.
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.