Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population
Abstract Background Keratoconus (KC) is a prevalent corneal condition with a modest genetic basis. Recent studies have reported significant genetic associations in multi-ethnic cohorts. However, the situation in the Chinese population remains unknown. This study was conducted to identify novel genet...
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BMC
2025-01-01
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| Series: | Eye and Vision |
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| Online Access: | https://doi.org/10.1186/s40662-024-00421-1 |
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| author | Yinghao Yao Xingyong Li Lan Wu Jia Zhang Yuanyuan Gui Xiangyi Yu Yang Zhou Xuefei Li Xinyu Liu Shilai Xing Gang An Zhenlin Du Hui Liu Shasha Li Xiaoguang Yu Myopia Associated Genetics Intervention and Consortiums Hua Chen Jianzhong Su Shihao Chen |
| author_facet | Yinghao Yao Xingyong Li Lan Wu Jia Zhang Yuanyuan Gui Xiangyi Yu Yang Zhou Xuefei Li Xinyu Liu Shilai Xing Gang An Zhenlin Du Hui Liu Shasha Li Xiaoguang Yu Myopia Associated Genetics Intervention and Consortiums Hua Chen Jianzhong Su Shihao Chen |
| author_sort | Yinghao Yao |
| collection | DOAJ |
| description | Abstract Background Keratoconus (KC) is a prevalent corneal condition with a modest genetic basis. Recent studies have reported significant genetic associations in multi-ethnic cohorts. However, the situation in the Chinese population remains unknown. This study was conducted to identify novel genetic variants linked to KC and to evaluate the potential applicability of a polygenic risk model in the Han Chinese population. Methods A total of 830 individuals diagnosed with KC and 779 controls from a Chinese cohort were enrolled and genotyped by whole-genome sequencing (WGS). Common and rare variants were respectively subjected to single variant association analysis and gene-based burden analysis. Polygenic risk score (PRS) models were developed using top single-nucleotide polymorphisms (SNPs) identified from a multi-ethnic meta-analysis and then evaluated in the Chinese cohort. Results The characterization of germline variants entailed correction for population stratification and validation of the East Asian ancestry of the included samples via principal component analysis. For rare protein-truncating variants (PTVs) with minor allele frequency (MAF) < 5%, ZC3H11B emerged as the top prioritized gene, albeit failing to reach the significance threshold. We detected three common variants reaching genome-wide significance (P ≤ 5 × 10−8), all of which are novel to KC. Our study validated three well known predisposition loci, COL5A1, EIF3A and FNDC3B. Additionally, a significant correlation of allelic effects was observed for suggestive SNPs between the largest multi-ethnic meta-genome-wide association study (GWAS) and our study. The PRS model, generated using top SNPs from the meta-GWAS, stratified individuals in the upper quartile, revealing up to a 2.16-fold increased risk for KC. Conclusions Our comprehensive WGS-based GWAS in a large Chinese cohort enhances the efficiency of array-based genetic studies, revealing novel genetic associations for KC and highlighting the potential for refining clinical decision-making and early prevention strategies. |
| format | Article |
| id | doaj-art-0a7d29512cd14546bd782401a373b158 |
| institution | Kabale University |
| issn | 2326-0254 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Eye and Vision |
| spelling | doaj-art-0a7d29512cd14546bd782401a373b1582025-01-12T12:08:20ZengBMCEye and Vision2326-02542025-01-0112111010.1186/s40662-024-00421-1Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese populationYinghao Yao0Xingyong Li1Lan Wu2Jia Zhang3Yuanyuan Gui4Xiangyi Yu5Yang Zhou6Xuefei Li7Xinyu Liu8Shilai Xing9Gang An10Zhenlin Du11Hui Liu12Shasha Li13Xiaoguang Yu14Myopia Associated Genetics Intervention and ConsortiumsHua Chen15Jianzhong Su16Shihao Chen17Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical UniversityNational Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityBeijing Institute of Genomics, Chinese Academy of Sciences and China National Center for BioinformationNational Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical UniversityInstitute of PSI Genomics, Wenzhou Global Eye & Vision Innovation CenterTaizhou Eye HospitalNational Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityNational Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityInstitute of PSI Genomics, Wenzhou Global Eye & Vision Innovation CenterInstitute of PSI Genomics, Wenzhou Global Eye & Vision Innovation CenterInstitute of PSI Genomics, Wenzhou Global Eye & Vision Innovation CenterNational Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical UniversityInstitute of PSI Genomics, Wenzhou Global Eye & Vision Innovation CenterBeijing Institute of Genomics, Chinese Academy of Sciences and China National Center for BioinformationOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical UniversityNational Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityAbstract Background Keratoconus (KC) is a prevalent corneal condition with a modest genetic basis. Recent studies have reported significant genetic associations in multi-ethnic cohorts. However, the situation in the Chinese population remains unknown. This study was conducted to identify novel genetic variants linked to KC and to evaluate the potential applicability of a polygenic risk model in the Han Chinese population. Methods A total of 830 individuals diagnosed with KC and 779 controls from a Chinese cohort were enrolled and genotyped by whole-genome sequencing (WGS). Common and rare variants were respectively subjected to single variant association analysis and gene-based burden analysis. Polygenic risk score (PRS) models were developed using top single-nucleotide polymorphisms (SNPs) identified from a multi-ethnic meta-analysis and then evaluated in the Chinese cohort. Results The characterization of germline variants entailed correction for population stratification and validation of the East Asian ancestry of the included samples via principal component analysis. For rare protein-truncating variants (PTVs) with minor allele frequency (MAF) < 5%, ZC3H11B emerged as the top prioritized gene, albeit failing to reach the significance threshold. We detected three common variants reaching genome-wide significance (P ≤ 5 × 10−8), all of which are novel to KC. Our study validated three well known predisposition loci, COL5A1, EIF3A and FNDC3B. Additionally, a significant correlation of allelic effects was observed for suggestive SNPs between the largest multi-ethnic meta-genome-wide association study (GWAS) and our study. The PRS model, generated using top SNPs from the meta-GWAS, stratified individuals in the upper quartile, revealing up to a 2.16-fold increased risk for KC. Conclusions Our comprehensive WGS-based GWAS in a large Chinese cohort enhances the efficiency of array-based genetic studies, revealing novel genetic associations for KC and highlighting the potential for refining clinical decision-making and early prevention strategies.https://doi.org/10.1186/s40662-024-00421-1KeratoconusHan ChineseWhole-genome sequencingGenome wide association analysisPolygenic risk prediction |
| spellingShingle | Yinghao Yao Xingyong Li Lan Wu Jia Zhang Yuanyuan Gui Xiangyi Yu Yang Zhou Xuefei Li Xinyu Liu Shilai Xing Gang An Zhenlin Du Hui Liu Shasha Li Xiaoguang Yu Myopia Associated Genetics Intervention and Consortiums Hua Chen Jianzhong Su Shihao Chen Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population Eye and Vision Keratoconus Han Chinese Whole-genome sequencing Genome wide association analysis Polygenic risk prediction |
| title | Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population |
| title_full | Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population |
| title_fullStr | Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population |
| title_full_unstemmed | Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population |
| title_short | Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population |
| title_sort | whole genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a han chinese population |
| topic | Keratoconus Han Chinese Whole-genome sequencing Genome wide association analysis Polygenic risk prediction |
| url | https://doi.org/10.1186/s40662-024-00421-1 |
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