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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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A total of 830 individuals diagnosed with KC and 779 controls from a Chinese cohort were enrolled and genotyped by whole-genome sequencing\u00a0(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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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)\u2009&lt;\u20095%, <jats:italic>ZC3H11B<\/jats:italic> emerged as the top prioritized gene, albeit failing to reach the significance threshold. We detected three common variants reaching genome-wide significance (<jats:italic>P<\/jats:italic>\u2009\u2264\u20095\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>), all of which are novel to KC. Our study validated three well known predisposition loci, <jats:italic>COL5A1<\/jats:italic>, <jats:italic>EIF3A<\/jats:italic> and <jats:italic>FNDC3B<\/jats:italic>. 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40662-024-00421-1","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T13:32:10Z","timestamp":1736170330000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population"],"prefix":"10.1186","volume":"12","author":[{"given":"Yinghao","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Gui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilai","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenlin","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoguang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Myopia Associated Genetics Intervention and Consortiums","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7646-8003","authenticated-orcid":false,"given":"Shihao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"issue":"4","key":"421_CR1","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S0039-6257(97)00119-7","volume":"42","author":"YS Rabinowitz","year":"1998","unstructured":"Rabinowitz YS. 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