{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:45:08Z","timestamp":1784904308829,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation China Grant","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"National Natural Science Foundation China Grant","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"National Natural Science Foundation China Grant","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]},{"name":"National Natural Science Foundation China (NSFC) Young Scientist Grant","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"National Natural Science Foundation China (NSFC) Young Scientist Grant","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"National Natural Science Foundation China (NSFC) Young Scientist Grant","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]},{"name":"Chinese University of Hong Kong","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"Chinese University of Hong Kong","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"Chinese University of Hong Kong","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]},{"name":"KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]},{"name":"Kunming Institute of Zoology","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"Kunming Institute of Zoology","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"Kunming Institute of Zoology","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]},{"name":"Hong Kong Branch of the Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"Hong Kong Branch of the Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"Hong Kong Branch of the Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]},{"name":"Research Project of Zhejiang Chinese Medical University","award":["81971706"],"award-info":[{"award-number":["81971706"]}]},{"name":"Research Project of Zhejiang Chinese Medical University","award":["31900495"],"award-info":[{"award-number":["31900495"]}]},{"name":"Research Project of Zhejiang Chinese Medical University","award":["2023RCZXZK32"],"award-info":[{"award-number":["2023RCZXZK32"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The coronavirus disease 2019 (COVID-19) pandemic has led to substantial health and financial burdens worldwide, and vaccines provide hope for reducing the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWASs) may identify potential genetic factors involved in the development of COVID-19 breakthrough infections (BIs); however, very few or no GWASs have been conducted for COVID-19 BI thus far. We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BIs in a European population via the UK Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BIs and hospitalized infections. The polygenic risk score (PRS) and Hoeffding\u2019s test were performed to reveal the genetic relationships between BIs and other medical conditions. Two independent loci (LD-clumped at r2 = 0.01) reached genome-wide significance (p &lt; 5 \u00d7 10\u22128), including rs36170929, which mapped to LOC102725191\/VWDE, and rs28645263, which mapped to RETREG1. A pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. The PRS analyses revealed significant genetic overlap between COVID-19 BIs and heart failure and between HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BIs and asthma, lung abnormalities, schizophrenia, and type 1 diabetes on the basis of Hoeffding\u2019s test. This GWAS revealed two significant loci that may be associated with COVID-19 BIs and a number of genes and pathways that may be involved in BIs. Genetic overlap with other diseases was identified. Further studies are warranted to replicate these findings and elucidate the mechanisms involved.<\/jats:p>","DOI":"10.3390\/ijms26136441","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T04:51:17Z","timestamp":1751604677000},"page":"6441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genome-Wide Association Study of COVID-19 Breakthrough Infections and Genetic Overlap with Other Diseases: A Study of the UK Biobank"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2920-5102","authenticated-orcid":false,"given":"Yaning","family":"Feng","sequence":"first","affiliation":[{"name":"School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou 310053, China"},{"name":"School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5397-6224","authenticated-orcid":false,"given":"Kenneth Chi-Yin","family":"Wong","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai Kai","family":"Tsui","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6089-7476","authenticated-orcid":false,"given":"Ruoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4378-3450","authenticated-orcid":false,"given":"Yong","family":"Xiang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7102-833X","authenticated-orcid":false,"given":"Hon-Cheong","family":"So","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology and The Chinese University of Hong Kong, Kunming 650204, China"},{"name":"Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"CUHK Shenzhen Research Institute, Shenzhen 518172, China"},{"name":"Margaret K.L. Cheung Research Centre for Management of Parkinsonism, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"Brain and Mind Institute, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"Hong Kong Branch of the Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.21105\/joss.02376","article-title":"COVID-19 data hub","volume":"5","author":"Guidotti","year":"2020","journal-title":"J. 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