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Vertical pleiotropy biases genetic variances and covariances, influencing essential estimates such as SNP-based heritability and genetic correlation in traditional methods. By addressing these biases, the HVP model enhances accuracy in parameter estimation. Real data analysis shows that horizontal pleiotropy significantly contributes to genetic correlations between metabolic syndrome (MetS) and traits such as type 2 diabetes, C-reactive protein (CRP), sleep apnoea, and cholelithiasis, whereas vertical pleiotropy is more relevant between body mass index (BMI) and MetS, and MetS and cardiovascular diseases. These findings suggest that action on modifiable factors like lowering BMI may effectively reduce MetS risk, while CRP\u2014though not causative\u2014serves as a useful marker in risk prediction through horizontal pleiotropic genes. These results confirm the HVP model\u2019s relevance and utility in revealing the complex genetic architecture underlying traits such as metabolic syndrome, highlighting its potential to inform precision healthcare.<\/jats:p>","DOI":"10.1007\/s00439-025-02762-w","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T05:18:29Z","timestamp":1757999909000},"page":"861-876","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Disentangling horizontal and vertical Pleiotropy in genetic correlation estimation: introducing the HVP model"],"prefix":"10.1007","volume":"144","author":[{"given":"Lamessa Dube","family":"Amente","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie T.","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuc Duy","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Hypp\u00f6nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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