Cross-ancestry GWAS meta-analysis identified 157 loci for VHD and subtypes, including 83 novel loci, revealing distinct genetic architectures and causal role of blood pressure.
This large-scale GWAS and cross-ancestry meta-analysis identified 157 genetic loci associated with valvular heart disease, revealing distinct genetic architectures for different VHD subtypes and highlighting the potential of polygenic risk scores for predicting VHD-related cardiovascular mortality.
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Abstract Background Valvular heart disease (VHD) is one of the critical determinants of human health that lead to heart failure. However, the genetic architectures of VHD and its subtypes have yet to be fully elucidated. Purpose We aimed to clarify the genetic architectures of VHD and its subtypes and to gain insights into VHD biology. Methods We performed deep-phenotyping by analysing detailed medical records and echocardiographic data from BioBank Japan. We classified VHD subtypes from stenosis to regurgitation and other abnormalities in the mitral, aortic, tricuspid, and pulmonary valves and the septum, followed by conducting East Asian-specific GWASs. Then, we also performed GWASs in the UK Biobank, applying deep-phenotyping using ICD-10 codes. In addition, we utilised other available GWAS summary statistics, mainly from FinnGen and VA’s Million Veteran Program. Finally, we conducted cross-ancestry meta-analyses. Results An East Asian-specific GWAS for VHD with 10,358 cases and 128,008 controls identified five genome-wide significant loci, while GWASs for VHD subtypes identified an additional 14 loci. Of the identified 19 loci, 14 had not been previously reported in GWASs for any valve diseases, whereas 12 exhibited very low allele frequencies (0.001) in other ancestries. Moreover, cross-ancestry meta-analysis for VHD, which involves 93,584 cases and 1,619,230 controls from East Asian, European, African, and American cohorts, revealed 89 loci. Then, meta-analyses for VHD subtypes identified an additional 68 loci, totalling 157 loci, including 83 novel loci. Valve regurgitation and stenosis shared only one locus, suggesting different aetiologies. Interestingly, all regurgitation subtypes (mitral, aortic, tricuspid, and pulmonary) shared a locus prioritised for PITX2 with relatively high absolute betas ( 0.1), indicating a pivotal role of PITX2. Pathway analysis revealed that genes associated with VHD were enriched for heart morphogenesis and cardiac cell differentiation. Additionally, VHD exhibited a significant genetic correlation with atrial fibrillation (AF), congestive heart failure (CHF), and blood pressure (BP), while Mendelian randomisation analysis indicated a causal role of BP in VHD. Furthermore, the polygenic risk score (PRS) for VHD stratified the risk of cardiovascular mortality in the other controls in BBJ. The combination of PRS for CHF or AF with that for VHD outperformed original PRS in the prediction of CHF or AF, suggesting that VHD has a genetically independent factor in these diseases. Conclusion We conducted the first systematic GWASs for VHD and its subtypes. These analyses elucidated the distinct genetic architectures of different VHD subtypes and their correlations with other cardiovascular conditions. Furthermore, this research demonstrated the potential of PRS in predicting VHD-related cardiovascular mortality and improving risk assessment for CHF and AF, highlighting the complex genetic basis of VHD.
Kurosawa et al. (Sat,) reported a other. Cross-ancestry GWAS meta-analysis identified 157 loci for VHD and subtypes, including 83 novel loci, revealing distinct genetic architectures and causal role of blood pressure.