Valvular & structural heart disease
Multisystem comorbidities and shared genetic pathways in calcific aortic stenosis: a phenome-wide and Mendelian randomisation analysis
Authors' conclusion
CAS is embedded within a broad multisystem comorbidity network, driven largely by genetic variation at LPA and elevated Lp(a). These findings highlight pleiotropic mechanisms linking valvular calcification with systemic disease and support LPA-targeted therapies as a promising avenue for reducing the multisystem burden of CAS.
Study context
- Population
- Participants from the UK Biobankparticipants from the UK Biobank
- Participants
- 467,484 participants
- Comparison
- Associations between calcific aortic stenosis (CAS) and 1571 phenotypes
- Outcome
- Associations of CAS with cardiovascular and non-cardiovascular conditions
Methodological detailsobservational and polygenic phenome-wide association studies, disease-trajectory analyses, two-sample Mendelian randomisation (MR), Polygenic risk score (PRS) analyses
- Observational and polygenic phenome-wide association studies
- Disease-trajectory analyses
- Two-sample Mendelian randomisation (MR)
- Polygenic risk score (PRS) analyses
Performance
As reported in the abstract
- CAS associated with higher risks of cardiovascular and non-cardiovascular conditions, most prominently metabolic, endocrine, haematological and respiratory disorders
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Further findings
Temporal patterns of comorbidities
- Circulatory and metabolic diseases typically precede other comorbidities in CAS trajectories
MR causal effects of CAS
- Consistent with causal effects of CAS on multiple cardiovascular diseases, iron-deficiency anaemia, mental disorders and pleural effusion
PRS analyses excluding LPA variants or adjusting for plasma Lp(a)
- Most associations lost significance, indicating a shared LPA/Lp(a)-mediated genetic pathway
Original publication
Multisystem comorbidities and shared genetic pathways in calcific aortic stenosis: a phenome-wide and Mendelian randomisation analysis. Heart. Published 29 December 2025. doi:10.
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