New Genetic Loci Implicated in Cardiac Morphology and Function Using Three-Dimensional Population Phenotyping.
Authors
Affiliations (9)
Affiliations (9)
- MRC Laboratory of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, United Kingdom. (C.L., K.A.M., S.L.Z., A.d.M., P.I., J.S.W., D.P.O.).
- National Heart and Lung Institute, Imperial College London, United Kingdom. (K.A.M., S.L.Z., J.S.W.).
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA (K.A.M., J.S.W.).
- Royal Brompton and Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, King's College London, United Kingdom. (S.L.Z., J.S.W.).
- Department of Women and Children's Health, King's College London, United Kingdom. (A.d.M.).
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, United Kingdom. (A.d.M.).
- Department of Computing, Imperial College London, United Kingdom. (W.B.).
- Department of Brain Sciences, Imperial College London, United Kingdom. (W.B.).
- Department of Cardiology, Imperial College Healthcare NHS Trust, King's College London, United Kingdom. (J.S.W.).
Abstract
Cardiac remodeling occurs in the mature heart and is a cascade of adaptations in response to stress, which are primed in early life. A key question remains as to the processes that regulate the geometry and motion of the heart and how it adapts to stress. We performed spatially resolved phenotyping using machine learning-based analysis of cardiac magnetic resonance imaging in 47 549 UK Biobank participants. We analyzed 16 left ventricular spatial phenotypes, including regional myocardial wall thickness and systolic strain in both circumferential and radial directions. In up to 40 058 participants, genetic associations across the allele frequency spectrum were assessed using genome-wide association studies with imputed genotype participants, and exome-wide association studies and gene-based burden tests using whole-exome sequencing data. We integrated transcriptomic data from the GTEx project and used pathway enrichment analyses to further interpret the biological relevance of identified loci. To investigate causal relationships, we conducted Mendelian randomization analyses to evaluate the effects of blood pressure on regional cardiac traits and the effects of these traits on cardiomyopathy risk. We found 42 loci associated with cardiac structure and contractility, many of which reveal patterns of spatial organization in the heart. Whole-exome sequencing revealed 3 additional variants not captured by the genome-wide association study, including a missense variant in <i>CSRP3</i> (minor allele frequency 0.5%). The majority of newly discovered loci are found in cardiomyopathy-associated genes, suggesting that they regulate spatially distinct patterns of remodeling in the left ventricle in an adult population. Our causal analysis also found regional modulation of blood pressure on cardiac wall thickness and strain. These findings provide a comprehensive description of the pathways that orchestrate heart development and cardiac remodeling. These data highlight the role that cardiomyopathy-associated genes have on the regulation of spatial adaptations in those without known disease.