Shared additive- and variance-associated genetic architecture of cardiac structure and function
- 1Division of Cardiovascular Medicine, Department of Medicine; Department of Genetics; Cardiovascular Institute, Perelman School of Medicine, University of Pennsy
Abstract
Cardiac remodeling underlies cardiomyopathy and heart failure, yet how common genetic effects are organized across the four chambers, and whether they influence phenotypic variability beyond additive genetic effects, remains unclear. We analyzed 22 cardiac magnetic resonance phenotypes in up to 77,271 UK Biobank participants. Additive mapping identified 748 locus-trait associations across 239 regions. Multivariate fine-mapping revealed that 96% of signals showed effects across multiple cardiac chambers, while resolving independent signals with distinct anatomical profiles, including predominantly atrial and ventricular signals at RBM20. Fine-mapped signal sharing formed three robust communities corresponding broadly to atrial function, chamber remodeling and ventricular systolic function. Variance mapping identified 19 associations, 13 without a nearby additive signal. Individual variance loci and polygenic effects generalized to clinical echocardiographic phenotypes and outcomes in the Penn Medicine Biobank. These findings reveal cardiac common-variant architecture as broadly shared yet locally heterogeneous and identify phenotypic variability as a partly distinct genetic dimension.
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BibTeX
@misc{tsaggaris2026shared,
title = {{Shared additive- and variance-associated genetic architecture of cardiac structure and function}},
author = {J. C. Tsaggaris and N. Mimouni and R. L. Judy and D. Xue and M. P. Morley and X. Wang and J. L. Cotney and D. P. Kelly and S. M. Day and T. P. Cappola and Penn Medicine BioBank and S. M. Damrauer and M. G. Levin},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.26367193},
url = {https://www.medrxiv.org/content/10.64898/2026.11.04.26367193v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Shared additive- and variance-associated genetic architecture of cardiac structure and function
AU - J. C. Tsaggaris
AU - N. Mimouni
AU - R. L. Judy
AU - D. Xue
AU - M. P. Morley
AU - X. Wang
AU - J. L. Cotney
AU - D. P. Kelly
AU - S. M. Day
AU - T. P. Cappola
AU - Penn Medicine BioBank
AU - S. M. Damrauer
AU - M. G. Levin
PY - 2026
DA - 2026/11/04
PB - medRxiv
DO - 10.64898/2026.11.04.26367193
UR - https://www.medrxiv.org/content/10.64898/2026.11.04.26367193v1
AB - Cardiac remodeling underlies cardiomyopathy and heart failure, yet how common genetic effects are organized across the four chambers, and whether they influence phenotypic variability beyond additive genetic effects, remains unclear. We analyzed 22 cardiac magnetic resonance phenotypes in up to 77,271 UK Biobank participants. Additive mapping identified 748 locus-trait associations across 239 regions. Multivariate fine-mapping revealed that 96% of signals showed effects across multiple cardiac chambers, while resolving independent signals with distinct anatomical profiles, including predominantly atrial and ventricular signals at RBM20. Fine-mapped signal sharing formed three robust communities corresponding broadly to atrial function, chamber remodeling and ventricular systolic function. Variance mapping identified 19 associations, 13 without a nearby additive signal. Individual variance loci and polygenic effects generalized to clinical echocardiographic phenotypes and outcomes in the Penn Medicine Biobank. These findings reveal cardiac common-variant architecture as broadly shared yet locally heterogeneous and identify phenotypic variability as a partly distinct genetic dimension.
ER -