Genetic architecture of cardiac structure and function

Abstract

The heart is the first organ to develop in the mammalian embryo and its architecture is dependent on the spatial organisation of diverse cell types and morphogenetic transformations shaped by biophysical forces. Cardiac remodelling occurs in the mature heart and is a cascade of adaptations in response to stress that 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. Here we performed a spatially-resolved genome-wide association study of three-dimensional cardiac traits in 47,549 participants of UK Biobank. We found 42 loci associated with cardiac structure and contractility many of which reveal patterns of spatial organisation in the heart. Newly discovered loci relate to pathways implicated in cardiomyocyte differentiation and chamber development as well as those linked to cardiomyopathies. These findings provide a comprehensive description of the pathways that orchestrate heart development and mechanisms that regulate adaptation in health and disease.