Rare variant and phenotype analyses of adult cardiac trabecular morphology in the UK Biobank

Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their function in adults remains unclear.

Using image-derived phenotypes of trabecular complexity, a recent genome-wide association study identified loci in genes associated with haemodynamic phenotypes, regulation of cytoskeletal arborization, and cardiomyopathy.

I will explore whether pathways that specify trabecular development are unrecognised modifiers of ventricular performance and are causally associated with the progression of remodelling in cardiomyopathy.

This BHF fellowship will identify for the first time, the rare variants with large influences over variation in trabecular complexity.

This will identify gene–trait associations, elucidate gene function, and pinpoint effector genes that underlie the common variant signals (Work Package, WP1). The first phenome-wide association study will identify phenotype and disease associations at scale (WP2).

I show in pilot analyses that changes in trabecular morphology may be seen a decade before a diagnosis of cardiomyopathy and I will explore whether this is an early manifestation of disease or implicates abnormal trabecular formation in the evolution of cardiomyopathic remodelling (WP3).

The identification of the genes and phenotypes with relationships to trabecular complexity will provide an understanding of key mechanisms of cardiac development and adaptive response.