Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. We report variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and ventricular development. Genome-wide association studies identified 68 novel loci in pathways that regulate sarcomeric function, differentiation of the conduction system, and cell fate determination. We found that trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease expression.

DPO has consulted for Bayer AG and Bristol Myers-Squibb. J.S.W. has consulted for MyoKardia, Inc., Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics, and has received research support from Bristol Myers-Squibb. None of these activities are directly related to the work presented here. All other authors have nothing to disclose.

This work was supported through a fellowship to K.A.M. from the British Heart Foundation [FS/IPBSRF/22/27059]. Other funds have contributed to data curation and supported the authors: British Heart Foundation, UK [RG/19/6/34387, RE/18/4/34215, RG/F/22/110078, FS/CRTF/21/24183], Medical Research Council, UK [MC-A658-5TY00, MC_UP_1605/13], Sir Jules Thorn Charitable Trust, UK [21JTA], Wellcome Trust, UK [107469/Z/15/Z, 200990/A/16/Z], the National Council for Scientific and Technological Development, Brazil [310790/2021-2, 465518/2014-1], Engineering and Physical Sciences Research Council (EPSRC), UK [EP/W01842X/1], NHLI Foundation, Royston Centre for Inherited Cardiovascular Conditions, and the NIHR Imperial College Biomedical Research Centre, UK

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UK National Research Ethics Service gave ethical approval for the UK Biobank study (11/NW/0382).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data arising from this analysis will be made available through the UK Biobank (https://biobank.ndph.ox.ac.uk/showcase/), GWAS catalog (https://www.ebi.ac.uk/gwas/), Github (https://github.com/ImperialCollegeLondon/trabecular_variants), and GWAS significant SNPs viewed on LocusZoom (https://my.locuszoom.org/).

https://github.com/ImperialCollegeLondon/trabecular_variants