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Epistasis regulates genetic control of cardiac hypertrophy.

ABSTRACT: The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.

SUBMITTER: Wang Q

PROVIDER: S-EPMC10659487 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Deciphering epistatic genetic regulation of cardiac hypertrophy.

Wang Qianru Q Tang Tiffany M TM Youlton Michelle M Weldy Chad S CS Kenney Ana M AM Ronen Omer O Hughes J Weston JW Chin Elizabeth T ET Sutton Shirley C SC Agarwal Abhineet A Li Xiao X Behr Merle M Kumbier Karl K Moravec Christine S CS Tang W H Wilson WHW Margulies Kenneth B KB Cappola Thomas P TP Butte Atul J AJ Arnaout Rima R Brown James B JB Priest James R JR Parikh Victoria N VN Yu Bin B Ashley Euan A EA

medRxiv : the preprint server for health sciences 20250411

Although genetic variant effects often interact non-additively, strategies to uncover epistasis remain in their infancy. Here, we develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy, using deep learning-derived left ventricular mass estimates from 29,661 UK Biobank cardiac MRIs. We report epistatic variants near CCDC141, IGF1R, TTN, and TNKS, identifying loci deemed insignificant in genome-wide associ ...[more]

PMID: 37987017

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Project description:BackgroundCardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These misfolded proteins can be removed by the adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated degradation (ERAD), which, as a biological process and rate, has not been studied in vivo. To investigate a role for ERAD in a pathophysiological model, we examined the function of the functional initiator of ERAD, valosin-containing protein-interacting membrane protein (VIMP), positing that VIMP would be adaptive in pathological cardiac hypertrophy in mice.MethodsWe developed a new method involving cardiac myocyte-specific adeno-associated virus serovar 9-mediated expression of the canonical ERAD substrate, TCRα, to measure the rate of ERAD, ie, ERAD flux, in the heart in vivo. Adeno-associated virus serovar 9 was also used to either knock down or overexpress VIMP in the heart. Then mice were subjected to transverse aortic constriction to induce pressure overload-induced cardiac hypertrophy.ResultsERAD flux was slowed in both human heart failure and mice after transverse aortic constriction. Surprisingly, although VIMP adaptively contributes to ERAD in model cell lines, in the heart, VIMP knockdown increased ERAD and ameliorated transverse aortic constriction-induced cardiac hypertrophy. Coordinately, VIMP overexpression exacerbated cardiac hypertrophy, which was dependent on VIMP engaging in ERAD. Mechanistically, we found that the cytosolic protein kinase SGK1 (serum/glucocorticoid regulated kinase 1) is a major driver of pathological cardiac hypertrophy in mice subjected to transverse aortic constriction, and that VIMP knockdown decreased the levels of SGK1, which subsequently decreased cardiac pathology. We went on to show that although it is not an ER protein, and resides outside of the ER, SGK1 is degraded by ERAD in a noncanonical process we call ERAD-Out. Despite never having been in the ER, SGK1 is recognized as an ERAD substrate by the ERAD component DERLIN1, and uniquely in cardiac myocytes, VIMP displaces DERLIN1 from initiating ERAD, which decreased SGK1 degradation and promoted cardiac hypertrophy.ConclusionsERAD-Out is a new preferentially favored noncanonical form of ERAD that mediates the degradation of SGK1 in cardiac myocytes, and in so doing is therefore an important determinant of how the heart responds to pathological stimuli, such as pressure overload.

Dataset Information

Epistasis regulates genetic control of cardiac hypertrophy.

Publications

Deciphering epistatic genetic regulation of cardiac hypertrophy.

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