| Autor: |
Wang Q, Tang TM, Youlton N, Weldy CS, Kenney AM, Ronen O, Weston Hughes J, Chin ET, Sutton SC, Agarwal A, Li X, Behr M, Kumbier K, Moravec CS, Wilson Tang WH, Margulies KB, Cappola TP, Butte AJ, Arnaout R, Brown JB, Priest JR, Parikh VN, Yu B, Ashley EA |
| Jazyk: |
angličtina |
| Zdroj: |
MedRxiv : the preprint server for health sciences [medRxiv] 2024 May 04. Date of Electronic Publication: 2024 May 04. |
| DOI: |
10.1101/2023.11.06.23297858 |
| Abstrakt: |
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 where variants were deemed insignificant in univariate genome-wide association analyses 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 found strong gene co-expression correlations between these statistical epistasis contributors in healthy hearts and a significant connectivity decrease in failing hearts. 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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