Uncovering modifiers of cardiomyopathy in the noncoding genome

Gacita, Anthony Martin

doi:https://doi.org/10.21985/n2-gjmz-fd75

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Uncovering modifiers of cardiomyopathy in the noncoding genome

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Heart failure due to genetic cardiomyopathy is associated with a range of phenotypic expression. The studies in this body of work interrogated the role of noncoding variation in modifying cardiomyopathy phenotypes. We used cap analysis of gene expression in heathy and failed left ventricles to define the regulatory environment of heart failure. By combining our data with publicly-available datasets, we identified enhancers regulating the cardiomyopathy genes, MYH7 and LMNA. We conducted functional validation of enhancer regions in induced pluripotent stem cell derived cardiomyocytes. To overcome technical challenges in these cells, we developed a multigene qPCR normalization panel. Our findings implicated a super enhancer in the switch of MYH6 and MYH7 expression. Sequence variants within transcription factor binding sites were shown to modify enhancer function. We extended our methodology genomewide using a computational pipeline and identified rs875908, which is 2KB 5’ of MYH7. This variant disrupts the function of an overlapping an MYH7 enhancer. rs875908 also correlated with longitudinal clinical features of cardiomyopathy in a biobank with clinical imaging and genetic data. Our findings indicate that noncoding variation is phenotypically relevant and may have clinical utility

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