Genomic structural variations lead to dysregulation of important coding and non‐coding RNA species in dilated cardiomyopathy

The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non‐coding RNA s. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome‐wide structural genomic variants ( SV s) and their association with gene expression in the human heart. We detected 3,898 individual SV s affecting all classes of gene transcripts (e.g., mRNA , mi RNA , lnc RNA ) and regulatory genomic regions (e.g., enhancer or TFBS ). In a cohort of patients ( n  = 50) with dilated cardiomyopathy ( DCM ), 80,635 non‐protein‐coding elements of the genome are deleted or duplicated by SV s, containing 3,758 long non‐coding RNA s and 1,756 protein‐coding transcripts. 65.3% of the SV ‐ eQTL s do not harbor a significant SNV‐eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein‐coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SV s in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SV s explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.