Abstract
A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those “fold-change” genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80–90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.
Highlights
Contrary to “Mendelian” diseases where causality can be traced back to strong effects of a single gene, common diseases result from modest effects of many interacting genes.[1]
At the gene level, such a response is typically where mi and m0i are the total heart mass of isogenic mice of the ith strain before and after ISO treatment, respectively; we use log[2] of expression fold-change to normalize microarrary data and log[2] of heart mass fold-change for consistency (Methods). This analyzed by looking for differentially expressed genes (DEGs) at the population level, i.e., genes for which the change in average expression with the stressor is significantly greater than the variability with and without the stressor (Fig. 1b)
We investigated the spectrum of cardiac hypertrophy and Heart failure (HF) development in 100+ genetically diverse npj Systems Biology and Applications (2018) 12
Summary
Contrary to “Mendelian” diseases where causality can be traced back to strong effects of a single gene, common diseases result from modest effects of many interacting genes.[1]. Heart failure (HF) is a well-studied example of a genetically complex disease involving multiple processes that eventually lead to a common phenotype of abnormal ventricular function and cardiac hypertrophy.[2] Numerous studies have attempted to pinpoint differentially expressed genes (DEGs) to find biomarkers for the prognosis of the disease and the design of appropriate drugs,[3] as well as explore underlying affected signaling pathways.[4]. Such studies typically compare the average gene expression between samples in healthy and diseased states, such as nonfailing vs failing hearts in murine,[5] canine,[6] or human samples (see[7] for a broad review). Genes are ranked by the strength of their differential expression, and top ranking genes are further investigated for pathway enrichment and biomarker potential
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
