Deciphering the genetic architecture of cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. Drosophila has gained importance as a useful model to study heart development and function and allows the analysis of organismal traits in a physiologically relevant and accessible system.

Our aim was to (i) identify in flies the variants associated to natural variations of cardiac performances among a natural population, (ii) decipher how these variants interact with each other and with the environment to impact cardiac traits, (iii) gain insights about the molecular and cellular processes affected, (iv) determine whether the genetic architecture of cardiac disorders is conserved with humans.

We used the Drosophila Genetic Reference Panel, a community resource of sequenced inbred lines. Genome Wide Associations (GWA) for single markers and epistatic interactions were analyzed on cardiac traits related to rhythm and contractility.

Genetic networks were unraveled and extensively validated in vivo. Non-coding variants were used to map potential regulatory non-coding regions and to predict Transcription Factors (TFs) binding sites. Cognate TFs were validated by heart specific knockdown. Natural variations of cardiac traits variance revealed unique features of the phenotypic plasticity of cardiac performance. Importantly, correlations between genes associated to GWAS for cardiac traits both in flies and humans supported conservation of the genetic architecture of cardiac disorders from arthropods to mammals. In addition, several conserved genes and pathways were validated in human iPSC-derived cardiomyocytes.

We provide an in-depth analysis of the genetic architecture of natural variations of cardiac performance in flies. Our data may guide the analysis of cardiac disorders in humans.