Title : Genetic architecture of natural variation of cardiac performance in flies Abstract : Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP)1. Genome Wide Associations Studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were extensively validated with in vivo cardiac-specific gene manipulation. Specifically, non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict Transcription Factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart specific knockdown. Although rarely studied, the genetic control of phenotypic variability is of primary importance, with both medical and fundamental implications. We showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping with those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability is also associated with gene regulatory network deviations. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans. Data : phenosnip_singleageanalysis.img : singularity v2.6 image with R 3.4.4 and python 2.7, used for preliminary statistical analysis. phenosnip_singleagegwas.img : singualrity v2.6 image with FastLMM and plink, used for GWAS analysis phenosnip_singleageepistasis.img : singualrity c2.6 image with fastEpistasis and plink, used for epistasis analysis Phenosnip.sqlite.tar.gz : SQlite database containing the genotype information from DGRP consortium and the phenotype data of the study (1 week aged drosophila) dgrp2.tar.gz : BED, BIM and FAM files with genetic information of the DGRP lines (data issued from the DGRP consortium) datasets_saha_et_al.zip : raw data (individual phenotypes of DGRP lines / variants identified by GWAS / individual phenotypes from validation experiments) and large scale datasets used for analyses (PPI and genetic interactions / regulatory variants)