With aging and in cardiac disease increasing fibrosis due to collagen deposition disturbs cell-cell coupling of cardiomyocytes, providing a substrate for arrhythmia. In this study we set out to identify genetic modifiers of collagen deposition in heart. We exploited the genetic variability among F2 progeny of 129P2 and FVBN/J mice carrying the Scn5a-1798insD/+ mutation to identify genes that influence the amount of collagen deposition in left ventricular (LV) myocardium.Relative amounts of collagen were determined in 65 F2 mice and combined with genome-wide genotypic and expression data to identify collagen-QTLs (cQTLs) and the underlying expression QTLs (eQTLs). In both collagen-QTL mapping as well as eQTL mapping we identified significant co-factors throuhgh multiple QTL mapping (MQM).A significant cQTLs was identified on mouse chr8 and after correction for cofactors using MQM an additional cQTL was found on mouse chr2. For both these loci a significant co-factor was identified on chr18. Of the 24 eQTLs mapping to the chr8-cQTL, 8 transcripts correlated to relative collagen amount. Similarly, of the 6 chr2-cQTL eQTLs only Gpr158 (significantly) and of the 12 eQTLs of chr18-co-factor-region only Fgf1 (suggestively) correlated with the relative collagen amount. Furthermore, two cQTL-eQTLs, Pdlim3 (chr8) and Itga6 (chr2), had a significant co-factor on chr18 that coincided with the chr18 collagen cofactor. We validated the interaction of Fgf1 with these transcripts and collagen production in vitro in isolated cardiac fibroblasts.In conclusion, we mapped, for the first time, a genetic network that modulates collagen deposition in mouse LV myocardium.