Enhancer variants that reduce the expression of MTSS1 in the human left ventricle have been associated with cardioprotective traits in genome-wide association studies. However, the effect of MTSS1 downregulation on the development of heart disease had not been studied in cell or animal models and warranted further investigation. In this study, we evaluated whether cardiac MTSS1 downregulation could be protective against dilated cardiomyopathy. To do this, we 1) assessed the associations of MTSS1 enhancer variants with a variety of cardiac structural and functional traits, as well as phenome-wide traits, in the UK Biobank cohort, both in the general cohort and stratified by sex. We also 2) used a mouse model of dilated cardiomyopathy [Tg(Myh6-Tpm1*D230N)HJcf] to test the effect of heterozygous knockout of the mouse Mtss1 ortholog on cardiac structural and functional traits separately in female mice and male mice. Finally, we 3) knocked out MTSS1 in two induced pluripotent stem cell-cardiomyocyte models of dilated cardiomyopathy [TNNT2 R173W] [TPM1 D230N] and measured their spontaneous beating rate response to isoproterenol induction. In summation, my thesis provides 1) evidence that cardiac MTSS1 downregulation in the female sex protects against dilated cardiomyopathy and 2) evidence that cardiac MTSS1 downregulation in the male sex has no effect against dilated cardiomyopathy.