The overarching goal of the studies presented in this thesis was to study and better understand the genes and mechanisms underlying human rare and common heart muscle disease in early- and late-onset disease, respectively, using a range of genomic and informatic approaches. Although largely attributed to Ischaemic Heart Disease (IHD)-associated muscle damage, many non-IHD genes and pathways have been associated with HF, including those associated with inherited cardiomyopathies. The importance of the role of Titin (TTN), a major determinant of myocardial and ventricular function in both familial and “idiopathic” Dilated Cardiomyopathy (DCM), has recently been ascertained. Identifying the contribution of TTN variants, in a population of well phenotyped patients with Cardiac Magnetic Resonance (CMR) evidence of Myocardial Infarction (MI) and disproportionately reduced Left Ventricular (LV) function (‘dual-pathology’), was undertaken here to test the hypothesis that variants in TTN may contribute to heart failure in the context of IHD. In addition, Whole Exome Sequencing and applied informatics methodologies were used to prioritize a causative (new) gene as the underlying genetic aetiology of an ultra rare cardiac phenotype (Histiocytoid Cardiomyopathy). Taken together these studies show genetic approaches for studying rare variant effect in heart muscle disease of the young and in the general population and identify new genes and biology that broaden our understanding and propose possible clinical applications.