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Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.
Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank
Coronary artery disease (CAD) is the leading cause of death in the UK. When CAD occurs prematurely, the role for inheritance is greater. DNA sequencing of the protein-coding portions of the human genome ('the exome') can identify genes responsible for CAD. Here, we seek to: 1) identify all individuals in the UK Biobank with premature CAD (mean=55y, women=65y); 2) identify controls free of CAD; 3) perform whole exome sequencing on cases and controls; 4) compare sequences to discover genes responsible for CAD; 5) perform a comprehensive phenotypic scan to understand the spectrum of consequences from CAD genes. A stated purpose of UK Biobank is to improve the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses. We have secured funding to exome sequence up to 20,000 UK Biobank participants with and without CAD. Successful completion of this study should result in the identification of novel genetic causes for MI, the leading cause of death in the UK. Genomic variation discovered in the UK Biobank associated with MI may prove useful to target preventive strategies, understand the biology of MI in humans, and to identify novel molecular targets for therapy. We propose to: 1) identify all individuals in the UK Biobank with CAD at an early age (=55 years old in men and =65 years old in women); 2) identify controls free of CAD; 3) perform whole exome sequencing on all cases and controls; 4) compare sequences of cases with controls to discover genes responsible for CAD; and 5) understand the range of phenotypic effects from genes associated with CAD. We have secured funding to exome sequence up to 20,000 UK Biobank participants. Of note, we have secured funding to exome sequence up to 20,000 UK Biobank participants. We seek to identify all individuals in the UK Biobank with CAD at an early age (=55 years old in men and =65 years old in women). In the latest data release, there are 10,450 participants with any diagnosis code for ischemic heart disease. Further work will be required to confirm this diagnosis and restrict to CAD onset at an early age.