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Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.
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.