From Genotype to Phenotype从基因型到临床表现型.ppt

Let’s walk through an example… Source: Cambien and Tiret (2007) Early discoveries shed light on basic mechanisms of disease Gene Function Defect apoE Protein involved in transport of lipids to tissue and cells 2 nonsynonymous mutations leading to 3 haplotypes with differing risk profiles LDLR Receptor for low-density cholesterol 700 mutations identified in coding sequence apoB100 Protein that plays a role in binding of LDL to receptor Single mutation in apoB gene Genetic risk factors for Coronary Heart Disease Single genetic risk factors identified are of limited clinical use Fails to take into account gene-environment interaction Fails to take into account gene-gene interactions Need to understand genetics at a systems-level Genome-Wide Association (GWA) addresses some of these issues. GWA has multiple advantages Discovery Studies not limited to current biological knowledge Quantitative Better characterize complex, quantitative traits GWA has multiple advantages Discovery Studies not limited to current biological knowledge Coronary Heart Disease (CHD) Type 2 Diabetes Recent GWA studies discovered: Associated regions containing no annotated genes Tagged SNPs not associated with any established risk factors GWA has multiple advantages Cardiac Arrhythmias Quantitative Better characterize complex, quantitative traits Identification of polymorphism accounting for variance of quantitative trait GWA enables characterization of quantitative traits Cardiac Arrhythmias QT interval (QTi) is a measure of the time to repolarization of cardiac cells during heart beat and an indicator of cardiac arrhythmias. Out-of-sync heartbeat can lead to sudden death QTi is a quantitative, heritable trait. Source: Wikipedia GWA helps explain genetic cause of quantitative traits Multi-stage GWA studied 2 extremes of QTi distribution to identify genomic regions of interest. Identified frequent polymorphisms in nitric oxide synthase 1 adap