Year: 2022
Type: article
Abstract: Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS-disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57-1.95) for type 2 diabetes to 2.38 (95% CI: 2.07-2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR > 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic.
Source: Nature Medicine
Authors: Limin Hao, Peter Kraft, Gabriel F. Berriz, Elizabeth D. Hynes, Christopher Koch, Prathik Korategere V Kumar, Shruti S. Parpattedar, Marcie Steeves, Wanfeng Yu, Ashley A. Antwi, Charles A. Brunette, Morgan Danowski, Manish K. Gala, Robert C. Green, Natalie E. Jones, Anna C. F. Lewis, Steven A. Lubitz, Pradeep Natarajan, Jason L. Vassy, Matthew S. Lebo
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: U.S. Department of Health and Human Services, American Heart Association, Massachusetts General Hospital, Fondation Leducq, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: Using genetic variation to study biology of blood lipids & coronary heart disease, G1286364831, G1289036858, G1331084331, G1356288539, G1449261147, G150744415, Precision Medicine in Ischemic Stroke and Atrial Fibrillation (PreMISe-AF), Clonal hematopoiesis in humans: determinants of development and progression, Return of Genomic Results and Estimating Penetrance in Population-Based Cohorts, G2659111364, G27918087, G3271462333, Pragmatic randomized trial of polygenic risk scoring for common diseases in primary care, G330955229, G3574050828, G3598829536, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, G3763011920, G4393855799, G4405986302, G5353991873, Clonal hematopoiesis of indeterminate potential and HIV in the REPRIEVE trial, G603018768, G6062545421, G6354290783, G6517355547, The Broad-LMM-Color Genome Center for All of Us, Clonal hematopoiesis in the Women's Health Initiative, G7218037041, G7249562365, G731149954, G7662707499, Stress-rest calf muscle perfusion: a functional diagnostic test for peripheral arterial disease (PAD), G852120859, G8630864450, G9000020190, G9000023455, G9000054274, G9000070171, G9000096488, G9000100009, G9000149391, G9000217218, Clonal hematopoiesis and atherosclerosis, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias, Enabling improved applicability and transferability of polygenic scores across populations, Clonal Hematopoiesis of Indeterminate Potential in Chronic Kidney Disease Patients, Genomics of Cardiac Arrhythmias
OpenAlex ID: W4223924706