Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Autor:	Halford JL; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Morrill VN; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Choi SH; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jurgens SJ; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Experimental Cardiology, Amsterdam UMC, Amsterdam, Netherlands., Melloni G; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA., Marston NA; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA., Weng LC; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Nauffal V; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Hall AW; Gene Regulation Observatory and Epigenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gunn S; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Austin-Tse CA; Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Pirruccello JP; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Khurshid S; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA., Rehm HL; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Benjamin EJ; NHLBI and Boston University's Framingham Heart Study, Framingham, MA, USA.; Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA., Boerwinkle E; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Brody JA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA., Correa A; Departments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA., Fornwalt BK; Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.; Heart Institute, Geisinger, Danville, PA, USA.; Department of Radiology, Geisinger, Danville, PA, USA., Gupta N; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Haggerty CM; Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.; Heart Institute, Geisinger, Danville, PA, USA., Harris S; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Heckbert SR; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA., Hong CC; University of Maryland School of Medicine, Baltimore, Maryland, USA., Kooperberg C; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA., Lin HJ; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA., Loos RJF; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA., Mitchell BD; University of Maryland School of Medicine, Baltimore, Maryland, USA.; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA., Morrison AC; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Post W; Division of Cardiology, Johns Hopkins Medicine, Baltimore, MD, USA., Psaty BM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA.; Department of Health Systems and Population Health, University of Washington, Seattle, Washington, USA., Redline S; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Rice KM; Department of Biostatistics, University of Washington, Seattle, WA, USA., Rich SS; Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA., Schnatz PF; Department of ObGyn, The Reading Hospital of Tower Health, Reading, PA, USA., Soliman EZ; Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA., Sotoodehnia N; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA., Wong EK; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Sabatine MS; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA., Ruff CT; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA., Lunetta KL; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Ellinor PT; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA., Lubitz SA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. slubitz@mgh.harvard.edu.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.; Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2022 Aug 30; Vol. 13 (1), pp. 5106. Date of Electronic Publication: 2022 Aug 30.
DOI:	10.1038/s41467-022-32009-5
Abstrakt:	Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity. (© 2022. The Author(s).)
Databáze:	MEDLINE
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