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

Jennifer L Halford, Valerie N Morrill, Seung Hoan Choi, Sean J Jurgens, Giorgio Melloni, Nicholas A Marston, Lu-Chen Weng, Victor Nauffal, Amelia W Hall, Sophia Gunn, Christina A Austin-Tse, James P Pirruccello, Shaan Khurshid, Heidi L Rehm, Emelia J Benjamin, Eric Boerwinkle, Jennifer A Brody, Adolfo Correa, Brandon K Fornwalt, Namrata Gupta, Christopher M Haggerty, Stephanie Harris, Susan R Heckbert, Charles C Hong, Charles Kooperberg, Henry J Lin, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Wendy Post, Bruce M Psaty, Susan Redline, Kenneth M Rice, Stephen S Rich, Jerome I Rotter, Peter F Schnatz, Elsayed Z Soliman, Nona Sotoodehnia, Eugene K Wong, Marc S Sabatine, Christian T Ruff, Kathryn L Lunetta, Patrick T Ellinor, Steven A Lubitz

Journal: Nature communications 2022;13(1):5106

PMID: 36042188

Abstract

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).

Address: Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Experimental Cardiology, Amsterdam UMC, Amsterdam, Netherlands.; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Gene Regulation Observatory and Epigenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.; 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.; 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.; 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.; 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.; 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.; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Departments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.; Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.; Heart Institute, Geisinger, Danville, PA, USA.; Department of Radiology, Geisinger, Danville, PA, USA.; Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.; Heart Institute, Geisinger, Danville, PA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA.; University of Maryland School of Medicine, Baltimore, Maryland, USA.; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.; 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.; 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.; University of Maryland School of Medicine, Baltimore, Maryland, USA.; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.; Division of Cardiology, Johns Hopkins Medicine, Baltimore, MD, USA.; 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.; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Department of Biostatistics, University of Washington, Seattle, WA, USA.; Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.; Department of ObGyn, The Reading Hospital of Tower Health, Reading, PA, USA.; Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA.; 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.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. [email protected].; Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA. [email protected].
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