@article{edfee28b33794f89a38195c442dbea36,
title = "Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes",
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.",
author = "Halford, {Jennifer L.} and Morrill, {Valerie N.} and Choi, {Seung Hoan} and Jurgens, {Sean J.} and Giorgio Melloni and Marston, {Nicholas A.} and Lu-Chen Weng and Victor Nauffal and Hall, {Amelia W.} and Sophia Gunn and Austin-Tse, {Christina A.} and Pirruccello, {James P.} and Shaan Khurshid and Rehm, {Heidi L.} and Benjamin, {Emelia J.} and Eric Boerwinkle and Brody, {Jennifer A.} and Adolfo Correa and Fornwalt, {Brandon K.} and Namrata Gupta and Haggerty, {Christopher M.} and Stephanie Harris and Heckbert, {Susan R.} and Hong, {Charles C.} and Charles Kooperberg and Lin, {Henry J.} and Loos, {Ruth J. F.} and Mitchell, {Braxton D.} and Morrison, {Alanna C.} and Wendy Post and Psaty, {Bruce M.} and Susan Redline and Rice, {Kenneth M.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Schnatz, {Peter F.} and Soliman, {Elsayed Z.} and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Nona Sotoodehnia and Wong, {Eugene K.} and Sabatine, {Marc S.} and Ruff, {Christian T.} and Lunetta, {Kathryn L.} and Ellinor, {Patrick T.} and Lubitz, {Steven A.}",
note = "Funding Information: All funding for this work is provided in Supplementary Note 1 in Supplementary Information. UK Biobank: Use of UK Biobank data was performed under application number 17488 and was approved by the local Massachusetts General Hospital institutional review board. Trans-Omics in Precision Medicine (TOPMed) program: We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) clinical trial: We wish to thank all participants on the FOURIER clinical trial. We would also like to acknowledge Giorgio Melloni and Nicholas Marston for facilitating our work with the FOURIER data. Clinical trial and exome sequencing was supported by Amgen. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "https://doi.org/10.1038/s41467-022-32009-5",
language = "English",
volume = "13",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}