| Title: | Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes |
| Journal: | Nature Communications |
| Published: | 30 Aug 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36042188/ |
| DOI: | https://doi.org/10.1038/s41467-022-32009-5 |
| URL: | https://www.nature.com/articles/s41467-022-32009-5.pdf |
| Citations: | 3 (2 in last 2 years) as of 8 Aug 2024 |
Publication 9817
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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.</p>
44 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
Enabling scientific discoveries that improve human health