Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.
Publication/Presentation Date
8-30-2022
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.
Volume
13
Issue
1
First Page
5106
Last Page
5106
ISSN
2041-1723
Published In/Presented At
Halford, J. L., Morrill, V. N., Choi, S. H., Jurgens, S. J., Melloni, G., Marston, N. A., Weng, L. C., Nauffal, V., Hall, A. W., Gunn, S., Austin-Tse, C. A., Pirruccello, J. P., Khurshid, S., Rehm, H. L., Benjamin, E. J., Boerwinkle, E., Brody, J. A., Correa, A., Fornwalt, B. K., Gupta, N., … Lubitz, S. A. (2022). Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. Nature communications, 13(1), 5106. https://doi.org/10.1038/s41467-022-32009-5
Disciplines
Medicine and Health Sciences
PubMedID
36042188
Department(s)
Department of Obstetrics and Gynecology
Document Type
Article