Faculty, Staff and Student Publications
Publication Date
8-30-2022
Journal
Nature Communications
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.
Keywords
Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence
DOI
10.1038/s41467-022-32009-5
PMID
36042188
PMCID
PMC9427940
PubMedCentral® Posted Date
8-30-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes