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- Title
Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.
- Authors
Halford, Jennifer L.; Morrill, Valerie N.; Choi, Seung Hoan; Jurgens, Sean J.; Melloni, Giorgio; Marston, Nicholas A.; Weng, Lu-Chen; Nauffal, Victor; Hall, Amelia W.; Gunn, Sophia; Austin-Tse, Christina A.; Pirruccello, James P.; Khurshid, Shaan; Rehm, Heidi L.; Benjamin, Emelia J.; Boerwinkle, Eric; Brody, Jennifer A.; Correa, Adolfo; Fornwalt, Brandon K.; Gupta, Namrata
- 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. Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.
- Subjects
GLYCOSYLATED hemoglobin; DISEASE susceptibility; MATURITY onset diabetes of the young; LONG QT syndrome; FAMILIAL hypercholesterolemia; CLINICAL medicine
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-32009-5