You are here

Nat Genet DOI:10.1038/s41588-022-01200-1

A combined polygenic score of 21,293 rare and 22 common variants improves diabetes diagnosis based on hemoglobin A1C levels.

Publication TypeJournal Article
Year of Publication2022
AuthorsDornbos, P, Koesterer, R, Ruttenburg, A, Nguyen, T, Cole, JB, Leong, A, Meigs, JB, Florez, JC, Rotter, JI, Udler, MS, Flannick, J
Corporate AuthorsAMP-T2D-GENES Consortium
JournalNat Genet
Date Published2022 Oct 24
ISSN1546-1718
Abstract

Polygenic scores (PGSs) combine the effects of common genetic variants to predict risk or treatment strategies for complex diseases. Adding rare variation to PGSs has largely unknown benefits and is methodically challenging. Here, we developed a method for constructing rare variant PGSs and applied it to calculate genetically modified hemoglobin A1C thresholds for type 2 diabetes (T2D) diagnosis. The resultant rare variant PGS is highly polygenic (21,293 variants across 154 genes), depends on ultra-rare variants (72.7% observed in fewer than three people) and identifies significantly more undiagnosed T2D cases than expected by chance (odds ratio = 2.71; P = 1.51 × 10). A PGS combining common and rare variants is expected to identify 4.9 million misdiagnosed T2D cases in the United States-nearly 1.5-fold more than the common variant PGS alone. These results provide a method for constructing complex trait PGSs from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.

DOI10.1038/s41588-022-01200-1
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36280733?dopt=Abstract

Alternate JournalNat Genet
PubMed ID36280733
Grant List2020096 / / Doris Duke Charitable Foundation (DDCF) /
R01HL151855 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) /
R01HL105756 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) /
1R01HL151855 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) /
UL1TR001881 / / U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS) /