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Rare variant association analysis in 51,256 type 2 diabetes cases and 370,487 controls informs the spectrum of pathogenicity of monogenic diabetes genes
We meta-analyzed array data imputed with the TOPMed reference panel and whole-genome sequence (WGS) datasets and performed the largest, rare variant (minor allele frequency as low as 5×10(−5)) GWAS meta-analysis of type 2 diabetes (T2D) comprising 51,256 cases and 370,487 controls. We identified 52...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557807/ https://www.ncbi.nlm.nih.gov/pubmed/37808701 http://dx.doi.org/10.1101/2023.09.28.23296244 |
Sumario: | We meta-analyzed array data imputed with the TOPMed reference panel and whole-genome sequence (WGS) datasets and performed the largest, rare variant (minor allele frequency as low as 5×10(−5)) GWAS meta-analysis of type 2 diabetes (T2D) comprising 51,256 cases and 370,487 controls. We identified 52 novel variants at genome-wide significance (p<5 × 10(−8)), including 8 novel variants that were either rare or ancestry-specific. Among them, we identified a rare missense variant in HNF4A p.Arg114Trp (OR=8.2, 95% confidence interval [CI]=4.6–14.0, p = 1.08×10(−13)), previously reported as a variant implicated in Maturity Onset Diabetes of the Young (MODY) with incomplete penetrance. We demonstrated that the diabetes risk in carriers of this variant was modulated by a T2D common variant polygenic risk score (cvPRS) (carriers in the top PRS tertile [OR=18.3, 95%CI=7.2–46.9, p=1.2×10(−9)] vs carriers in the bottom PRS tertile [OR=2.6, 95% CI=0.97–7.09, p = 0.06]. Association results identified eight variants of intermediate penetrance (OR>5) in monogenic diabetes (MD), which in aggregate as a rare variant PRS were associated with T2D in an independent WGS dataset (OR=4.7, 95% CI=1.86–11.77], p = 0.001). Our data also provided support evidence for 21% of the variants reported in ClinVar in these MD genes as benign based on lack of association with T2D. Our work provides a framework for using rare variant imputation and WGS analyses in large-scale population-based association studies to identify large-effect rare variants and provide evidence for informing variant pathogenicity. |
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