Rare variant association analysis in 51,256 type 2 diabetes cases and 370,487 controls informs the spectrum of pathogenicity of monogenic diabetes genes

Alicia Huerta‐Chagoya; Philip H. Schroeder; Ravi Mandla; Jiang Li; Lowri Morris; Maheak Vora; Ahmed N. Alkanaq; Dorka Nagy; Łukasz Szczerbiński; Jesper Grud Skat Madsen; Sílvia Bonàs‐Guarch; Fanny Mollandin; Joanne B. Cole; Bianca Porneala; Kenneth E. Westerman; Josephine H. Li; Toni I. Pollin; José C. Florez; Anna L. Gloyn; David J. Carey; Inês Cebola; Uyenlinh L. Mirshahi; Alisa Knodle Manning; Aaron Leong; Miriam S. Udler; Josep Maria Mercader

doi:10.1038/s41588-024-01947-9

Genetic & Genomic MedicineNature GeneticsOct 8, 2024

Peer-reviewed journal article

Rare variant association analysis in 51,256 type 2 diabetes cases and 370,487 controls informs the spectrum of pathogenicity of monogenic diabetes genes

Alicia Huerta‐Chagoya iD, Philip H. Schroeder iD, Ravi Mandla iD, Jiang Li iD, Lowri Morris, Maheak Vora iD, Ahmed N. Alkanaq iD, Dorka Nagy iD, Łukasz Szczerbiński iD, Jesper Grud Skat Madsen iD, Sílvia Bonàs‐Guarch iD, Fanny Mollandin iD, Joanne B. Cole iD, Bianca Porneala iD, Kenneth E. Westerman iD, Josephine H. Li iD, Toni I. Pollin iD, José C. Florez iD, Anna L. Gloyn iD, David J. Carey iD, Inês Cebola iD, Uyenlinh L. Mirshahi iD, Alisa Knodle Manning iD, Aaron Leong iD, Miriam S. Udler iD, Josep Maria Mercader iD

Abstract

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 5x10-5) 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 (p5) 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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