276-OR: Common Variant Polygenic Risk Score Influences Penetrance of Rare Variants in Monogenic Diabetes Genes

Monogenic diabetes (MD) accounts for 0.4% of diabetes cases and is a paradigm for precision medicine. However, a high fraction of variants in MD genes reported in ClinVar have uncertain significance (VUS) or conflicting interpretations of pathogenicity (CIP), making potential MD diagnosis a challenge.We hypothesized that using large-scale rare variant association data for type 2 diabetes (T2D) risk could inform variant pathogenicity in the MD genes. We tested the association with T2D of 1,157 VUS/CIP in 52 established MD genes, in the largest rare-variant T2D genome-wide association study (51,256 T2D, 370,487 controls), using rare variant imputation and whole-genome sequencing. We identified 9 variants with intermediate penetrance (VIP) (odds ratio OR 5) in HNF1A, HNF4A, GCK, KCNJ11, WFS1, and POLD1, including a missense variant in HNF4A (p.Arg114Trp) associated with an 8-fold increased risk of diabetes (OR=8.2, 4.6-14, p=1.1×10-13). The penetrance of this variant was influenced by a T2D polygenic risk score (PRS), with carriers in the highest tertile of the PRS showing a risk (OR=18.3 7.2-46.9, p=1.2×10-9) comparable to the effect of confirmed pathogenic HNF4A MODY variants (OR=19.3 6.1-60.6, p=4.1×10-7), and carriers within the lower tertile of the PRS showing a much smaller risk (OR=2.6 0.9,7.1, p=0.06). We also provided support for 21% of rare variants in the MD genes as benign based on their sufficient statistical power but null association with T2D. We show that large-scale association data can inform variant pathogenicity and that rare variant penetrance is influenced by PRS. Our findings support the existence of a spectrum between common and monogenic forms of diabetes rather than a categorical distinction. Disclosure A. Huerta: None. R. Mandla: None. D. Nagy: None. L. Szczerbinski: None. J.G.S. Madsen: None. J.B. Cole: None. B. Porneala: None. K.E. Westerman: None. J.H. Li: None. T.I. Pollin: None. J.C. Florez: Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, AstraZeneca. A.L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. I. Cebola: None. A. Manning: None. A. Leong: Other Relationship; Merck Up-To-Date. J.M. Mercader: None. Funding A.H.C. is supported by American Diabetes Association 11-23-PDF-35 grant. J.M.M. is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068