A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies.
Srinivasan S., Wu P., Mercader JM., Udler MS., Porneala BC., Bartz TM., Floyd JS., Sitlani C., Guo X., Haessler J., Kooperberg C., Liu J., Ahmad S., van Duijn C., Liu C-T., Goodarzi MO., Florez JC., Meigs JB., Rotter JI., Rich SS., Dupuis J., Leong A.
CONTEXT: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight. OBJECTIVE: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D. RESULTS: The T1D PS was not associated with T2D both in CHARGE (P = .15) and in the MGB Biobank (P = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, P = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, P = .03) in CHARGE T2D cases but not with other outcomes. CONCLUSION: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.