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Systematic Heritability and Heritability Enrichment Analysis for Diabetes Complications in UK Biobank and ACCORD Studies

posted on 08.02.2022, 16:02 by Juhyun Kim, Aubrey Jensen, Seyoon Ko, Sridharan Raghavan, Lawrence S. Phillips, Adriana Hung, Yan Sun, Hua Zhou, Peter Reaven, Jin J. Zhou
Diabetes-related complications reflect longstanding damage to small and large vessels throughout the body. In addition to the duration of diabetes and poor glycemic control, genetic factors are important contributors to the variability in the development of vascular complications. Early heritability studies found strong familial clustering of both macrovascular and microvascular complications. However, they were limited by small sample sizes and large phenotypic heterogeneity, leading to less accurate estimates. We take advantage of two independent studies­­—UK Biobank and the Action to Control Cardiovascular Risk in Diabetes trial to survey the SNP-heritability for diabetes microvascular (diabetic kidney disease and diabetic retinopathy) and macrovascular (cardiovascular events) complications. Heritability for diabetic kidney disease was estimated at 29%. Heritability estimates for microalbuminuria ranged from 24% to 60% and was 41% for macroalbuminuria. Heritability estimates of diabetic retinopathy ranged from 6% to 33%, depending on the phenotype definition. More severe diabetes retinopathy possessed higher genetic contributions. We show, for the first time, that rare variants account for much of the heritability of diabetic retinopathy. This study suggests that a large portion of the genetic risk of diabetes complications is yet to be discovered and emphasizes the need for additional genetic studies of diabetes complications.


This research was partially funded by grants from the National Institute of General Medical Sciences (R35GM141798 HZ), the National Human Genome Research Institute (R01HG006139 HZ and JJZ), the National Science Foundation (DMS-2054253 HZ and JJZ), the National Institute of Diabetes and Digestive and Kidney Disease (K01DK106116 JJZ; P30DK116073 SR), and the National Heart, Lung, and Blood Institute (R21HL150374 JJZ), the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (2020R1A6A3A03037675, SK), and Veterans Affairs (IK2-CX001907 SR).