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

• Type of Material: Article
• Authors: Juhyun Kim, University of California Los Angeles; Aubrey Jensen, University of California Los Angeles; Seyoon Ko, University of California Los Angeles; Sridharan Raghavan, University of Colorado, Aurora; Lawrence Phillips, Emory University; Adriana Hung, Tennessee Valley Healthcare System and Vanderbilt University; Yan Sun, Emory University; Hua Zhou, University of California Los Angeles; Peter Reaven, Phoenix Veterans Affairs Health Care System; Jin J Zhou, University of California Los Angeles
• Language: English
• Date: 2022-05-01
• Publisher: AMER DIABETES ASSOC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the American Diabetes Association
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.2337/db21-0839
• Title of Journal or Parent Work: DIABETES
• Volume: 71
• Issue: 5
• Start Page: 1137
• End Page: 1148
• Grant/Funding Information: This research was partially funded by grants from the National Institute of General Medical Sciences (R35GM141798 to H.Z.), the National Human Genome Research Institute (R01HG006139 to H.Z. and J.J.Z.), the National Science Foundation (DMS-2054253 to H.Z. and J.J.Z.), the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK116073 to S.R. and K01DK106116 to J.J.Z.), the National Heart, Lung, and Blood Institute (R21HL150374 to J.J.Z.), the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (2020R1A6A3A03037675 to S.K.), and the U.S. Department of Veterans Affairs (IK2-CX001907 to S.R.).
• Keywords: POPULATION; NEPHROPATHY; RETINOPATHY; Life Sciences & Biomedicine; KIDNEY-DISEASE; MICROVASCULAR OUTCOMES; Endocrinology & Metabolism; Science & Technology; GENOME-WIDE ASSOCIATION; FAMILIAL AGGREGATION; MANIFESTATIONS; METAANALYSIS; LOCI
• Research Categories: Biology, Biostatistics; Health Sciences, Epidemiology

Abstract

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 single nucleotide polymorphism heritability for diabetes microvascular (diabetic kidney disease and diabetic retinopathy) and macrovascular (cardiovascular events) complications. Heritability for diabetic kidney disease was estimated at 29%. The heritability estimate 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.