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

Author:

Kim Juhyun12,Jensen Aubrey1,Ko Seyoon1,Raghavan Sridharan34,Phillips Lawrence S.56,Hung Adriana7,Sun Yan8,Zhou Hua1,Reaven Peter9,Zhou Jin J.191011ORCID

Affiliation:

1. Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA

2. Department of Biostatistics, University of Michigan, Ann Arbor, MI

3. University of Colorado School of Medicine, Aurora, CO

4. Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO

5. Division of Endocrinology, Emory University School of Medicine, Atlanta, GA

6. Atlanta Veterans Affairs Medical Center, Decatur, GA

7. Tennessee Valley Healthcare System and Vanderbilt University, Nashville, TN

8. Department of Epidemiology, Emory University, Atlanta, GA

9. Phoenix Veterans Affairs Health Care System, Phoenix, AZ

10. Department of Epidemiology and Biostatistics, University of Arizona, Tucson, AZ

11. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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