Genetics of Diabetic Retinopathy


Diabetic retinopathy (DR) is a common, vision‐threatening microvascular complication of diabetes mellitus (DM). Early epidemiologic studies revealed a potential heritable component as differences in disease risk persisted between ethnic groups even when controlling for common diabetes risk factors. These insights spawned sib‐pair genetic linkage analyses which confirmed a genetic component to DR risk. Insights from large genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with DR risk, but these largely could not be replicated in other studies or across ethnic groups. Whole‐exome sequencing (WES) is an emerging technology better positioned than GWAS to identify rare variants conferring risk of DR among diabetic patients. Although the multifactorial, polygenic nature of DR complicates the search for significant genetic risk variants, advances in sequencing technology with large patient cohorts may provide novel actionable insights to improve care for DR patients.

Key Concepts

  • Diabetic retinopathy is the most common microvascular complication of diabetes mellitus.
  • Diabetic retinopathy is a leading cause of blindness worldwide.
  • Early epidemiologic studies suggested a strong heritable component to risk of diabetic retinopathy.
  • Genome wide association studies have demonstrated many weak genetic associations with risk of developing diabetic retinopathy but are difficult to reproduce across ethnic groups.
  • Whole exome sequencing is a newer technology that provides more detailed analysis of rare genetic variants and has revealed several diabetic retinopathy risk variants.
  • Epigenetics and pharmacogenomics are emerging areas of research that may guide future personalised therapies for diabetic retinopathy.
  • Diabetes mellitus and diabetic retinopathy are heterogeneous disorders with multifactorial causes, including environmental and genetic factors.

Keywords: diabetic retinopathy; genome‐wide association study; whole‐exome sequencing; microvascular complications; single nucleotide polymorphism; case‐control study; VEGF; polygenic inheritance


Abhary S , Hewitt AW , Burdon KP and Craig JE (2009) A systematic meta‐analysis of genetic association studies for diabetic retinopathy. Diabetes 58 (9): 2137–2147.

Agardh E , Lundstig A , Perfilyev A , et al. (2015) Genome‐wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Medicine 13 (1): 182.

Agarwal A , Soliman MK , Sepah YJ , Do DV and Nguyen QD (2014) Diabetic retinopathy: variations in patient therapeutic outcomes and pharmacogenomics. Pharmacogenomics and Personalized Medicine 7: 399–409.

Arar NH , Freedman BI , Adler SG , et al. (2008) Heritability of the severity of diabetic retinopathy: the FIND‐eye study. Investigative Ophthalmology and Visual Science 49 (9): 3839–3845.

Awata T , Yamashita H , Kurihara S , et al. (2014) A genome‐wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non‐coding RNA. PLoS One 9 (11): e111715.

Bain SC , Klufas MA , Ho A and Matthews DR (2019) Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: a review. Diabetes, Obesity and Metabolism 21 (3): 454–466.

Berdasco M , Gomez A , Rubio MJ , et al. (2017) DNA methylomes reveal biological networks involved in human eye development, functions and associated disorders. Scientific Reports 7 (1): 11762.

Burdon KP , Fogarty RD , Shen W , et al. (2015) Genome‐wide association study for sight‐threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene. Diabetologia 58 (10): 2288–2297.

Cabrera AP , Monickaraj F , Rangasamy S , et al. (2020) Do genomic factors play a role in diabetic retinopathy? Journal of Clinical Medicine 9 (1): 216.

Chen Z , Miao F , Paterson AD , et al. (2016) Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proceedings of the National Academy of Sciences of the United States of America 113 (21): E3002–E3011.

Chen D , Wang J , Dan Z , Shen X and Ci D (2018) The relationship between methylenetetrahydrofolate reductase C677T polymorphism and diabetic retinopathy: a meta‐analysis in multiethnic groups. Ophthalmic Genetics 39 (2): 200–207.

Cheung N , Mitchell P and Wong TY (2010) Diabetic retinopathy. Lancet 376 (9735): 124–136.

El‐Shazly SF , El‐Bradey MH and Tameesh MK (2014) Vascular endothelial growth factor gene polymorphism prevalence in patients with diabetic macular oedema and its correlation with anti‐vascular endothelial growth factor treatment outcomes. Clinical and Experimental Ophthalmology 42 (4): 369–378.

Emanuele N , Sacks J , Klein R , et al. (2005) Ethnicity, race, and baseline retinopathy correlates in the veterans affairs diabetes trial. Diabetes Care 28 (8): 1954–1958.

Fu YP , Hallman DM , Gonzalez VH , et al. (2010) Identification of diabetic retinopathy genes through a genome‐wide association study among Mexican‐Americans from Starr County, Texas. Journal of Ophthalmology 2010: 1–9.

Graham PS , Kaidonis G , Abhary S , et al. (2018) Genome‐wide association studies for diabetic macular edema and proliferative diabetic retinopathy. BMC Medical Genetics 19 (1): 71.

Grassi MA , Tikhomirov A , Ramalingam S , et al. (2011) Genome‐wide meta‐analysis for severe diabetic retinopathy. Human Molecular Genetics 20 (12): 2472–2481.

Grassi MA , Tikhomirov A , Ramalingam S , et al. (2012) Replication analysis for severe diabetic retinopathy. Investigative Ophthalmology and Visual Science 53 (4): 2377–2381.

Group DCaCTR (1997) Clustering of long‐term complications in families with diabetes in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes 46 (11): 1829–1839.

Hallman DM , Boerwinkle E , Gonzalez VH , et al. (2007) A genome‐wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas. Diabetes 56 (4): 1167–1173.

Hietala K , Forsblom C , Summanen P , Groop PH and FinnDiane Study Group (2008) Heritability of proliferative diabetic retinopathy. Diabetes 57 (8): 2176–2180.

Huang YC , Lin JM , Lin HJ , et al. (2011) Genome‐wide association study of diabetic retinopathy in a Taiwanese population. Ophthalmology 118 (4): 642–648.

Imperatore G , Hanson RL , Pettitt DJ , et al. (1998) Sib‐pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. pima diabetes genes group. Diabetes 47 (5): 821–830.

Kuo JZ , Wong TY and Rotter JI (2014) Challenges in elucidating the genetics of diabetic retinopathy. JAMA Ophthalmology 132 (1): 96–107.

Leslie RD and Pyke DA (1982) Diabetic retinopathy in identical twins. Diabetes 31 (1): 19–21.

Liu C , Chen G , Bentley AR , et al. (2019) Genome‐wide association study for proliferative diabetic retinopathy in Africans. NPJ Genomic Medicine 4 (1): 1–7.

Looker HC , Nelson RG , Chew E , et al. (2007) Genome‐wide linkage analyses to identify loci for diabetic retinopathy. Diabetes 56 (4): 1160–1166.

Luo S , Shi C , Wang F and Wu Z (2016) Association between the angiotensin‐converting enzyme (ACE) genetic polymorphism and diabetic retinopathy‐A meta‐analysis comprising 10,168 subjects. International Journal of Environmental Research and Public Health 13 (11): 1142.

Meng W , Shah KP , Pollack S , et al. (2018) A genome‐wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes. Acta Ophthalmologica 96 (7): e811–e819.

Meng W , Chan BW , Ezeonwumelu C , et al. (2019) A genome‐wide association study implicates that the TTC39C gene is associated with diabetic maculopathy with decreased visual acuity. Ophthalmic Genetics 40 (3): 252–258.

Pollack S , Igo RP Jr Jensen RA , et al. (2019) Multiethnic genome‐wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control. Diabetes 68 (2): 441–456.

Sabanayagam C , Banu R , Chee ML , et al. (2019) Incidence and progression of diabetic retinopathy: a systematic review. Lancet Diabetes and Endocrinology 7 (2): 140–149.

Sheu WH , Kuo JZ , Lee IT , et al. (2013) Genome‐wide association study in a Chinese population with diabetic retinopathy. Human Molecular Genetics 22 (15): 3165–3173.

Shtir C , Aldahmesh MA , Al‐Dahmash S , et al. (2016) Exome‐based case‐control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy. Human Genetics 135 (2): 193–200.

Sobrin L , Green T , Sim X , et al. (2011) Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the candidate gene association resource (CARe). Investigative Ophthalmology and Visual Science 52 (10): 7593–7602.

Tetikoglu M , Yuksel Z , Aktas S , Sagdik HM and Ozcura F (2018) VEGF‐A gene polymorphisms and responses to intravitreal ranibizumab treatment in patients with diabetic macular edema. International Ophthalmology 38 (6): 2381–2388.

Ung C , Sanchez AV , Shen L , et al. (2017) Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Research 139: 168–176.

Vuori N , Sandholm N , Kumar A , et al. (2019) CACNB2 is a novel susceptibility gene for diabetic retinopathy in type 1 diabetes. Diabetes 68 (11): 2165–2174.

Wong TY , Klein R , Islam FM , et al. (2006) Diabetic retinopathy in a multi‐ethnic cohort in the United States. American Journal of Ophthalmology 141 (3): 446–455.

Zhang X , Saaddine JB , Chou CF , et al. (2010) Prevalence of diabetic retinopathy in the United States, 2005–2008. JAMA 304 (6): 649–656.

van Zuydam NR , Ahlqvist E , Sandholm N , et al. (2018) A genome‐wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes 67 (7): 1414–1427.

Further Reading

Reed E and Pyeritz RE (2018) Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Clinical Principles and Applications, 7th edn. Elsevier: San Diego, CA.

Wellcome Trust Case Control Consortium (2007) Genome‐wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661–678.

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Moore, Spencer M, and Chao, Daniel L(Jul 2020) Genetics of Diabetic Retinopathy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026933]