title: Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.
abstract: OBJECTIVE
  Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.
  
  
  METHODS
  Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot.
  
  
  RESULTS
  The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.
  
  
  CONCLUSIONS
  Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia. Kathryn.burdon@utas.edu.au.|Menzies Institute for Medical Research, University of Tasmania, Private bag 23, Hobart, TAS, 7000, Australia. Kathryn.burdon@utas.edu.au.
authors.forename: Kathryn P
authors.identifier: http://orcid.org/0000-0001-8217-1249
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
authors.forename: Rhys D
authors.initials: RD
authors.lastname: Fogarty
authors.affiliation: Save Sight Institute, Clinical Ophthalmology and Eye Health, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Weiyong
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
authors.forename: Sotoodeh
authors.initials: S
authors.lastname: Abhary
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Kaidonis
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
authors.forename: Binoy
authors.initials: B
authors.lastname: Appukuttan
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, East Melbourne, VIC, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
authors.forename: Shiwani
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Ophthalmology, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Daniell
authors.affiliation: Academic Unit of Ophthalmology, Australian National University, Canberra, ACT, Australia.
authors.forename: Rohan W
authors.initials: RW
authors.lastname: Essex
authors.affiliation: School of Medical Sciences, University of NSW, Sydney, NSW, Australia.|Medical Retina Service, Moorfields Eye Hospital, London, UK.
authors.forename: John H
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Department of Anatomical Pathology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Klebe
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
authors.forename: Stewart R
authors.initials: SR
authors.lastname: Lake
authors.affiliation: Medical Retina Service, Moorfields Eye Hospital, London, UK.
authors.forename: Bishwanath
authors.initials: B
authors.lastname: Pal
authors.affiliation: St Vincent's Hospital, Fitzroy, VIC, Australia.
authors.forename: Alicia
authors.initials: A
authors.lastname: Jenkins
authors.affiliation: Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India.
authors.forename: Gowthaman
authors.initials: G
authors.lastname: Govindarjan
authors.affiliation: Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India.
authors.forename: Periasamy
authors.initials: P
authors.lastname: Sundaresan
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, East Melbourne, VIC, Australia.|Department of Population Health, Singapore Eye Research Institute, Singapore, Singapore.
authors.forename: Ecosse L
authors.initials: EL
authors.lastname: Lamoureux
authors.affiliation: Retina Clinic, Aravind Eye Hospital, Madurai, Tamil Nadu, India.
authors.forename: Kim
authors.initials: K
authors.lastname: Ramasamy
authors.affiliation: Medical Retina Service, Moorfields Eye Hospital, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Pefkianaki
authors.affiliation: Medical Retina Service, Moorfields Eye Hospital, London, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Hykin
authors.affiliation: Department of Endocrinology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Petrovsky
authors.affiliation: Diamantina Institute, The University of Queensland, Translational Research Institute Princess Alexandra Hospital, Brisbane, QLD, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Save Sight Institute, Clinical Ophthalmology and Eye Health, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gillies
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia. Jamie.craig@flinders.edu.au.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000818:Animals; D001315:Australia; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics*; D051380:GRB2 Adaptor Protein / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide
chemical_list: D051380:GRB2 Adaptor Protein
keywords: Blinding retinopathy; Diabetic complications; Genetic risk factors; Genome-wide association study; Müller cell; Proliferative retinopathy