Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Author(s): Gharahkhani P (1), Burdon KP (2), Cooke Bailey JN (3), Hewitt AW (2), Law MH (4), Pasquale LR (5), (6), Kang JH (6), Haines JL (3), Souzeau E (7), Zhou T (7), Siggs OM (7), Landers J (7), Awadalla M (7), Sharma S (7), Mills RA (7), Ridge B (7), Lynn D (8), Casson R (9), Graham SL (10), Goldberg I (11), White A (11), (12), Healey PR (11), (12), Grigg J (11), Lawlor M (11), Mitchell P (12), Ruddle J (13), Coote M (13), Walland M (13), Best S (14), Vincent A (14), Gale J (15), RadfordSmith G (4), (16), Whiteman DC (4), Montgomery GW (4), (17), Martin NG (4), Mackey DA (2), (18), Wiggs JL (5), MacGregor S (4), Craig JE (19); NEIGHBORHOOD consortium

1 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Puya.Gharahkhani@qimrberghofer.edu.au.
2 University of Tasmania, Hobart, Tasmania, Australia.
3 Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
4 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
5 Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
6 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7 Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
8 South Australian Health & Medical Research Institute, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
9 South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia.
10 Ophthalmology and Vision Science, Macquarie University, Sydney, New South Wales, Australia.
11 Department of Ophthalmology, University of Sydney, Sydney, Australia.
12 Centre for Vision Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia.
13 Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
14 Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
15 Department of Ophthalmology, University of Otago, Dunedin, Otago, New Zealand.
16 School of Medicine, University of Queensland, Herston Campus, Brisbane, QLD, Australia.
17 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
18 Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
19 Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. jamie.craig@flinders.edu.au.

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - response to fluid shear stress and abnormal retina morphology - in pathway-based tests.

Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

Sci Rep. 2018 Feb 15;8(1):3124. doi: 10.1038/s41598-018-20435-9.

http://www.ncbi.nlm.nih.gov/pubmed/29449654

Experimental Paper of the Month manager: Andreas Boehm