Publishing date: October 2017
Author(s): Aschard H (1), Kang JH (2), Iglesias AI (3), Hysi P (4), Cooke Bailey JN (5,6), Khawaja AP (7), Allingham RR (8), Ashley-Koch A (9), Lee RK (10), Moroi SE (11), Brilliant MH (12), Wollstein G (13), Schuman JS (13), Fingert JH (14), Budenz DL (15), Realini T (16), Gaasterland T (17), Scott WK (18), Singh K (19), Sit AJ (20), Igo RP Jr (5), Song YE (5,6), Hark L (21), Ritch R (22), Rhee DJ (23), Gulati V (24), Haven S (24), Vollrath D (25), Zack DJ (26), Medeiros F (27), Weinreb RN (27), Cheng CY (28,29,30), Chasman DI (31), Christen WG (31), Pericak-Vance MA (18), Liu Y (32), Kraft P (1,33), Richards JE (11), Rosner BA (1,2), Hauser MA (8,9); International Glaucoma Genetics Consortium, Klaver CCW (3,34), vanDuijn CM (3), Haines J (5,6), Wiggs JL (35), Pasquale LR (2,35)
1 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, MA, USA.
2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3 Department of Epidemiology, Genetic Epidemiology Unit, Erasmus Medical Center, Rotterdam, The Netherlands.
4 Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
5 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
6 Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
7 Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.
8 Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
9 Department of Medicine, Duke University Medical Center, Durham, NC, USA.
10 Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
11 Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
12 Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
13 Department of Ophthalmology, NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA.
14 Departments of Ophthalmology and Anatomy/Cell Biology, University of Iowa, College of Medicine, Iowa City, IO, USA.
15 Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA.
16 Department of Ophthalmology, WVU Eye Institute, Morgantown, WV, USA.
17 Scripps Genome Center, University of California at San Diego, San Diego, CA, USA.
18 Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
19 Department of Ophthalmology, Stanford University, Palo Alto, CA, USA.
20 Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA.
21 Wills Eye Hospital, Glaucoma Research Center, Philadelphia, PA, USA.
22 Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA.
23 Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
24 Department of Ophthalmology &Visual Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
25 Department of Genetics, Stanford University, Palo Alto, CA, USA.
26 Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, MD, USA.
27 Department of Ophthalmology, Hamilton Eye Center, University of California at San Diego, San Diego, CA, USA.
28 Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore.
29 Ophthalmology &Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
30 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
31 Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
32 Department of Cellular Biology &Anatomy, Augusta University, Augusta, GA, USA.
33 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, MA, USA.
34 Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
35 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.European Journal of Human Genetics advance online publication, 30 August 2017; doi:10.1038/ejhg.2017.136.
Eur J Hum Genet. 2017 Aug 30. doi: 10.1038/ejhg.2017.136.
Clinical Paper of the Month manager: Andreas Boehm