Open-angle glaucoma

306 Pages·2016·13.98 MB·English

Open-angle glaucoma:
from epidemiology to molecular
aspects and anatomical features
Hendrika Springelkamp
Acknowledgements:
The research described in this thesis was supported by the NWO Graduate Programme
2010 BOO (022.002.023). The Rotterdam Study and ERF were supported by the Netherlands
Organisation of Scientific Research (NWO; 91111025); Erasmus Medical Center and Erasmus
University, Rotterdam, The Netherlands; Netherlands Organization for Health Research
and Development (ZonMw); UitZicht; the Research Institute for Diseases in the Elderly; the
Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the
European Commission (DG XII); the municipality of Rotterdam; the Netherlands Genomics
Initiative/NWO; Center for Medical Systems Biology of NGI; Stichting Lijf en Leven;
Stichting Oogfonds Nederland; Landelijke Stichting voor Blinden en Slechtzienden; Prof.
Dr. Henkes Stichting; Algemene Nederlandse Vereniging ter Voorkoming van Blind-
heid; MD Fonds; Glaucoomfonds; Medical Workshop; Heidelberg Engineering; Topcon
Europe BV. The generation and management of GWAS genotype data for the Rotterdam
Study is supported by the Netherlands Organisation of Scientific Research NWO
Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research
Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative
(NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810.
The publication of this thesis was financially supported by:
Glaucoomfonds, Prof.Dr. Henkes Stichting, Landelijke Stichting voor Blinden en Slecht-
zienden, Erasmus MC (Department of Epidemiology), Allergan BV, Bayer B.V., Théa Pharma
Cover & lay-out: Jessy Wijgerde
Printing: Ridderprint BV
ISBN: 9789491462252
© 2016 H. Springelkamp
All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or
transmitted in any form or by any means without permission of the author, or, when appro-
priate, of the publisher of the publications.
OPEN-ANGLE GLAUCOMA:
FROM EPIDEMIOLOGY TO MOLECULAR ASPECTS AND ANATOMICAL FEATURES
Open kamerhoek glaucoom:
van epidemiologie naar moleculaire aspecten en anatomische kenmerken
Proefschrift
ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de
rector magnificus
Prof.dr. H.A.P. Pols
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 13 januari 2016 om 15.30 uur
door
Hendrika Springelkamp
geboren te Apeldoorn
PROMOTIECOMMISSIE
Promotoren:
Prof.dr.ir. C.M. van Duijn
Prof.dr. N.M. Jansonius
Prof.dr. C.C.W. Klaver
Overige leden:
Prof.dr. R.M.W. Hofstra
Prof.dr. P.J. Foster
Prof.dr. L.R. Pasquale
Voor mijn ouders

TABLE OF CONTENTS
Part 1 Introduction 9
1.1 General introduction 11
1.2 The genetics of primary open-angle glaucoma 17
Part 2 The role of optical coherence tomography in glaucoma 27
2.1 Optimizing the information yield of 3-D OCT in glaucoma 29
2.2 Population-based evaluation of retinal nerve fiber layer, retinal ganglion 47
cell layer, and inner plexiform layer as a diagnostic tool for glaucoma
Part 3 Risk factors for intraocular pressure and glaucoma 69
3.1 Incidence of glaucomatous visual field loss after two decades of follow-up: 71
the Rotterdam Study
3.2 Relationship between sleep apnea and open-angle glaucoma: 85
a population-based cohort study
3.3 Associations with intraocular pressure across Europe: The European Eye 99
Epidemiology (E3) Consortium
Part 4 Genetics of intraocular pressure and optic nerve head measurements 123
4.1 Genome-wide analysis of multi-ancestry cohorts identifies new loci 125
influencing intraocular pressure and susceptibility to glaucoma
4.2 Meta-analysis of genome-wide association studies identifies novel loci that 139
influence cupping and the glaucomatous process
4.3 Meta-analysis of genome-wide association studies identifies novel loci 153
associated with optic disc morphology
4.4 ARHGEF12 influences the risk of glaucoma by increasing intraocular 171
pressure
4.5 New insights into genetics of primary open-angle glaucoma based on 189
meta-analyses of intraocular pressure and optic disc characteristics

Part 5 Functional consequences of genetic variants 245
5.1 Exome sequencing and functional analyses suggest SIX6 is a gene involved 247
in an altered proliferation-differentiation balance early in life and optic
nerve degeneration at old age

Part 6 General discussion 271
Part 7 289
Samenvatting 290
Summary 293
Acknowledgements – Dankwoord 296
PhD Portfolio 300
List of publications 302
About the author 305

part 1
introduction