Genetic Epidemiology of Glaucoma

Purpose. The genetic etiology of primary open-angle glaucoma (POAG) is still largely unknown, because of its complexity and disparities in its classification. We aimed to determine the genetic contribution to various early, continuous markers of POAG by assessing the heritability of intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, and neuroretinal rim and optic disc parameters in a genetically isolated population. Methods. A total of 2620 subjects (mean age, 48 yrs; range 18 – 86) from extended pedigrees living in a small town in the Netherlands underwent an extensive ophthalmic examination. Their IOP was measured by Goldmann applanation tonometry, their RNFL thickness by scanning laser polarimetry (GDx VCC), and their optic disc parameters by confocal scanning laser ophthalmoscopy (HRT II). Risk associations were explored by linear regression analyses and heritability estimates by variance component methods. results. Inbreeding was present in 2042 (81%) participants, and was significantly associated with a higher IOP (P < 0.001). The heritability estimate for IOP was 0.35 (95% confidence interval [CI], 0.27-0.43); for RNFL thickness, 0.48 (95% CI, 0.35-0.60); and for neuroretinal rim area, 0.39 (95% CI, 0.20-0.58). Non-genetic factors accounted for only a small proportion (≤ 0.13) of the variance in all 3 traits. conclusions. Early, continuous markers of POAG are strongly determined by additive genetic effects. Our results support a quantitative trait strategy to discover new genes for POAG. Leonieke BW 1.6.indd 58 01-08-11 09:16 Heritability of quantitative glaucoma traits 59 iNtroDUctioN Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide.1 The sharp rise in the ageing population will probably cause a 30% increase in the number of patients with POAG by 2020, with an estimate of 58.6 million affected and 5.9 million bilaterally blind.2 Established risk factors for POAG are age, race, intraocular pressure (IOP), central corneal thickness (CCT), high myopia, and a positive family history.3,4 Dissection of the genetic background has resulted in an association with 20 genetic loci and 3 genes (MYOC, OPTN, WDR36).5-7 In addition, genes causing congenital glaucoma or glaucoma-associated developmental syndromes may contribute to adultonset POAG. Some (e.g. CYP1B1) are already recognized to be involved, the role of others (PITX2, FOXC1, PAX6, LMX1B) remains to be fully assessed in adult cases.8-13 The currently identified genes probably contribute to the pathogenesis of POAG in less than 5% of cases in the general population.14-19 Hence, genes that explain a more significant fraction of POAG remain to be identified. Gene-finding in POAG has been hampered by etiological and clinical heterogeneity, partly due to non-uniformity of diagnostic criteria. Its insidious onset and slow natural course impede a definite diagnosis at an early stage, whereas including only late-stage, outright POAG will greatly limit genetic studies because relatively few people would be available to participate. These difficulties fuel the question of whether studying heritable, continuous markers of POAG may improve the chance of success in gene-finding. Quantitative markers of POAG, apart from IOP, are retinal nerve fiber layer (RNFL) thickness and optic disc rim area, both indicators of the number of existing retinal ganglion cells, or indirectly, of any of their loss, typical of glaucoma.20-22 Previous studies, mostly performed in twins or nuclear families, reported heritability estimates for IOP ranging from 0.29 to 0.50 and for cup-to-disc ratio ranging from 0.48 to 0.80.23-26 The ranges of these heritability estimates are relatively large, and studies based on more extended pedigrees may provide more precise figures. We performed a family-based cohort study in a genetically isolated population in the Netherlands and thereby had the opportunity to study large extended pedigrees. As a first investigation into the genetic etiology of early markers of POAG, we explored the heritability estimates for IOP, RNFL thickness, and optic disc rim area. We used the imaging techniques scanning laser polarimetry (SLP) and confocal scanning laser ophthalmoscopy (CSLO) to obtain objective measurements. This study also allowed us to demonstrate the effect of inbreeding and non-genetic factors on these POAG markers. Leonieke BW 1.6.indd 59 01-08-11 09:16