Heritability of Risk Factors for Primary Open-Angle Glaucoma: The Beaver Dam Eye Study

Abstract

purpose. To investigate the family aggregation and heritability of risk indicators of primary open-angle glaucoma.

methods. During the baseline examination of the Beaver Dam Eye Study, standardized measurements of intraocular pressure were performed with a Goldmann applanation tonometer. Stereoscopic photographs of the optic discs were taken of both eyes of each study participant. The eyes were graded for the size of the optic disc and cup according to a standardized protocol, with graders masked to other subject characteristics. Family members who had participated in the examination phase were identified.

results. Correlations in sibling pairs (n = 1136), parent–child pairs (n = 514), and cousin pairs (n = 1807) for intraocular pressure were 0.17, 0.18, and 0.12, respectively and were all statistically significant, whereas the spouse pair correlation was not. Correlations for sibling, parent–child, and avuncular pairs were higher for vertical optic disc, vertical optic cup, and vertical cup-to-disc ratio than for intraocular pressure. Heritability estimates were 0.36, 0.55, 0.57, and 0.48 for intraocular pressure, optic cup diameter, optic disc diameter, and cup-to-disc ratio, respectively. Correlations for the optic disc parameters were compatible with the amount of gene sharing in relative pairs of different degrees.

conclusions. Risk indicators of open-angle glaucoma correlate highly in families, and the patterns are consistent with the hypothesis of genetic determinants of these factors.

Primary open-angle glaucoma is a diagnosis that is often made after damage extensive enough to cause functional deficit, as manifest by a visual field defect. By this time, it is likely that many optic nerve fibers have been lost. ¹ Based on incidence data, ^{2 3 4 5} overt glaucoma is more likely to develop in those with higher baseline intraocular pressures than in those with lower pressures. The relationship appears to be monotonic, with no evidence of a threshold of increased risk at any particular pressure. The risk rose acutely from approximately 1% in those with pressures below 16 mm Hg to as high as 40% in those with pressures greater than 30 mm Hg in the Ocular Hypertension Treatment Study (OHTS). ⁶ The most persuasive data in support of the importance of intraocular pressure as a risk factor for primary open-angle glaucoma are from the OHTS which demonstrated that lowering the intraocular pressure by medical treatment resulted in a hazard ratio of 0.40 (95% confidence interval, 0.27–0.59) for open-angle glaucoma at 60 months after treatment was begun. ⁶ Cup-to-disc ratios, both vertical and horizontal, as well as other ocular factors that may be associated with risk of glaucoma were also evaluated in that trial. Although larger ratios have been considered to be caused by glaucoma, the Ocular Hypertension Treatment Study found that relatively larger ratios preceded the diagnosis of glaucoma, with the hazard ratio being slightly greater for the vertical than for the horizontal ratio. 

Family studies of primary open-angle glaucoma, ^{7 8 9} a study of individuals with the disease, ¹⁰ and large epidemiologic studies ^{11 12 13} are all consistent with the notion of genetic determinants of this condition. Twin studies ^{14 15} as well as other family studies ^{16 17} support the hypothesis of genetic determinants of intraocular pressure. There are few data in the literature concerning family similarity of optic disc morphology, but there are data indicating that there are genetic determinants of the number of retinal ganglion cells in mice, ^{18 19} which would be likely to affect optic disc morphology in that species. 

The clinical diagnosis of glaucoma is not made according to a uniform set of guidelines. The lack of uniformity may lead to phenotypic heterogeneity. This may hamper the search for determinants of this condition, both environmental and genetic. Also, it is likely that identifying affected individuals early in the disease is hard to do with certainty. Waiting for the appearance of late-stage unequivocal disease may impede the search for causes, because the number of persons with overt disease may be small relative to the number with early-onset disease. Therefore, the search for either early markers or strong risk factors may facilitate understanding the genetic mechanisms underlying this disease as it occurs in populations. We sought to investigate the heritability of intraocular pressure and vertical cup and disc diameters in a large, population-based study. 

Methods

Methods used to identify the population and description of participants and nonparticipants appear in previous reports. ^{20 21} Briefly, a private census of the population of Beaver Dam, Wisconsin, was performed from fall 1987 through spring 1988. All 5924 persons 43 to 84 years of age were eligible to participate in a baseline examination that took place from March 1988 to September 1, 1990. Tenets of the Declaration of Helsinki were observed and institutional review board approval was obtained. The baseline examination included measurements of intraocular pressure in each eye according to the following protocol: A drop of fluorescein sodium (Fluress; Armour, Kankakee, IL) was instilled in each eye. The tonometer was set at 10. The measurement was taken as the examiner viewed the mires through the prism. When the end point was reached, the examiner moved the slit lamp away from the eye and read and recorded the reading. The procedure was repeated for the other eye. The time of the measurement was recorded. The pupils were dilated and photographs of the ocular fundus including stereoscopic images of the optic discs of both eyes were taken. Grading of optic disc and cup dimensions was performed according to a specified protocol. ²² In brief, the stereoscopic pairs of photographs of each optic disc were examined, and both vertical and horizontal disc and cup diameters were measured with a template of grade circles of increasing sizes (in fractions of an inch). Vertical cup and disc measurements were used in analyses in this study, because they have been shown to be slightly more commonly associated with incident glaucoma than have horizontal dimensions. ⁶  

Persons with one or more siblings who were identified during the initial census of Beaver Dam were grouped into families. The families were expanded to include cousin and avuncular relationships by telephone interviews and obituaries. Family relationships were confirmed by interview and extended pedigrees constructed. There were 2783 persons in these families. There were additional spouses without other relatives in the population. 

Statistical analyses were accomplished using FCOR, a procedure for estimating multivariate family correlations, in the SAGE software. ²³ Logistic regression was used to assess the odds of a person being affected given that a family member was affected, adjusting for age and sex. Generalized estimating equations (GEE) were used to adjust for contributions from multiple family members. ²⁴  

Results

There were no consistent systematic differences between the eyes in the measurements of intraocular pressure or optic disc. Data for these continuous variables are given for the eye with the higher intraocular pressure and larger cup-to-disc ratio. The mean intraocular pressure was 16.3 ± 3.3 mm Hg in women and 15.9 ± 3.5 mm Hg in men (Table 1) . Intraocular pressure increased with each decade of current age. Mean vertical optic cup diameters were 0.069 ± 0.025 inches in women and 0.069 ± 0.025 inches in men. Mean vertical optic disc diameters were 0.172 ± 0.018 inches in women and 0.172 ± 0.018 inches in men. Both increased with age. The average vertical cup-to-disc ratio was 0.403 ± 0.128 for women and 0.404 ± 0.123 for men. There was an increase with age. 

Because of the effects of age on all measures and on sex for intraocular pressure, the following correlation analyses were adjusted for these two variables (Table 2) . The correlation of intraocular pressure in siblings was 0.17, in parents and children, 0.18; in avunculars, 0.02; in cousins, 0.12; and in spouses, 0.06. Heritability (h²) derived from the parent–child correlation was 0.36. The correlation of vertical cup-to-disc ratio in siblings was 0.25; in parents and children, 0.24; in avunculars, 0.14; in cousins, 0.04; and in spouses, 0.01. Heritability was 0.48. The correlations and heritability for optic disc and cup separately were higher than for the cup-to-disc ratio. 

Discussion

These analyses support the hypothesis of strong familial effects on risk indicators of glaucoma. Especially noteworthy was the consistent and strong quantitative relationship of intraocular pressures and (vertical) optic cup dimensions in siblings and in parents and children and the lack of correlation of these parameters in spouses. The pattern for optic disc parameters is compatible with the amount of gene-sharing in relative pairs of different degrees. 

The correlations for intraocular pressure between family members was lower than for the optic disc and cup measures. This may be a reflection of the quantity and variability of correlates of intraocular pressure which include not only age and sex, but medical intervention by drops or surgery, time of day of measurement (diurnal variation) as well as systolic blood pressure, body mass index, refractive error, serum cholesterol, hematocrit, month of measurement, pulse rate, severity of nuclear sclerosis, diastolic blood pressure, and glycolsylated hemoglobin. ²⁵  

We present data for the eye with the higher value, because data on glaucoma reflect these values and data from other studies do indicate that genetic factors are important in this disease. We did not find a consistent difference in the patterns of correlations when we analyzed data from like-side eyes (data not shown). 

We note that primary open-angle glaucoma occurs in approximately 2% of many adult white ^{22 26 27 28} populations, but the frequency is probably more than twice that in black populations. ^{26 29} It would be of interest to know whether there is a familial tendency to intraocular pressure and to larger cup-to-disc ratios in diverse black populations and whether the correlations are of the same magnitude that we found in whites. It would also be of interest to determine whether the same genes are related to these characteristics across ethnic groups. 

 Supported by the Grants EY06594 and EY13438 from the National Eye Institute, and by US Public Health Service Resource Grant RR03655 from the National Center for Research Resources.

 Submitted for publication May 23, 2003; revised August 12, 2003; accepted August 16, 2003.

 Disclosure: B.E.K. Klein, None; R. Klein, None; K.E. Lee, None

 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Table 1.

 

 

Age and Sex Distributions of Mean Intraocular Pressure and Optic Disc Characteristics in Family Members

Table 1.

 

Age and Sex Distributions of Mean Intraocular Pressure and Optic Disc Characteristics in Family Members

Sex	Age (y)	n	Mean	SD
Intraocular pressure (mm Hg)
Women	43–54	319	15.8	3.0
	55–64	293	16.1	3.1
	65–74	390	16.8	3.4
	75+	307	16.6	3.7
Total		1309	16.3	3.3
Men	43–54	321	15.5	3.4
	55–64	291	16.1	3.2
	65–74	268	16.1	3.5
	75+	153	16.1	4.0
Total		1033	15.9	3.5
Women vs. men P = 0.002; age P < 0.0001
Vertical optic cup diameter (inches)
Women	43–54	317	0.066	0.023
	55–64	290	0.068	0.025
	65–74	385	0.067	0.025
	75+	273	0.074	0.026
Total		1265	0.069	0.025
Men	43–54	319	0.066	0.023
	55–64	290	0.069	0.023
	65–74	261	0.071	0.027
	75+	140	0.073	0.027
Total		1010	0.069	0.025
Women vs. men P > 0.5; age P < 0.0001
Vertical optic disc diameter (inches)
Women	43–54	317	0.169	0.017
	55–64	291	0.171	0.018
	65–74	387	0.173	0.018
	75+	283	0.177	0.019
Total		1278	0.172	0.018
Men	43–54	319	0.168	0.017
	55–64	290	0.172	0.018
	65–74	262	0.176	0.019
	75+	144	0.177	0.020
Total		1015	0.172	0.018
Women vs. men P > 0.9; age P < 0.0001
Vertical cup to disc ratio
Women	43–54	317	0.395	0.114
	55–64	290	0.403	0.133
	65–74	384	0.395	0.128
	75+	272	0.424	0.138
Total		1263	0.403	0.128
Men	43–54	319	0.396	0.117
	55–64	290	0.405	0.115
	65–74	261	0.407	0.132
	75+	140	0.418	0.132
Total		1010	0.404	0.123
Women vs. men P > 0.9; age P = 0.006

Table 2.

 

 

Adjusted Family Correlations for Risk Factors for Primary Glaucoma

Table 2.

 

Adjusted Family Correlations for Risk Factors for Primary Glaucoma

Trait	n	Corr.	95% CI	H*
Sibling
IOP	1136	0.17	(0.10–0.24)
Vertical cup	1091	0.28	(0.21–0.36)
Vertical disc	1105	0.38	(0.31–0.45)
Cup–disc ratio	1091	0.25	(0.18–0.32)
Parent-Child
IOP	514	0.18	(0.09–0.27)	0.36
Vertical cup	472	0.27	(0.18–0.36)	0.55
Vertical disc	482	0.29	(0.20–0.37)	0.57
Cup–disc ratio	469	0.24	(0.15–0.33)	0.48
Avuncular
IOP	748	0.02	(−0.07–0.11)
Vertical cup	710	0.17	(0.07–0.27)
Vertical disc	721	0.19	(0.09–0.30)
Cup–disc ratio	708	0.14	(0.04–0.23)
Cousin
IOP	1807	0.12	(0.06–0.18)
Vertical cup	1764	0.05	(−0.02–0.11)
Vertical disc	1782	0.10	(0.03–0.18)
Cup–disc ratio	1764	0.04	(−0.02–0.10)
Spouse
IOP	1154	0.06	(0.00–0.12)
Vertical cup	1125	0.03	(−0.03–0.09)
Vertical disc	1142	0.03	(−0.03–0.09)
Cup–disc ratio	1124	0.01	(−0.05–0.06)