Genetic factors in open-angle (simple and capsular) glaucoma. A population-based twin study

A nationwide record linkage of the Finnish Twin Cohort Study (FTCS) with the Hospital Discharge Registry and the Registry of Rights for Free medication is presented. This study consists of 108 pairs (114 individuals) of twins with chronic open-angle glaucoma. Of the twin pairs 29 were monozygotic (MZ), while 79 pairs were dizygotic (DZ). Three monozygotic and 3 dizygotic pairs were concordant for chronic open-angle glaucoma (OAG), while 26 monozygotic and 76 dizygotic pairs were discordant. Seventy-three twins had chronic simple glaucoma, while 34 twins had capsular glaucoma, and in 7 patients chronic simple glaucoma was noted in one eye and capsular glaucoma in the second eye. The heritability of chronic open angle glaucoma was 13%. The higher O/E-ratio of concordant twin pairs among MZ twins indicates that genetic factors play a role in this disease. The difference is anyhow surprisingly low compared to former estimates of heritability of open angle glaucoma. The steep rise in prevalence in older age groups was confirmed. The age-adjusted prevalence of chronic open-angle glaucoma in this study was 0.63%.     

Twin study of age-related macular degeneration

PURPOSE To evaluate the genetic contribution in age-related macular degeneration (ARMD) by a disease-ascertained twin study. METHODS Concordance rates for ARMD in 25 twins were obtained by using four masked graders to confirm the diagnosis of ARMD and place subjects in one of three categories; concordant, intermediate, or discordant. Demographic features and known risk factors for ARMD were compared between monozygotic and dizygotic twin pairs. RESULTS Of the 25 twin pairs, 15 were monzygotic and 10 were dizygotic. All 15 monozygotic twins were concordant or intermediate for ARMD. Of the dizygotic twin pairs, only one was concordant and five were discordant. In the demographic and risk factor analysis no unusual contributing or confounding variables were detected. CONCLUSIONS The association between zygosity and concordance for ARMD suggests a major importance for genetics in the etiology of ARMD. Our data further support a multi-factorial, primarily polygenic etiology for the condition.     

Primary open-angle glaucoma in 2 monozygotic twin pairs

Two monozygotic twin pairs with primary open-angle glaucoma (POAG) derived from the Finnish Twin Cohort Study were studied. The first female twin pair was concordant, and the second female pair was discordant for primary open-angle glaucoma. The nondiseased member of this second pair showed preglaucomatous signs in the form of ocular hypertension. The clinical study of the patients included a careful ophthalmologic examination, retinal nerve fiber layer (RNFL) photography and optic disc stereophotography. Visual fields were tested with an automated perimeter (Octopus 2000). The small number of twin pairs in the present study does not permit quantitative analysis of heritability, but it is obvious that whenever a clinical diagnosis of primary open-angle glaucoma in a monozygotic twin is made, the co-twin should be carefully examined.     

Discordance for keratoconus in two pairs of monozygotic twins.

PURPOSE: We present two pairs of monozygotic twins discordant for keratoconus. METHODS: Two pairs of twins, each with one twin with keratoconus, and available family members were examined clinically and with computer-assisted videokeratography. Polymerase chain reaction-based zygosity assays using between nine and 11 unique, anonymous DNA markers were performed on blood obtained from the twins and surviving parents to assess the probability of genetic monozygosity. RESULTS: DNA probes showed a >99% probability that each of the two sets of twins was monozygotic. One twin from each pair had clinically diagnosed keratoconus. The remaining twins were normal by clinical examination and corneal topography. Clinical results for all family members examined were normal except that five of 13 from one family and one of six from the other family demonstrated "suspicious" corneal topography. CONCLUSION: Recent advances in knowledge and understanding of the twinning process suggest that monozygotic twins discordant for keratoconus does not preclude the possibility of a significant genetic component.     

Genetic and environmental effects on oculometric traits

Twenty twin pairs (9 monozygotic and 11 dizygotic) were examined to test the effect of genetic and environmental factors on the etiology of refractive error, axial length of the eyeball, and total astigmatism. The twins pairs were ascertained from the nationwide Finnish Twin Cohort Study (FTCS). The monozygosity was confirmed for nine pairs by a blood group analysis adopted for paternity testing procedures. The mean ages of the monozygotic twin pairs was 69 years and of the dizygotic twin pairs 63 years. Spherical equivalent of refractive error and axial length of the eyeball showed higher intrapair correlations among monozygotic pairs than among dizygotic pairs. This suggests, at least in part, a genetic etiology of these traits. Total astigmatism measured by retinoscopy did not show a significant difference in intrapair correlations between monozygotic and dizygotic twin pairs.     

Comparative corneal topography and refractive variables in monozygotic and dizygotic twins

PURPOSE: To investigate the role of heredity in determining corneal shape, axial length, and overall refractive error. METHODS: Twenty monozygotic and 19 dizygotic twin pairs, age 12 to 73 years, were enrolled in the study. Zygosity was determined by physical similarity and by responses to questions adapted from surveys. Two twin pairs were excluded because of undetermined zygosity and one pair because of keratoconus (both siblings). Refractive error was determined by an automated refractor. Manifest refraction was also recorded, as well as cycloplegic refraction in subjects under age 18 years. Corneal topography data and manual keratometer readings were also obtained. Axial lengths were determined by A-scan ultrasound. Data were analyzed by Student t tests only in the right eye. Left-eye data were comparable for all variables. RESULTS: Mean intrapair difference in refractive error (spherical equivalent) was less for monozygotic than for dizygotic twins (RE: 0.41 vs 1.53; P = .001). Mean intrapair difference in axial length was less for monozygotic twins (RE: 0.39 vs 0.76 mm; P = .031). Corneal topography data (power and meridian) in all zones (3, 5, and 7 mm) also showed smaller mean differences among monozygotic pairs than dizygotic, but the difference was statistically significant only for the 5-mm zone. In addition, most Holladay Diagnostic Summary variables that were studied did not show any statistically significant differences. CONCLUSIONS: Axial length and overall refractive error have a significant genetic basis. Corneal topography data appear to have other overriding determining factors for several of the variables studied.     

Chronic open-angle glaucoma and associated ophthalmic findings in monozygotic twins and their spouses in Iceland

PURPOSE: To determine the concordance of glaucoma and ocular parameters in monozygotic twins and their spouses. METHODS: This was a prospective study that included 50 twin pairs 55 years of age or older and 47 of their spouses. Zygosity was determined by genetic laboratory testing. RESULTS: The concordance of open-angle glaucoma in monozygotic twin pairs was 98.0%, which significantly exceeded that of twin/spouse pairs (70.2%). There was a significant association in mean intraocular pressure (IOP), mean axial length, anterior chamber depth, and refractive error in the twin pairs. However, there was no association between the twins and their spouses for these ocular parameters. Eight twin pairs were found to have pseudoexfoliation syndrome (PXFS), five of which were concordant. There was no association between glaucoma and mean axial length or glaucoma and refractive error in the twin pairs studied. CONCLUSION: The statistically significant higher concordance of glaucoma--and the high correlation of mean IOP, mean axial length, anterior chamber depth, and refractive error--in twin pairs and the lack of association of these factors in twin/spouse pairs strongly suggests the importance of genetic factors for these ocular parameters.     

Twin study on cup/disc ratio of the optic nerve head.

Seventeen healthy twin pairs (10 monozygotic and seven dizygotic) from the Finnish Twin Cohort Study were examined to study the impact of heredity v environment in the determination of cup-to-disc area ratio. These twins were free from any known eye disease. The cup/disc ratio was determined using stereo photography and a computer assisted analysis technique. The zygosity of all twin pairs was confirmed with the DNA 'fingerprint' technique. The intrapair correlations were high among monozygotic pairs compared with those among dizygotic twin pairs. The difference of cup/disc area ratios between the right eyes of members of monozygotic twin pairs was statistically significantly smaller than that of dizygotic twin pairs (p < 0.001). The same was true for left eyes (p < 0.01). This result confirms a genetic determination in cup/disc area ratio in normal eyes.     

Keratoconus in 18 pairs of twins

Purpose: To describe the concordance of keratoconus in 18 sets of twins. Methods: Thirteen monozygotic (MZ) and five dizygotic (DZ) pairs of twins were identified during an investigation of familial keratoconus. We used 16 forensic microsatellite markers to confirm the zygosity of same sex twins. Patients and available relatives were examined for signs of keratoconus using corneal topography. For each pair of twins, the severity of keratoconus in each eye was graded according to the steepest keratometry value and the average difference in score between the MZ and DZ twins compared. Results: All of the MZ twins and four of the five DZ twins were concordant for keratoconus but with differences in age of onset and severity of disease. The subjective age of onset of keratoconus tended to be earlier in the MZ twins (16.4?years, SD 4.66) than in the DZ twins (20.3?years, SD 7.55) (p?=?0.086). Additional relatives with keratoconus were identified in two (16%) of the families with MZ twins and in three (60%) of the families of DZ twins. The mean difference in severity scores was 1.4 (SD 1.73) for the MZ twins and 3.0 (SD 1.00) for the DZ twins (p?=?0.035). Conclusion: This data provide evidence that the severity of keratoconus is more concordant in MZ than in DZ twins. The results support the currently accepted hypothesis of an important genetic contribution towards the pathogenesis of keratoconus, but suggest that there is also an environmental effect on the expression of disease.     

Genetic and environmental effects on the development of myopia in Chinese twin children

In order to assess the relative and interactive importance of genetic and environmental components on the development of myopia in Chinese school children aged from 10 to 15 years, a population-based sample of 361 same-sexed twin pairs recruited through stratified cluster sampling was studied. Zygosity of twin pairs was determined by Mendelian traits, red cell antigen systems, and continuous dermatoglyphic characteristics; while myopia was diagnosed by both objective and subjective techniques. Studying and reading habit was obtained from cotwins and their parents through a life style questionnaire. Age-sex-adjusted concordance rate derived from multiple regression equation was used in the analysis.

Conventional comparison of intrapair concordance between monozygotic (MZ) and dizygotic (DZ) twins was used to assess the importance of a genetic component in the determining of myopia, and a significant genetic influence was observed. Environmental influence on myopia was evaluated through MZ cotwin method, and MZ cotwins with concordant studying and reading habits were significantly more concordant in myopia than those MZ cotwins with discordant habits. The possible effect of gene-environment interaction on myopia was explored, and concordance in myopia was found significantly associated with the interaction between zygosity and habit of studying and reading. These observations suggested that the impact of the environmental factor on the development of myopia may be influenced by genotype, and vice versa.     

Genetic aspects of esotropia in homozygous twins

The present paper reports on 14 pairs of monozygotic twins with ocular motility disorders. Eight pairs were concordant and two partially concordant, while four pairs were discordant. Four pairs were born prematurely; two pairs were born by cesarean section, one of them also prematurely. Of the 24 patients with motility disorders, 10 had congenital squint syndrome, nine microtropia, one accommodative esotropia, two esophoria, and two orbital strabismus due to premature synostosis of the coronal suture. Genetic and exogenic factors and the forms of strabismus are discussed.     

Concordant bilateral Duane's Retraction Syndrome (type 1) in female monozygotic twins

We report a single case study of concordant bilateral Duane's Retraction Syndrome (DRS) (type 1) in female monozygotic (MZ) twins aged 47 years. The twin pair were recruited through the Australian Twin Registry as part of a twin study on myopia. This twin pair were full term and had a similar birth weight: 2.27 kg and 1.81 kg in twin 1 and twin 2, respectively. There was no report of any other childhood medical conditions in either twin. Both twins had an equal amount of restriction in right and left abduction. Narrowing of the palpebral fissures and globe retraction in right and left adduction was also observed in both twins. To our knowledge this is the first case to report concordant bilateral DRS (type 1) in female MZ twins. The concordance for the presence of DRS and associated clinical signs observed in this MZ twin pair supports a genetic origin to DRS.     

Lens thickness and insulin dependent diabetes mellitus: a population based twin study.

AIM: To investigate the relation between lens thickness and duration of insulin dependent diabetes mellitus (IDDM). METHODS: From the new population based Danish twin register, containing 20,888 twin pairs born between 1953 and 1982 (inclusive), all twin pairs having one or both partners affected with IDDM were searched. Among the 45 twin pairs available for clinical eye examination there were 15 monozygotic pairs, 14 dizygotic pairs of same sex, and 16 dizygotic pairs of opposite sex. Lens thickness was measured by ultrasonography. Using a twin control design, the relation between lens thickness and duration of IDDM was assessed by estimating the correlation between the intrapair difference in lens thickness and the intrapair difference in diabetes duration. RESULTS: In monozygotic twin pairs a statistically highly significant correlation between duration of diabetes and lens thickness was found (right eye: r = 0.88, p < 0.0001; left eye: r = 0.90, p < 0.0001). In dizygotic twin pairs of the same sex the correlations were r = 0.58 (p = 0.029) and r = 0.53 (p = 0.053) for right eye and left eye, respectively. For dizygotic twin pairs of opposite sex the correlations were r = 0.58 (p = 0.018) and r = 0.69 (p = 0.005) for right eye and left eye, respectively. The slope in regression analysis were similar for monozygotic twin pairs (0.025, common for both eyes) and dizygotic twin pairs grouped (0.024, common for both eyes). CONCLUSIONS: There is a statistically significant positive correlation between duration of IDDM and lens thickness, as assessed by the twin control method. The higher correlation in monozygotic twins compared with dizygotic twins suggests that genetic factors play an additional role in the determination of lens thickness. The similar slopes in regression analysis indicate that the effect of diabetes duration on lens thickness is independent of zygosity.     

Concordance of strabismic phenotypes in monozygotic versus multizygotic twins and other multiple births

PURPOSE: The concordance of strabismic phenotypes was examined in monozygotic versus multizygotic twins and other multiple births to study the role of genetic background in different types of commitant strabismus. METHODS: Medical charts of 45 consecutive pairs of twins (16 monozygotic and 18 dizygotic twins, and 11 with unknown zygosity), 3 sets of triplets (one monozygotic and 2 trizygotic triplets), and one set of quadruzygotic quadruplets examined at 6 institutions between 1973 and 1999 were reviewed retrospectively. The concordance was defined as both or all members having either esotropia or exotropia in common. RESULTS: The concordance of strabismic phenotypes was noted in 33 of 49 pairs or sets (67.3%): 14 of 17 monozygotic twins or triplets (82.4%), 10 of 21 multizygotic twins, triplets, or quadruplets (47.6%), and 9 of 11 twins with unknown zygosity (81.8%). The concordance rate was significantly higher in monozygosity than in multizygosity (P =.043, Fisher exact probability test). The predominant concordant phenotypes in monozygosity were accommodative esotropia and intermittent exotropia. CONCLUSION: A high concordance rate of strabismic phenotypes, predominantly of accommodative esotropia and intermittent exotropia in monozygosity, suggests the genetic background for these types of strabismus.     

The genetic effect on refractive error and anterior corneal aberration: twin eye study

PURPOSE: To investigate the role of heredity in determining refractive variables, anterior corneal curvature, and anterior corneal aberrations. METHODS: Thirty-three monozygotic and 10 dizygotic twin pairs were enrolled in this study. Corneal curvature, corneal astigmatism, and corneal topography were obtained from computerized videokeratoscope. The CTView program was used to compute anterior corneal aberrations from corneal height data of the videokeratoscope. Correlation analysis was performed to investigate the symmetry of the refractive error, corneal curvature, corneal astigmatism, and anterior corneal aberrations between right and left eyes of each twin pair. Heritability (h2) of these parameters was also calculated. RESULTS: Positive correlations were noted between right and left eyes for spherical power, total astigmatism, mean corneal curvature, and corneal astigmatism. In monozygotic twins, vertical coma, secondary vertical coma, spherical aberration, and secondary spherical aberration were moderately correlated. In dizygotic twins, vertical coma, secondary horizontal coma, and spherical aberration were moderately correlated. In unrelated controls, secondary vertical coma, secondary horizontal coma, and secondary spherical aberration were moderately correlated. Root-mean-square (RMS) of higher order aberrations (3rd to 6th orders), RMS of spherical aberration, and RMS of coma were moderately correlated between right and left eyes in all three groups. Heritability of spherical aberration, RMS of spherical aberration, and corneal astigmatism (h2 = 0.56, 0.44, and 0.46) were greater than those of refractive power, corneal curvature, and other higher order aberrations. CONCLUSIONS: These results suggest that corneal astigmatism and spherical aberration possess a greater genetic predisposition than those of other refractive errors and higher order aberrations.     

Corneal endothelial cell density in twins.

Corneal endothelial cell density was measured in normal subjects and in a group of monozygotic and dizygotic twins. Cell density was found to decline with age and to be similar in right and left eyes in normal subjects. Both monozygotic and dizygotic twins were found to have very similar mean endothelial cells densities and particularly so in like-sided eyes.     

Trabeculectomy combined with cataract extraction: a follow-up study.

Fifty-nine eyes undergoing combined cataract extraction and trabeculectomy were studied. The follow-up period ranged from 6 months to 2 years. The visual outcome and postoperative control of intraocular pressure have been compared in chronic open-angle, chronic closed-angle, and secondary glaucoma. Good results were obtained in both primary open- and closed-angle glaucoma, but not in secondary glaucoma.     

Monozygotic twins concordant for bilateral Duane's retraction syndrome

Duane's retraction syndrome applies to a wide spectrum of motility disturbances associated with retraction of the globe and narrowing of the palpebral fissure. Although many different anatomic and physiologic disturbances of the oculomotor system are implicated, the underlying cause remains obscure. Twin studies are often useful in determining the contribution of genetics or heredity to disease, but the occurrence of Duane's retraction syndrome in twins is rare. One of a pair of monozygotic twins concordant for bilateral Duane's retraction syndrome developed a 12-diopter esotropia in primary gaze but the other has not. Neither child has a head tilt and both can fix and follow with either eye.     

Squint in monozygotic twins

In a group of monozygotic twins, in which at least one of the pair squinted, strabismus was observed in both twins in only about half of the cases. Within the concordant group there was variation in the way in which the anomaly became manifest.Author's address: Ophthalmological Clinic Academic Hospital Oostersingel 59 Groningen The Netherlands