Abstract
purpose. To determine whether the distribution of naturally occurring myopia in Labrador Retrievers has a genetic component.
methods. Pedigree records of a large canine family were analyzed. Pure Labrador Retrievers, 1 to 8 years of age, free of ocular disease, and available for testing were studied. Refractive error was measured by cycloplegic retinoscopy in both eyes. The family included mating loops, and so an expectation maximization (EM) algorithm (multivar program, MORGAN software; University of Washington, Seattle) was used to calculate log likelihoods of refractive error with environmental and additive genetic models. The fixed effects of coat color, sex, and litter size were also tested.
results. In our sample of 116 dogs from this one family, the average spherical equivalent refraction (SER) was −0.41 D (range, −5.38 to +1.65 D, mean of both eyes, n = 116): 31% were myopic (SER ≤ −0.50 D), 60% were emmetropic (SER = −0.49 to +0.99 D), and 9% were hyperopic (SER ≥ +1.00 D). The significance of fixed and genetic effects was tested by comparing the full model (including genetic and all fixed effects) to models with one effect removed. Litter size and additive genetic effects were significant (P = 0.0013 and P = 0.000093, respectively), whereas sex and coat color were not. The overall variance in SER was accounted for approximately equally by additive genetic variance and residual/environmental variance. Narrow sense heritability of SER was 0.506.
conclusions. The distribution of refractive error within this family of Labrador Retrievers had a significant genetic component, but was also influenced by other factors (litter size, and undefined residual/environmental effects). The dog represents a unique model for the study of naturally occurring, heritable, high-prevalence, low-degree myopia.
A variety of animals, including the chick,
1 guinea pig,
2 tree shrew,
3 marmoset,
4 and monkey
5 have been used as animal models of human myopia. In these models, the eyes are not naturally myopic: rather, myopia is induced in developing eyes by manipulation of the visual environment. Myopia is typically induced by imposing retinal defocus (with negative lens wear) or by visual form deprivation, both of which cause axial elongation of the vitreous chamber and myopia in all eyes. Furthermore, when the inducing stimulus is removed, the myopia recovers over time.
1 The link between these animal models and myopia commonly found within the human population is questionable because human myopia, including high myopia and the much more common juvenile onset myopia, both appear to have a significant genetic component. Children with myopic parents have a higher than normal risk of myopia,
6 7 8 and high between-sibling correlations for refractive error and progression of myopia have been reported.
9 10 Also, twin studies show a higher level of concordance of common myopia in monozygotic compared to dizygotic twins.
6 7 The clear familial nature of high myopia
8 (refractive error ≤ −6.00 D) has led to many investigations of chromosomal regions linked to high myopia in humans, which have identified possible candidate loci at Xq28 (MYP1),
11 18p11 (MYP2),
12 12q21 to 23 (MYP3),
13 7q36 (MYP4),
14 17q21-22 (MYP5),
15 4q22-27 (MYP11),
16 2q37 (MYP12),
17 and Xq23-25 (MYP13).
18 Recent studies have also investigated the genetics of common myopia, which is more prevalent in the population. These studies have revealed possible candidate regions at 22q12 (MYP6),
19 11p13 (MYP7),
20 3q26 (MYP8),
20 4q12 (MYP9),
20 8p23 (MYP10),
20 and 1p36 (MYP14).
21 Families from a range of ethnicities and geographic backgrounds have been investigated in studies of high myopia and common myopia, and the results have not always been the same.
One animal species in which myopia occurs naturally is the domestic dog. Although the prevalence of myopia in dogs is breed dependent, approximately 8% to 15% of Labrador Retrievers are reported to have myopia ranging from −0.50 to −5.00 D.
22 23 The fact that the dog is the only animal species identified as having significant levels of naturally occurring myopia is interesting, but what is not clear is whether that myopia has a heritable component. If it does, then the dog may serve as a powerful animal model of human myopia. Moreover, the dog would have several advantages over humans for the study of the genetics of myopia. The use of dogs could minimize the confounding environmental effects of near work, education levels, and mode of upbringing typically identified as risk factors in humans.
24 Pedigree dogs also provide well-documented multigeneration ancestry that is often unknown or uncertain in human families. Furthermore, dogs mature relatively rapidly and have large litters and a high reproduction rate, so that many individuals from different generations can be studied relatively quickly.
The purpose of this study was to evaluate the inheritance of myopia in the dog as a prelude to possible genotyping. We have studied the Labrador Retriever because it is the only dog breed in which myopia has been shown to be based on vitreous chamber elongation,
22 as is the case in human myopia. Several studies have used segregation analysis methods to investigate the mode of inheritance of other canine diseases, such as deafness
25 and hip dysplasia.
26 However, the Statistical Analysis for Genetic Epidemiology (SAGE; 1997) software package that they used (Case Western University, Cleveland, OH) was not designed to cope with consanguinity and multiple matings within the sample population. We have chosen to use an expectation maximization (EM) algorithm that can fit an additive variance components genetic model to large pedigrees with multiple mates and consanguinity,
27 because our sample population contained many such loops.
Dogs were identified from the records of a colony specializing in breeding service dogs, situated in Auckland, New Zealand. Of the 1342 dogs in the colony’s records, 76% were Labrador Retrievers, registered with The New Zealand Kennel Club Purebred Dog Registry. Breeding and veterinary records, including regular ophthalmic records from 6 weeks of age onward, were available for all animals. Because all originated from the same colony, all dogs in the study had experienced a similar visual environment to the extent that, as puppies, they remained indoors with regular time outdoors from birth until 6 weeks of age. They were then separated from their littermates to live in a domestic environment.
A large family of Labrador Retrievers originating from a stud dog known to have myopia (−2.00 D) and having 407 descendents in 64 litters was selected for study. Several exclusion criteria were used in selecting the dogs from this family for further analysis. First, animals outside the age range of 1 to 8 years were excluded. This age range is developmentally and physiologically equivalent to a human age range of 18 to 56 years for dogs the size of Labrador Retrievers.
28 The upper age limit (8 years) was selected to reduce the likelihood of including dogs with lenticular changes that may induce a myopic shift in refraction.
23 Animals under 1 year of age were excluded on the grounds that while the rate of refractive development in dogs is unknown, dogs reach sexual maturity between 6 and 12 months of age.
29 Thus, by 1 year of age (equivalent to 18 years of age in humans), their refractive status would be expected to be stable. Dogs were excluded from the study, or were not able to be tested for a variety of reasons which are detailed in
Table 1 . All dogs that were phenotyped were included in the study. Selection bias was minimized, as there were no behavioral or other prior indicators of the refractive error of any of the dogs. In total, 116 dogs were included in the study, as they were registered as pure Labrador Retrievers within the specified age range, were members of the same extended family, were free of ocular disease, were traceable and were available for testing. Pedigree drawing software (CraneFoot, ver. 3.2.2; Helsinki University of Technology) was used to map out phenotyped individuals and mating loops within the sample pedigree.
MORGAN software version 2.8.2 (University of Washington, Seattle, WA) was used to analyze the data because it allowed analysis of large pedigrees with multiple mates and consanguinity, which characterized our sample. Our analysis accounted for all known relationships between the phenotyped dogs and their shared ancestors.
The
pedcheck program of MORGAN was used to check for relationship errors within the pedigree. The
multivar program of MORGAN was used to obtain maximum-likelihood estimates for additive polygenic models of quantitative traits by the expectation-maximization (EM) algorithm; this program did not allow other (e.g., dominant) models to be investigated. We analyzed the inheritance of refractive error as a quantitative trait, with three fixed effects: sex, litter size, and coat color. We included sex, as there is some suggestion of a sex effect in human studies.
32 Although there is no previous literature to suggest that either coat color or litter size would be associated with myopia, both are phenotypic descriptors that do not alter with age. Both were available for all dogs and were included because of the chance that they might be relevant. The MORGAN package was also used to calculate inbreeding coefficients between individuals of interest, by using the
kin program. The inbreeding coefficient (
F) is a measure of the probability of homozygosity by descent (i.e., the chance of an animal’s inheriting the same ancestral gene from both parents because they are related). Narrow sense heritability (the additive genetic variance as a proportion of total variance) was calculated using variances computed by
multivar for the best fitting model only.
The additive model used by
multivar 27 is
y = μ +
z +
e, where
y is the quantitative trait, μ is a vector of fixed effects,
z is a vector of additive genetic effects, and
e is a vector of residual/environmental effects. The distributions of
e and
z are assumed to be normal. The elements of
e are assumed to be independent with common variance. The elements of
z have correlations proportional to the coefficients of kinship. The
multivar program fits the model using the EM algorithm, which is an iterative approach to finding the parameter values that maximize the model likelihood. The stability of parameter values was typically achieved by 50 iterations, although we always used 200 iterations, which is the default for
multivar.
A histogram of refractive error distribution within the sample showed that it was left skewed. Approximate normality was obtained by the transformation √(1.65 − SER). This transformation was chosen to obtain positive right-skewed values first (the largest untransformed SER value was +1.65 D), and then to reduce the skewness through use of the square-root transformation. The transformed values were used as the quantitative trait in subsequent analysis with the
multivar program. We also ran the analysis using a normal deviates transform
33 of the refractive error distribution. Litter size ranged between 1 and 13 puppies and was coded as small (litter size between 1 and 7) or large (between 8 and 13).
To test for statistical significance of the fixed and genetic effects, we compared nested models. For example, we compared the full model with genetic effects, sex, coat color, and litter size to submodels, in which each one of these effects was removed in turn. The null hypothesis was that the submodel was as good as the full model at explaining the variability of the trait. Twice the difference in log likelihoods from the two models was compared to a χ2 distribution with degrees of freedom equal to the difference in the number of estimated parameters between the two models. As each of our fixed effects had two possible states (apart from missing values) the degrees of freedom was equal to one in each case. If the resulting probability was significant (P < 0.05), the null hypothesis was rejected, and we concluded that the variable that was removed from the full model to create the submodel was statistically significant in helping to explain the variability of the trait.
The statistical significance of fixed effects (sex, coat color, and litter size) and genetic effects was tested by comparing the full model (with genetic and all fixed effects) to models with one of these effects removed
(Table 2) . Litter size and additive genetic effects were significant (
P = 0.0013 and
P = 0.000093, respectively), whereas sex and coat color were not significant (
P = 0.20 and
P = 0.15, respectively). Similar results (in terms of statistical significance of each effect) were obtained by comparing a null model (with residual/environmental effects only) to models with only one of the fixed or genetic effects added. Analysis using the normal deviates transform confirmed the significance of litter size and additive genetic effects.
The final model, with litter size and genetic effects, had the form:
\[f(y){=}{\mu}{+}{\alpha}_{1}1{\{}\mathrm{small}{\}}{+}{\alpha}_{2}1{\{}\mathrm{large}{\}}{+}z{+}e\]
where
y is the SER,
f is the transformation to improve normality
f(
y) = √(1.65 −
y); μ is the overall mean; 1{small} is 1 if the individual comes from a small litter and 0 otherwise; while 1{large} is 1 if the individual comes from a large litter and 0 otherwise (each individual comes from either a small or a large litter, so 1{small} and 1{large} always sum to 1); α
1 and α
2 give the effects of small or large litter size;
z is the additive genetic effect, which has a normal distribution with mean 0 and variance σ
g 2 (with correlations between individuals being described by the matrix of kinship coefficients); and
e is the residual/environmental effect, which has a normal distribution with mean 0 and variance σ
e 2. The fitted values for these parameters were: μ = 1.218, α
1 = 0.112, α
2 = −0.062, σ
g 2 = 0.128, and σ
e 2 = 0.118. There were 38 dogs from small litters and 68 from large litters, and the variance for litter size was 0.007. Thus, total variance was 0.128 + 0.118 + 0.007 = 0.253, and narrow-sense heritability was 0.128/0.253 = 0.506 (computed from the best-fitting values).
The overall variance after accounting for litter size was split approximately equally between additive genetic variance and residual/environmental variance. Thus, genetic and undefined residual/environmental factors played approximately equal roles in determining refractive error in this family. Litter size made a much smaller contribution to refractive error. Dogs from small litters had an average transformed trait value of 1.218 + 0.112 = 1.330, which corresponds to SER = 1.65 − 1.332 = −0.119 D. On the other hand, dogs from large litters had an average transformed trait value of 1.218 − 0.062 = 1.156, which corresponds to SER = 1.65 − 1.1562 = 0.314 D. Thus, the model indicated that dogs from large litters had refractive errors that were, on average, 0.43 D more hyperopic than dogs from small litters.
The results of our study indicate that myopia in Labrador Retrievers has a significant genetic component. To our knowledge, this is the first study to demonstrate a genetic component responsible for naturally occurring myopia in any species other than humans. A large number of animals of several species including monkeys have been examined during studies of refractive development.
1 2 3 4 5 Variability in response (e.g., to lens wear) among individual animals has sometimes been attributed to differences in genetic susceptibility to retinal defocus.
3 However, there have been no consistent reports of naturally occurring myopia in any animals other than dogs.
In the dogs in our study, the prevalence of myopia (SER ≤ −0.50 D) was 31%, which is much greater than that reported in Labrador Retrievers by Mutti et al.,
22 who found that 8% of their sample of 75 dogs were myopic in both eyes by at least −0.50 D. However, this difference most likely reflects the fact that our sample was selected from a family with a known myopic progenitor. This is a limitation of our study that restricts generalization of our myopia prevalence data to within our sample. Of interest, the ranges of refractive error found for dogs in this study (+1.65 to −5.38 D) and that of Mutti et al. (+3.50 to −5.00 D)
22 were similar, particularly for the limit of myopia. Therefore, the data from both studies on prevalence and degree of myopia suggest that myopia in dogs more closely resembles common myopia rather than high myopia in humans. Human high myopia typically has a prevalence of 1% to 2% and a degree of −6.00 D or more minus, whereas common human myopia has a variable prevalence (10%–75%) with a degree less minus than −6.00 D.
8 Thus, dogs appear to provide a unique animal model for examining the genetics of common (i.e., high-prevalence, low-degree) myopia.
Dogs provide an interesting perspective on development of myopia. In the Labrador Retriever family that we studied, additive genetic effects accounted for about half of the variance in SER, a level similar to that reported in human family studies,
32 34 although much less than the high levels reported in twin studies in which additive genetic effects account for more than 80% of variance in refraction.
35 36
Many service dogs have a domestic environment comparable to that of humans and also enjoy a good-quality diet and a high level of medical care. However, dogs do not experience many of the environmental influences that have been implicated in the development of myopia in humans (i.e., prolonged near work like reading). Dogs are not subject to near work, which may suggest that myopia in susceptible dogs has developed as a response to some environmental influence other than near work, for example an indoors environment. However, valid comparison between dogs and humans is difficult. The amplitude of accommodation in the dog is reportedly 2 to 3 D,
37 whereas that of a child is much greater (e.g., for a 10-year-old child it is typically approximately 12 D
38 ). Thus, in terms of accommodative demand relative to available amplitude (and possibly consequent lag of accommodation
39 ) a near stimulus (e.g., demanding half the available amplitude of accommodation) would correspond to a stimulus at approximately 17 cm distance for a 10-year-old child but approximately 1.0 m distance for a dog.
An interesting finding from this study was that dogs from small litters were likely to be more myopic than dogs from large litters. The origin of this effect remains unclear. It may suggest some link between the genetic determinants of litter size and those of refractive error. Alternatively, it may result from an environmental effect. Although all dogs in the study were raised in the same indoors environment from birth to 6 weeks of age, dogs from small litters may have developed more rapidly under these early myopiagenic conditions than dogs from large litters, which may have developed later. Another possibility is that the myopiagenic environments were the same for both litter types, but greater levels of physical activity were required to live and feed in large litters than in small ones. It has been reported recently that increased levels of activity may have a protective effect on progression of myopia in humans.
31 40
Our statistical analysis was complicated by the processing of consanguineous relationships and multiple pairings. The
multivar program used the trait information for all members of the pedigree rather than having to split the family into smaller nuclear groups, as has been done in some previous studies.
25 26 However, our analysis method did not allow study of the mode of transmission, although the finding that sex was not significant implies that myopia in dogs has an autosomal inheritance pattern.
In conclusion, dogs may provide a uniquely useful animal model for examining the genetics of common myopia, as they do for many other diseases.
41 42 This finding is particularly relevant after the completion and public availability of the dog genome.
42 Moreover, several microsatellite marker screening sets
43 44 45 46 have also been completed for use in canine genome scans in linkage studies, and linkage studies have successfully identified causative genes for canine eye disease such as Collie eye anomaly.
47 Furthermore, studies of environmental influences on puppy refractive development may provide insight into the subtle environmental factors responsible for the emergence of common myopia in genetically susceptible young humans.
Supported by Grant 3607018 from the New Zealand Optometric and Vision Research Foundation.
Submitted for publication February 3, 2008; revised April 28 and June 11, 2008; accepted August 26, 2008.
Disclosure:
J. Black, None;
S.R. Browning, None;
A.V. Collins, None;
J.R. Phillips, 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.
Corresponding author: John R. Phillips, Department of Optometry and Vision Science, University of Auckland, Private Bag 92019, Auckland, New Zealand;
[email protected].
Table 1. Status of Dogs in the Family of Labrador Retrievers Studied, at the Time of Analysis
Table 1. Status of Dogs in the Family of Labrador Retrievers Studied, at the Time of Analysis
Total refracted | 116 |
Outside age range (<1 or >8 y) | 131 |
In New Zealand but not available for testing | 71 |
Outside New Zealand | 40 |
Ocular disease | 24 |
Cross-breed | 14 |
Deceased | 11 |
Total family | 407 |
Table 2. Models Used to Test for Statistical Significance of Variables
Table 2. Models Used to Test for Statistical Significance of Variables
Model | Comment | Log Likelihood | χ2 | P |
G + S + C + L + E | Full model | −66.50 | N/A | N/A |
S + C + L + E | Test for additive genetic effect | −74.14 | 15.28 | 9.3× 10−5 * |
G + C + L + E | Testing for effect of sex | −67.31 | 1.62 | 0.20 |
G + S + L + E | Testing for effect of coat color | −67.56 | 2.12 | 0.15 |
G + S + C + E | Testing for effect of litter size | −71.64 | 10.28 | 0.0013* |
The authors thank the staff at the breeding colony, in particular Nicola Cadogan, and also Scott Bruce, Joe Walker, Janice Lloyd, Ian Cox, Denise Ireland, Kim Malcolm, and Helen Grant for assistance; Elizabeth Thompson for help related to the multivar program; Nicola Anstice and Simon Backhouse for help with refractive error testing; and Andrew Shelling for advice.
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