Linkage Analysis of Quantitative Refraction and
Refractive Errors in the Beaver Dam Eye Study
Alison P. Klein,1,2,3Priya Duggal,3Kristine E. Lee,4Ching-Yu Cheng,5,6Ronald Klein,4
Joan E. Bailey-Wilson,5and Barbara E. K. Klein4
PURPOSE. Refraction, as measured by spherical equivalent, is the
need for an external lens to focus images on the retina. While
genetic factors play an important role in the development of
refractive errors, few susceptibility genes have been identified.
However, several regions of linkage have been reported for
myopia (2q, 4q, 7q, 12q, 17q, 18p, 22q, and Xq) and for
quantitative refraction (1p, 3q, 4q, 7p, 8p, and 11p). To repli-
cate previously identified linkage peaks and to identify novel
loci that influence quantitative refraction and refractive errors,
linkage analysis of spherical equivalent, myopia, and hyperopia
in the Beaver Dam Eye Study was performed.
METHODS. Nonparametric, sibling-pair, genome-wide linkage
analyses of refraction (spherical equivalent adjusted for age,
education, and nuclear sclerosis), myopia and hyperopia in 834
sibling pairs within 486 extended pedigrees were performed.
RESULTS. Suggestive evidence of linkage was found for hypero-
pia on chromosome 3, region q26 (empiric P ? 5.34 ? 10?4),
a region that had shown significant genome-wide evidence of
linkage to refraction and some evidence of linkage to hypero-
pia. In addition, the analysis replicated previously reported
genome-wide significant linkages to 22q11 of adjusted refrac-
tion and myopia (empiric P ? 4.43 ? 10?3and 1.48 ? 10?3,
respectively) and to 7p15 of refraction (empiric P ? 9.43 ?
10?4). Evidence was also found of linkage to refraction on
7q36 (empiric P ? 2.32 ? 10?3), a region previously linked to
CONCLUSIONS. The findings provide further evidence that genes
controlling refractive errors are located on 3q26, 7p15, 7p36,
and 22q11. (Invest Ophthalmol Vis Sci. 2011;52:5220–5225)
eyes were myopic (?0.75 D or more) and 49.0% were hyper-
opic (?0.75 D or more).1Genetic and environmental factors
both play an important role in the development of refraction
errors. Near-work or its surrogate, educational level, is associ-
ated with both myopia and increased severity of myopia.1–6
Despite the importance of near-work on the development
of myopic refractive errors, it explains only a small portion of
the variability in refraction. Familial aggregation studies have
demonstrated a strong correlation of refractive errors between
twins as well as between family members.1,7–12We reported
sibling odds ratios for myopia of 3.36 (95% confidence interval
[CI], 1.56–7.12) for brothers, 4.64 (95% CI, 1.91–11.28) for
sisters, and 4.52 (95% CI, 2.44–8.37) for brother–sister pairs in
the Beaver Dam Eye Study (BDES). Point estimates for sibling
odds ratios for hyperopia were slightly lower at 2.47 (95% CI,
1.05–5.28) for sisters, 3.16 (95% CI, 1.60–6.26) for brothers,
and 2.95 (95% CI, 1.75–5.00) for brother–sister pairs.1Herita-
bility analysis demonstrated strong genetic effects throughout
the entire range of refraction, with estimated heritability of
refraction of 57.8% after adjustment for age, education, and
nuclear sclerosis.12Segregation analysis of refraction in the
BDES indicated that several genes of small to modest effect may
also play a role in refraction.10
Numerous linkage studies of myopia and quantitative refrac-
tion have been conducted. Genome-wide significant evidence of
linkage to 2q(MYP12), 4q(MYP11), 12q(MYP3), 17q(MYP5),
18p(MYP2), and Xq(MYP1, MYP13) has been reported for high
myopia (? ?6D)13–18as well as to chromosome 22q(MYP6)19,20
for moderate myopia (? ?1 D). In addition, genome-wide evi-
on 7q36.21The MYP1 locus on Xq28 has been replicated and is
associated with Bornholm eye disease.22Quantitative trait locus
(QTL) linkage analysis using the full range of spherical equivalent
as a quantitative trait has demonstrated genome-wide significant
evidence of linkage to regions on 1p(MYP14), 3q(MYP8),
4q(MYP9), 7p(MYP17), 8p(MYP10), and 11p(MYP7)23–25with
to the guidelines established by Lander and Kruglyak26for repli-
cation: P ? 0.01.
In the BDES, we used 385 short tandem repeat polymor-
phisms (STRP) markers and found evidence suggestive of link-
age to regions on 1q and 22q. Our results confirmed linkage to
22q(MYP6) for quantitative refraction.27However, linkage
efractive errors in adults are common worldwide. In the
Beaver Dam Eye Study (BDES), we observed that 26.2% of
From the Departments of1Oncology and2Pathology, Johns Hop-
kins School of Medicine, Baltimore, Maryland; the
Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, Maryland; the4Department of Ophthalmology and Visual
Sciences, University of Wisconsin School of Medicine and Public
Health, Madison Wisconsin; and the5Statistical Genetics Section, In-
herited Disease Research Branch, National Human Genome Research
Institute, National Institutes of Health, Baltimore, Maryland.
6Present affiliation: Department of Ophthalmology and Depart-
ment of Epidemiology and Public Health, Yong Loo Lin School of
Medicine, National University of Singapore, Singapore.
Supported by National Eye Institute Grants EY06594 (RK, BEKK)
and EY015286 (BEKK) from the National Eye Institute; grants from
Research to Prevent Blindness (RK, BEKK); and the Intramural Re-
search Program of the National Human Genome Research Institute.
Some of the results of this paper were obtained by using the software
program S.A.G.E., which is supported by U.S. Public Health Service
Resource Grant RR03655 from the National Center for Research Re-
sources. Genotyping services were provided by the Center for Inher-
ited Disease Research (CIDR). CIDR is funded through a federal con-
tract from the National Institutes of Health to The Johns Hopkins
University, Contract HHSN268200782096C. APK has full access to the
data and takes responsibility for the integrity of the data and the data
Submitted for publication December 20, 2010; revised March 25,
2011; accepted April 19, 2011.
Disclosure: A.P. Klein, None; P. Duggal, None; K.E. Lee , None;
C.-Y. Cheng, None; R. Klein, None; J.E. Bailey-Wilson, None;
B.E.K. Klein, None
Corresponding author: Alison P. Klein, Sidney Kimmel Compre-
hensive Cancer Center, Johns Hopkins University, School of Medicine,
1550 Orleans Street, Baltimore, MD 21231; email@example.com.
Investigative Ophthalmology & Visual Science, July 2011, Vol. 52, No. 8
Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc.
studies using more densely spaced SNPs (single-nucleotide
polymorphisms) have been shown to provide greater power
than STRP panels to detect linkage, especially when genotype
information on pedigree founders is missing or unavailable, as
in the BDES.28,29Therefore, we conducted additional SNP
genotyping in the BDES population and conducted linkage
analysis using the combined SNP and STRP marker set to
identify genetic loci harboring genes for quantitative refrac-
tion, myopia, and hyperopia, using Haseman-Elston regression
The BDES, which began in 1987, is a longitudinal population-based
cohort study of age-related eye diseases. This study has been approved
by the Institutional Review Board of the University of Wisconsin
School of Medicine and conforms to the Declaration of Helsinki. A
detailed description of the BDES, including the protocols used to
measure spherical equivalent, has been published elsewhere,30–32The
baseline examination of the BDES included 4926 participants of the
5924 eligible individuals who were 43 to 86 years of age and resided in
the township of Beaver Dam, Wisconsin. Follow-up examinations were
completed every 5 years. As part of the examination, refraction and
best corrected visual acuity measured with a modified Early Treatment
of Diabetic Retinopathy Study (ETDRS) protocol was obtained. After
dilation, slit lamp photographs were taken of the lens of each eye to
assess the severity of nuclear sclerosis and cortical and posterior
subcapsular opacities. Photographs were then graded by trained,
masked observers according to a standard protocol.33Family relation-
ships were recorded and medical, social, and lifestyle information,
including years of education, was obtained at the baseline examina-
tion. Confirmation of family relationships was obtained at the first
follow-up examination (1993 and 1995), and 2783 persons were clas-
sified into one of 602 pedigrees. Complete age, sex, education, and
spherical equivalent data were recorded for 2138 individuals at the
baseline examination. Using phenotype data from the BDES, we pre-
viously published familial correlations, heritability analysis, and segre-
gation analysis of spherical equivalent.12After excluding noninforma-
tive pedigrees (i.e., parent–offspring pairs), we conducted analyses on
the 834 sibling pairs within 486 extended pedigrees.
Spherical equivalent and covariates including age and education were
assessed at the baseline examination of the BDES. Automated refractive
error measurements were obtained for ?96% of the eyes; for the remain-
der (4%) when corrected visual acuity was 20/40 or worse, the refractions
were performed using ETDRS protocol. Refraction measurements from
the current prescription (?1% of eyes) were used if other data were not
available.1The following individuals were excluded: those with an intra-
ocular lens in any eye, those with best corrected visual acuity of 20/200 or
worse in at least one eye, and those with data missing for at least one eye.
Spherical equivalent was calculated from the refraction measurements.
The average of spherical equivalent in the right and left eyes was used in
the linkage analysis, because there is very high correlation of spherical
equivalent between the two eyes in most individuals.7Thirteen partici-
pants with differences in spherical equivalent ? ? 4 D between the eyes
different interocular spherical equivalent measurements. Myopia was de-
fined as spherical equivalent of ? ?1 D in either eye, with spherical
equivalent ? ?0.5 D in the opposite eye. Nonmyopes were individuals
with spherical equivalent ? ?0.25 D in both eyes. Individuals meeting
none of the criteria were coded as unknown. Hyperopes were defined as
individuals with spherical equivalent ? ?1 D in either eye with spherical
equivalent ? ?0.5 D in the opposite eye. Nonhyperopes were individuals
of the criteria were coded as unknown.
Age, education, and nuclear sclerosis have been shown to have
strong effects on spherical equivalent and were significant covariates in
our heritability analysis, therefore linkage analyses were conducted on
unadjusted spherical equivalent and spherical equivalent after adjust-
ment for these covariates. Age (in years), education (in years), and
nuclear sclerosis were modeled as quantitative predictors. Nuclear
sclerosis was graded on a five point scale, with 1 being no nuclear lens
opacity and 5 being severe,33and the sum of the grading of the right
and left eyes was used in the analysis. The maximum likelihood esti-
mates of the covariate effects of age and education were derived from
the segregation models,10and traits were adjusted before analysis.
DNA samples from 2231 individuals were sent for genotyping at the
Center for Inherited Disease Research (CIDR). Samples were first
genotyped using 385 STRP markers. The results of our linkage analysis
of quantitative spherical equivalent using these markers has been
published previously.27Given that SNP markers have been shown to
provide increased information content and thereby greater power to
detect linkage, all remaining available samples were regenotyped (Link-
age Panel I; Illumina, San Diego, CA). Genotype data on 6008 SNPs
were generated on 2170 samples with a minimum call rate per sample
of 96%. Markers were dropped if they had either poorly defined (n ?
148) or atypical (n ? 10) clusters, leaving 5850 high-quality SNPs, of
which 5525 were located on the autosomes. All SNPs had a call rate
?96%. For the SNP markers, we then used Haploview 4.0 to identify
linkage disequilibrium (LD) blocks, as LD can cause false-positive
linkage signals (http://www.broad.mit.edu/mpg/haploview/ The Broad
Institute, Massachusetts Institute of Technology, Cambridge, MA). A
total of 525 singletons and 43 trios from 431 families were used for LD
calculations. SNP markers were excluded if they had (1) Hardy-
Weinberg Equilibrium P ? 0.001, (2) Mendelian errors ?1 per marker,
or (3) call frequency ?0.98. Blocks were defined based on solid spine
of LD (i.e., the spine was extended if D? ? 0.8). Within an LD block,
the SNP with the highest minor allele frequency was retained. After
quality control of the marker data, we merged the SNP and STRP marker
sets based on the Marshfield genetic map (research.marshfieldclinic.
org/genetics/ Marshfield Clinic, Marshfield, WI). The Marshfield ge-
netic position of the 385 microsatellite markers was obtained from the
UCSC Genome Browser (http://genome.ucsc.edu/; provided by the
University of California at Santa Cruz) and UniSTS database (http://
www.ncbi.nlm.nih.gov/unists/ National Center for Biotechnology In-
formation [NCBI], Bethesda, MD; and the website of Mammalian Geno-
typing Service at Marshfield, sponsored by the National Heart Lung
blood institute (http://www.marshfieldclinig.org/mgs/). We could not
obtain a precise genetic position for marker D2S1780, and thus this
marker was dropped. To obtain a common genetic map for SNPs and
STRPS we used 7756 microsatellite markers with known Marshfield
genetic position from the USCS website to interpolate the genetic
position for each SNP by using the physical position. Relationship
errors were identified using PREST34and RELPAL (S.A.G.E., ver. 6.0)
and residual Mendelian errors using MARKERINFO (S.A.G.E., ver.
6.029), and SIBPAIR.35We obtained clear evidence of misspecified
relationships in 20 pedigrees, and these errors were resolved by re-
moving the problematic individuals or re-assigning the relationship.
Our final dataset consisted of 4892 SNP markers and 384 STRP markers
on the 22 autosomes.
Autosomal nonparametric linkage analyses were conducted using the
Haseman-Elston regression as implemented in SIBPAL (S.A.G.E. ver.
6.0).36Allele frequency estimates were obtained from the sample data
by using FREQ (S.A.G.E.) The results reported include multipoint and
single-point, nominal P values from SIBPAL.36Because of the non-
normality of these data, allele-sharing among the pairs was permuted
with Monte Carlo simulations of up to 2,000,000 replicates, to obtain
empiric P values. We report both the nominal and permuted P values.
IOVS, July 2011, Vol. 52, No. 8
Linkage Analysis of Refraction and Refractive Errors5221
We used the criteria proposed by Lander and Kruglyak26for declaring
genome-wide significance (P ? 2.2 ? 10?5) and evidence suggestive
(P ? 7.4 ? 10?4) of linkage, a well as for replication (P ? 0.01) in the
interpretation of our results as these thresholds control the genome-
wide type 1 error rates while allowing for correlation between mark-
ers. Regions that provided some evidence of linkage (P ? 0.001) but
did not meet Lander and Kruglyak criteria are also summarized.
A detailed description of the subset of the Beaver Dam Cohort
included in our linkage study is presented in Table 1. Overall,
there were 1897 individuals in 482 pedigrees. Mean refraction
(spherical equivalent) among these individuals was ?0.46 D,
mean age was 62.47 years, and mean years of education was
11.25. Overall, the mean sum of the nuclear sclerosis grade in
the right and left eye was 4.97. Within these families, 1569
individuals were classified as meeting our criteria of myopic
(n ? 406, 25.9%) or nonmyopic (n ? 1136, 74.1%). In addi-
tion, 1498 individuals could be classified as hyperopic (n ?
894, 59.8%) versus nonhyperopic (n ? 602, 40.3%).
The results of our linkage analysis are presented in Table 2
and in Figures 1 and 2. We had evidence of replication to
several previously reported genome-wide significant linkage
regions. Genomewide evidence suggestive of linkage to hyper-
opia was found on 3q23 (empiric P ? 5.34 ? 10?4at
D3S1763). Spherical equivalent adjusted for age, education,
and nuclear sclerosis provided evidence of linkage to chromo-
some 22q11 (empiric P ? 4.43 ? 10?3at rs737923). There
was evidence of linkage to myopia in this same region (empiric
P ? 1.48 ? 10?3at rs737923). In addition, in our data,
spherical equivalent was linked to 7q36 (empiric P ? 2.32 ?
10?3at rs2536007), a region that provided genome-wide evi-
dence suggestive of linkage to 7q36.21A second peak on
chromosome 7q15 provided evidence of linkage to refraction
(P ? 9.43 ? 10?3). We first reported evidence of linkage in the
region in an earlier microsatellite marker analysis.27
In addition to replication of the above-mentioned peaks,
evidence of linkage was also detected in several additional
regions. Chromosome 2, region q12 showed an indication of
linkage to refraction (empiric P ? 1.06 ? 10?3). Two regions
on chromosome 4 also demonstrated an indication of linkage
to refraction in the Beaver Dam population. Adjusted refraction
was linked to a region on 4q26 (empiric P ? 1.29 ? 10?3near
marker rs291079). Both refraction and myopia provided some
evidence of linkage to 4q31 (refraction empiric P ? 4.16 ?
10?3at marker rs978752, myopia empiric P ? 4.24 ? 10?3at
marker D4S1625). Chromosome 6, region q15, gave evidence
of linkage to adjusted refraction (empiric P ? 1.15 ? 10?3at
marker rs2610715). A region on 12q24 was linked to adjusted
refraction (empiric P ? 4.19 ? 10?3at marker rs918044). For
each of these peaks, we provide the results of the additional
trait measurement (refraction, adjusted refraction, and myopia
or hyperopia) that provided some evidence of linkage (P ?
0.001) in Table 2. Consistent results were obtained across
quantitative trait parameterizations as shown in Figure 1.
In addition to the 3q23 region for hyperopia and the 22q11
and 4q26 regions for myopia, several additional regions of
linkage were detected for these qualitative traits. There was
some evidence of linkage to hyperopia at 16q13 (empiric P ?
TABLE 1. Demographic of the Study Population: A Subset of the Beaver Dam Eye Cohort
Refraction, spherical equivalent diopters
Myopia, n (%)
Hyperopia, n (%)
Nuclear sclerosis, n
43 to 86
?12.13 to ?8.38
2 to 21
2 to 10
TABLE 2. Results of SIBPAL Linkage Analysis
Previous Linkage Evidence
UK Twins, Quantitative Refraction23
7p15 (MYP17) French and Algerian Families, High Myopia37
7q36 French and Algerian Families, High Myopia21
22q11 (MYP6)US Ashkenazi Jewish Families, Myopia19
5222 Klein et al.
IOVS, July 2011, Vol. 52, No. 8
2.94 ? 10?3at rs741175). For myopia, there was some evi-
dence of linkage to regions on 2p25 (empiric P ? 1.35 ? 10?3
at rs1309) and 16q24 (empiric P ? 1.25 ? 10?3at rs452176).
Refraction, like most complex traits, is probably influenced by
multiple genetic factors. This supposition is supported by the
fact that many regions of genetic linkage have been reported
for both quantitative refraction and myopia. Given the inherent
difficulties in replicating linkage findings when there is locus
heterogeneity, it is not surprising that many of these reported
linkage regions have not yet been replicated. However, in our
current linkage analysis of refraction and refractive errors we
were able to replicate several previously reported linkage
There is considerable debate regarding what constitutes
evidence of replication in linkage studies. While statistical
criteria, P ? 0.01, have been established, it is less clear how
differences in phenotype definition and chromosomal location
of maximum LOD scores across studies should be evaluated.
For example, can evidence of linkage in a population-based
family study of quantitative refraction replicate a linkage peak
identified in families with high myopia? It is well established
that refractive errors are etiologically complex. This complex-
ity may arise, in part, from the different mutations within the
same gene that lead to differences in the severity of refractive
errors and/or interactions between genes and environmental
factors that influence the severity of the phenotype. It is pos-
sible that genes involved in the more severe forms of myopia
also play a role in the more modest forms of refractive errors.
Therefore, we feel that replication of linkage peaks can occur
when different phenotype definitions are used. Furthermore,
linkage signals are often quite broad (?10 Mb) and the location
of the causal gene varies with respect to the maximum LOD
score. Therefore, it is unclear how far apart a replication
linkage peak can be from the initial linkage signal; however,
overlap of the linkage regions is supportive of replication.
Our data support linkage to refractive errors, particularly
hyperopia on 3q26. Genomewide significant linkage for refrac-
tion to this region was first reported in 506 dizygotic twins
enrolled in the Twin Eye study. A maximum LOD of 3.7 was
observed at marker D3S1614 with markers D3S1279 (168.1
Mb) and D3S1565 (175.3 Mb) flanking the linkage regions.23
To examine whether this linkage peak was due to genetic
sharing among myopes versus hyperopes, Hammond et al.23
also conducted qualitative analysis refractive errors in these
same families. Although there was little evidence to support
linkage to this region in myopes (LOD?1), there was support
for linkage of this region to hyperopia (LOD ?2.5). This finding
is consistent with ours of genome-wide evidence suggestive of
linkage to this region for hyperopia. Our minimum empiric P ?
of 5.34 ? 10?4was observed at marker D3S1763, with our
linkage region spanning marker rs937478 (159.8 Mb) to
rs1920122 (169.5 Mb), which overlaps that of Hammond et al.
However, there was only slight evidence of linkage in the
thresholds for evidence of replication (P ? 0.01) and evidence suggestive (P ? 0.0074) of linkage.31
SIBPAIR linkage analysis of refraction (red) and adjusted refraction (green). The y-axis is ?log (exact P value). Horizontal lines:
IOVS, July 2011, Vol. 52, No. 8
Linkage Analysis of Refraction and Refractive Errors5223
region to quantitative refraction, with a minimum empiric P ?
of 0.036 near marker rs920417. Hammond et al. conducted
follow-up linkage and association analysis of the 3q26 locus
and found evidence of association for three genes, MFN1
(179.0 Mb), SOX2OT (181.3Mb) and PSARL (183.5 Mb).38
These genes are located downstream of our linkage region.
Follow-up studies are needed to determine whether genetic
variation in the genes explains the linkage in these regions or
additional genes are responsible for the linkage signal on 3q26.
While we had previously reported linkage on 22q to refrac-
tion,27here we demonstrate linkage in this region to myopia as
well as refraction, but little evidence of linkage to hyperopia.
This finding is consistent with the initial report by Stambolian
et al.19of genome-wide significant evidence of linkage in this
region to myopia, with an LOD (HLOD) of 3.54, at marker
D22S685 (physical position 34.4 Mb) and a linkage region
spanning D22S689 (28.7 Mb) and D22S445 (37.4 Mb). How-
ever, our linkage peak is located adjacent to that reported by
them, with a minimum P ? 4.43 ? 10?3at rs737923 (19.1 Mb)
with the region spanning rs2097596 (17.9 Mb) to rs374225
(20.0 Mb) for myopia and from rs3747026 (18.2 Mb) to
rs1476445 (19.6 Mb) for adjusted refraction.19There is addi-
tional evidence of linkage to refraction in our data at rs5762174
(27.9 Mb, empiric P ? 1.31 ? 10?3). Given that linkage signals
can extend for several megabases and the location of the peak
around a causal locus can vary markedly due to genetic heter-
ogeneity and marker information content, these results could
represent the same locus or they could be due to multiple loci
on chromosome 22. In addition, the families studied by Stam-
bolian et al. were highly ascertained for multiple myopes in
each family, whereas the BDES families were population based.
However the consistent linkage signals for myopia and refrac-
tion to this region of chromosome 22 strongly indicate that at
least one major locus resides in this region.
Evidence suggestive of linkage to high myopia (? ?6 D) on
7q36 was first reported by Naiglin et al.21In their analysis of 21
French and 2 Algerian families, they reported a maximum LOD
of 2.81 at D7S550, with the region of linkage extending from
D7S798 (152.7 Mb) to D7S2423 (157.4 Mb). Our linkage
region for refraction ranged from rs1547958 (150.6 Mb) to
rs1389240 (156.0 Mb), overlapping the region that they re-
ported. However, there was no evidence supporting linkage to
myopia in this region for our families.
In addition to the region on 7q36, we also had evidence of
linkage to 7p15-21. Our previous linkage analysis of refraction
in the BDES using microsatellite markers alone provided some
evidence of linkage to this region, with the minimum multi-
point P ? 2.2 ? 10?3at marker D7S3051.27This linkage
region spanned markers rs957960 (18.8 Mb) to rs1725074
(27.1 Mb). Ciner et al.24have reported linkage to refraction
adjacent to this region among 96 African American families. In
their analysis they observed a maximum LOD of 5.87 with an
associated P ? 5 ? 10?5with the linkage peak ranging from
markers D7S1808 (27.9 Mb) to D7S2846 (38.0 Mb), respec-
tively, which is adjacent to our region.
thresholds for evidence of replication (P ? 0.01) and evidence suggestive (P ? 0.0074) of linkage.31
SIBPAIR linkage analysis of myopia (blue) and hyperopia (orange). The y-axis is ?log (exact P value). Horizontal lines: denote
5224Klein et al.
IOVS, July 2011, Vol. 52, No. 8
In addition to the linkage loci identified for refraction, Download full-text
myopia, and hyperopia, several genomewide association stud-
ies for myopia have recently been conducted. Linkage studies
are better suited to detecting rare alleles associated with a
strong effect (high odds ratio or high penetrance) of disease
and are robust to allelic heterogeneity (multiple mutations in
the same gene which result in the same phenotype). Associa-
tion studies are better suited to detecting lower-penetrance
common variation associated with disease. While variation on
5p15, 11q24, 15q14, and 15q25 have been associated with
myopia it is not surprising that we did not detect linkage in
these regions, given the relative strengths of linkage versus
association methods (Verhoeven VJM, et al. IOVS 2010;51:
ARVO E-Abstract 2972).39–41
Work is ongoing to refine these linkage peaks and to identify
the genes underlying these linkage signals, with particular empha-
sis on the interesting regions on 3q36, 22q11, 7p21, and 7q36.
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