Assessment of TGIF as a Candidate Gene for Myopia
Kelly K. Pertile,1,2Maria Scha ¨che,1,2F. M. Amirul Islam,1,2Christine Y. Chen,1,2
Mohamed Dirani,1,2Paul Mitchell,2,3and Paul N. Baird1,2
PURPOSE. Transforming growth ?-induced factor (TGIF) has
been identified as a candidate gene for high myopia through
genetic linkage studies and through its role in ocular growth in
animal studies. However, the association of single nucleotide
polymorphisms (SNPs), based solely on myopia refraction, has
so far been inconclusive. This is the first study conducted to
investigate the association of TGIF with refraction and ocular
METHODS. Twelve tag SNPs (tSNPs) encompassing the TGIF
gene and 2 kb upstream of its promoter region were used to
evaluate the association between TGIF variants with both oc-
ular biometric measures and refraction. A total of 257 cases of
myopia (spherical equivalent [SE] worse than ?0.50 D) and
294 control subjects (no myopia) were genotyped. Genotype
frequencies were analyzed by ?2test and one-way ANOVA.
RESULTS. Two tSNPs showed significant association with bio-
metric measures, with the SNP rs8082866 being associated
with both axial length (P ? 0.013) and corneal curvature (P ?
0.007) and the SNP rs2020436 being associated with corneal
curvature (P ? 0.022). However, these associations became
nonsignificant after multiple testing (Bonferroni correction).
CONCLUSIONS. Findings of this study suggest that the TGIF gene
is unlikely to play a major role in either ocular biometric
measures or refraction in a Caucasian population. Future stud-
ies should focus on other genes in the MYP2 linkage region or
other linked regions to identify myopia-causing genes. (Invest
Ophthalmol Vis Sci. 2008;49:49–54) DOI:10.1167/iovs.07-
of individuals in Western and European countries.1–4Ocular
components, such as corneal curvature, anterior chamber
depth, lens power, and ocular axial length are all seen to be
important determinants in the development of myopia.5
yopia is one of the leading causes of visual impairment
and blindness in the world, affecting approximately 25%
Myopia is a complex disease with both genetic and envi-
ronmental factors implicated in its pathogenesis. Family studies
have shown an increased risk of myopia in children with
myopic parents, compared with those with no myopic par-
ents,6,7as well as a four-fold increased sibling risk.8In addition,
parental myopia has been shown to influence an offspring’s
ocular components. Children with two myopic parents have
longer eyes than do children with only one myopic parent or
no myopic parents.9A genetic component for ocular biometric
measures and refraction has also been demonstrated in popu-
lation, twin, and family-based studies.10–17
Genetic (genome-wide linkage) studies of myopia have so
far identified 15 chromosomal regions harboring a disease gene
(MYP1–15). Of these candidate loci, nine have been identified
for high myopia (spherical equivalent [SE] ?4.25 D or worse;
MYP1–5, -11, -12, -13, and -15)18–26and six for low/moderate
myopia (? ?1.00 D; MYP6–10 and MYP14).12,27,28Six of
these regions (MYP2, -3, -6, -10, -12, and -13) have been repli-
cated in independent linkage studies.29–35The MYP2 region
has been replicated twice in high-myopia families and there-
fore provides a likely location for a candidate gene in high
The transforming growth ?–induced factor (TGIF) gene
(National Center for Biotechnology Information [NCBI] Entrez
Gene ID: 7050), is a good candidate gene for myopia because
of its physical location within the MYP2 region and its func-
tional role in ocular development. TGIF is expressed in the
sclera, retina, cornea, and optic nerve and competitively inhib-
its binding of the retinoic acid receptor to a retinoid-responsive
promoter.19,36–38Animal studies using form-deprivation myo-
pia have demonstrated that transforming growth factor
(TGF)-?, which is induced by TGIF, mediates retinal control of
Genetic evidence supporting a role for TGIF in myopia has
come from analysis of a Chinese cohort where six single-
nucleotide polymorphisms (SNPs) were significantly associated
with high myopia (? ?6.00 D).41However, a significant asso-
ciation with this gene could not be replicated in a second
Chinese case–control study of high myopia individuals.42A
Japanese case–control study of high myopia individuals also
analyzed this gene by using 13 SNPs across the TGIF gene and
failed to identify significant association.43In the only Caucasian
study to date, coding regions, and intron–exon boundaries of
TGIF were sequenced in 10 cases (? ?6.00 D) from European
high-myopia families and 10 unrelated emmetropic control
individuals (0.00 D). No significant sequence variants were
detected in the high-myopia individuals compared to control
Currently published studies of the TGIF gene have concen-
trated on the myopia phenotype (refraction) as the trait of
interest. Given that the TGIF gene has a biological role in eye
growth, it may be more prudent to examine whether associa-
tion of this gene exists at the individual trait level. As a conse-
quence, we undertook a tag SNP (tSNP) approach to examine
association of the TGIF gene with not only refraction but also
the individual and continuous ocular biometric traits of axial
length, corneal curvature, and anterior chamber depth, which
would provide an alternative approach to studying myopia
From the1Centre for Eye Research Australia, Department of Oph-
thalmology University of Melbourne, East Melbourne, Victoria, Austra-
lia; the2Vision Cooperative Research Centre, Sydney, Australia; and the
3Centre for Vision Research, Department of Ophthalmology, West-
mead Millennium Institute, University of Sydney, Westmead, New
South Wales, Australia.
Supported by the Australian Federal Government through the
Cooperative Research Centres Program, the Ernest and Grace Matthaei
Trust, the Joan and Peter Clemenger Trust, the L. E. W. Carty Trust, the
Angior Family Foundation Stoicescu Trust, the William Buckland Foun-
dation, the Sunshine Foundation, and the Eye Research Australia Foun-
Submitted for publication July 17, 2007; revised September 20,
2007; accepted November 19, 2007.
Disclosure: K.K. Pertile, None; M. Scha ¨che, None; F.M.A. Is-
lam, None; C.Y. Chen, None; M. Dirani, None; P. Mitchell, None;
P.N. Baird, None
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked “advertise-
ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Kelly K. Pertile, Centre for Eye Research
Australia, The University of Melbourne, 32 Gisborne Street, East Mel-
bourne, 3002 Australia; firstname.lastname@example.org.
Investigative Ophthalmology & Visual Science, January 2008, Vol. 49, No. 1
Copyright © Association for Research in Vision and Ophthalmology
MATERIALS AND METHODS
Individuals used in this study were recruited through the Genes in
Myopia (GEM) Study,44the GEM Twin Study,16the Melbourne Visual
Impairment Project (VIP),45and the Blue Mountains Eye Study
(BMES).46The methodologies for each study have been published
elsewhere.16,44–46Individuals from this study were categorized into
high myopia (? ?6.00 D), low/moderate myopia (? ?5.99 D and ?
?0.50 D), emmetropia (? ?0.50 D and ? ?0.75 D), and hyper-
metropia (? ?0.76). Individuals with a history of ocular diseases, such
as age-related macular degeneration or keratoconus or eye insult that
may affect an individual’s refraction were excluded from the analysis of
this study. The ocular biometric measurements of axial length, corneal
curvature (average of K1 and K2), and anterior chamber depth were
also obtained. There was no significant difference (P ? 0.05) for all eye
measurements between the right and left eye; therefore, only the right
eye measures were used in the final analysis.
Written informed consent was obtained from all individuals before
any testing, and ethics approval was provided by the Human Research
and Ethics Committee of the Royal Victorian Eye and Ear Hospital
(RVEEH), Melbourne. The study was conducted in accordance with the
tenets of the Declaration of Helsinki.
Twelve SNPs were identified for the TGIF gene using an SNP tagging
approach.47This approach began with the identification of all TGIF
SNPs from the International HapMap Project (Phase II Release 21; NCBI
Build 35; www.hapmap.org). These SNPs were analyzed using a pair-
wise tagging algorithm in the Tagger program (incorporated in the
Haploview program, ver. 3.32)47to identify the final subset of 12
tSNPs. The tagging criteria included common SNPs that had a mini-
mum minor allele frequency (MAF) of ?0.1 and an r2threshold of ?0.8
in the CEPH (CEU) population. The CEU population consists of Utah
residents with ancestry from northern and western Europe.
Genomic DNA was isolated from peripheral blood lymphocytes of
all participants using standard techniques.48Genotyping was per-
formed by the Australian Genome Research Facility (AGRF; Brisbane,
Australia) using the MassArray platform and MALDI-TOF analysis (Se-
quenom, San Diego, CA).49
Hardy-Weinberg Equilibrium Test
Genotyping data from the AGRF was assessed with the ?2test for
deviations from Hardy-Weinberg equilibrium [HWE]. This analysis was
performed with the software program JLIN: a Java-based linkage dis-
equilibrium plotter.50Any SNPs not passing this test were excluded
from further analysis.
Qualitative Genetic Analysis
A series of ?2tests were performed with commercial software (SPSS;
ver. 14.0; SPSS Inc, Chicago, IL) to compare the allele and genotype
frequencies between affected (individuals with high and low/moderate
myopia) individuals and unrelated control subjects (emmetropes and
hypermetropes). Seven comparisons were undertaken including (1)
any myopia versus no myopia, (2) high myopia versus no myopia, (3)
low/moderate myopia versus no myopia, (4) high myopia versus em-
metropia, (5) high myopia versus hypermetropia, (6) low/moderate
myopia versus emmetropia, and (7) low/moderate myopia versus hy-
Quantitative Genetic Analysis
Ocular biometric measures of axial length, corneal curvature, and
anterior chamber depth were analyzed by using quantitative analysis,
performed by comparing the mean value for each trait in a one-way
ANOVA test. Sex has been found to be a significant covariate for ocular
biometric components11,16; therefore, separate analyses were also con-
ducted on the men and the women.
A total of 551 unrelated subjects (358 women; 193 men; mean
age ? SD, 55.41 ? 12.65 years) were included in the study.
The cohort consisted of 257 cases and 294 controls, for the
number of individuals in each refractive category, refer to
Table 1. The mean age of individuals with high myopia was
50.62 ? 13.33 years; low/moderate myopia, 52.09 ? 12.65
years; and emmetropia, 55.12 ? 9.51 years and was 62.70 ?
11.70 years in individuals with hypermetropia. Refraction and
ocular biometric measures (axial length, corneal curvature, and
anterior chamber depth) for the right eye of participants are
described in Table 1.
Tag SNPs Identified and HWE Test
In total, 12 tSNPs were genotyped for TGIF, including 9 in
intronic regions, 1 in an exon–intron boundary, 1 in an exon,
and 1 upstream of the 5? region (Table 2, Fig. 1). All known
common variants (MAF ? 0.1) of TGIF were tagged by the
selected panel of tSNPs with r2? 0.8. However, no tSNPs
could be selected to cover SNPs at the end of the TGIF gene
because there were none that met our criteria. SNPs within this
region were rare and had MAF’s less than 0.1 (most had an
MAF ? 0.0, according to the HapMap data). Therefore, these
SNPs were not tagged by our set of 12 tSNPs.
TABLE 1. Refractive Status and Ocular Biometric Measures of Participants
n ? 117
(< ?6.00 D)
n ? 140
(< ?0.50 to > ?5.99 D)
n ? 148
(> ?0.50 to < ?0.75 D)
n ? 146
(> ?0.76 D)
D (n ? 551)
(n ? 416)
(n ? 418)
(n ? 406)
?6.00 to ?19.25 (?8.57) (2.39) ?5.88 to ?2.00 (?3.77) (0.96)
?0.50 to 0.75 (0.11) (0.28) 2.12 to 16.63 (4.22) (1.96)
24.42 to 31.41 (26.74) (1.31)23.27 to 27.53 (24.92) (0.87) 22.08 to 25.53 (23.30) (0.67) 16.11 to 23.44 (22.15) (0.89)
2.34 to 4.90 (3.59) (0.46)2.07 to 4.79 (3.54) (0.39)2.61 to 5.14 (3.39) (0.39)2.21 to 5.06 (3.10) (0.44)
41.15 to 49.66 (44.13) (1.52)41.24 to 47.06 (44.27) (1.31) 40.33 to 47.98 (44.06) (1.46) 41.06 to 47.88 (43.98) (1.31)
Data are the range (mean) (SD).
50 Pertile et al.
IOVS, January 2008, Vol. 49, No. 1
No evidence of departure from HWE in the tSNPs was
observed except for rs11081045 (P ? 0.05). Consequently,
rs11081045 was replaced by another tSNP, rs12457997, to
cover this same haplotype block. A deviation from HWE (P ?
0.027) was observed for rs238135 in the control group but this
deviation was not present in cases, suggesting that it was a
chance result. Data for this SNP was included in further anal-
Qualitative Genetic Analysis
Using a bivariate approach for refraction (SE), we analyzed the
genotype frequencies for each tSNP comparing the groups of
“any myopia” versus “no myopia,” “high myopia” versus “no
myopia,” “low/moderate myopia” versus “no myopia,” “high
myopia” versus “emmetropia,” “high myopia” versus “hyper-
metropia,” “low/moderate myopia” versus “emmetropia,” and
“low/moderate myopia” versus “hypermetropia.” None of the
12 tSNPs showed a significant difference of P ? 0.05 in geno-
type frequencies between the groups (Supplementary Table S1,
online at http://www.iovs.org/cgi/content/full/49/1/49/DC1).
Quantitative Genetic Analysis
We undertook a quantitative analysis using ocular biometric
traits to examine the associations of these tSNPs with contin-
uous data. Measurements of the participant’s axial length, an-
terior chamber depth, and corneal curvature were all normally
distributed. Significant associations were observed for the tSNP
rs8082866 with axial length (P ? 0.013) and corneal curvature
(P ? 0.007), as well as for the tSNP rs2020436 with corneal
curvature (P ? 0.022; Table 2). Since multiple tests were
undertaken in this analysis, we used the Bonferroni correction
to identify tSNPs that showed significance at P ? 0.004. After
this correction, none of the previously identified tSNP re-
When the men and women were analyzed separately we
found that the tSNPs rs8082866 and rs2020436 were no longer
significant. SNP rs238135 previously showed no significant
associations when looking at the men and women combined;
there was a significant association in the men for corneal
curvature (P ? 0.034). However, after a Bonferroni correction
of P ? 0.004, this tSNP did not remain significant.
This is the first case–control study to undertake a tSNP ap-
proach in a myopia candidate gene to examine associations
with refraction and ocular biometric measures.
Previous studies of the TGIF gene have involved either SNP
analysis or direct sequencing of coding regions and intron–
exon boundaries.37,41–43Only one study, in a Chinese popu-
lation, has suggested significant association of six SNPs using
71 high-myopia and 105 unrelated control individuals.41All the
significant SNPs were located in the equivalent of the current
exon 10 of this gene (NCBI Build 36). This region was not
covered in our study using tSNPs as all SNPs in this region of
the gene had an MAF of ?0.1. In addition, the Lam study did
not adjust for multiple testing, which is important in identify-
ing false-positive associations. In the previous Japanese study
high-myopia cases were defined according to an unconven-
tional control definition of ? ?9.25 D and ? ?4.00 D.43This
definition may have underrepresented high myopia in the
range between ?9.25 and ?4.00 D. Selection of SNPs was
through the NCBI dbSNP database based on their population
frequency validation, multiple submitters, and high-profile sub-
mitters using the public dbSNP database.43A more compre-
hensive way to examine the TGIF gene is through a tSNP
approach that efficiently encompasses all the known common
TABLE 2. Quantitative Analysis of TGIF tSNPs with Ocular Biometric Measures
Anterior Chamber Depth
N ? 416
n ? 273
n ? 143
N ? 418
n ? 273
n ? 145
N ? 406
n ? 262
n ? 144
Within 2 kb of
SNP IDs are reference SNP numbers from the public dbSNP database. SNPs with genotype frequencies significantly different within the ocular biometric measures are in bold (P ? 0.05); however,
after the Bonferroni adjustment, none of these tSNPs are significant (P ? 0.004). Based on one-way ANOVA.
IOVS, January 2008, Vol. 49, No. 1
TGIF as a Candidate Gene for Myopia 51
variants and most of the unknown common variants in the
gene. This approach also does not require a causative variant to
be directly tested, but can highlight regions (haplotypes) that
harbor disease-associated variants. Therefore, association stud-
ies that incorporate linkage disequilibrium information may
offer more power than individual SNP analysis to identify
causal genetic variants underlying complex disease.51
Our tag SNP approach identified 12 tSNPs that efficiently
tagged common variants with a MAF ? 0.1 in the TGIF gene.
Using these 12 tSNPs, we undertook association studies using
the qualitative measure of refractive error, as previously used
in other studies as well as a quantitative analysis based on
individual ocular biometric measures. The advantage of this
approach is that myopia most likely represents a phenotype
based on a varied etiological spectrum of environmental and
genetic effects. Thus, the examination of individual quantita-
tive traits may be more useful in identifying specific genetic
drivers that underlie this condition. We were able to confirm
that the TGIF gene was not associated with high, moderate, or
low myopia in our population. However, our association study
with biometric measures indicated a significant association
(P ? 0.05) of the tSNP rs8082866 with both axial length and
corneal curvature, whereas the tSNP rs2020436 was associated
only with corneal curvature. Through breaking the sample
group down into male and female components and analyzing
these separately, we hoped that the association would be
strengthened if the underlying genetic variant was different in
both sexes, but the association was not strengthened. How-
ever, dividing the group into men and women evidently re-
duced the sample size and this reduction may caused a positive
result to be undetectable.
One of the main issues in association studies is how to
evaluate the significance of multiple testing of SNPs. The Bon-
ferroni correction is commonly applied, but it is usually too
conservative, whereas an alternative approach would be to use
replication of a nominal probability in a second data set. This
method is less stringent; however, we did not have access to a
second dataset, and so we applied the Bonferroni correction.
Significant associations for this study would therefore require
an adjusted P ? 0.004. None of the previously significant tSNPs
were significant at this level. We realize that this correction is
a limitation and may lead to loss of significant findings, but in
light of not having verification, this approach appeared to be
the most efficacious. A larger case–control study of the two
tSNPs significant before Bonferroni correction in a separate
population would be a more definitive way to determine
whether our findings are real or false.
In this study, tSNPs with an MAF ? 0.1 were analyzed,
which excluded the 3? end of TGIF. This meant that we were
unable to test those SNPs initially identified by Lam et al.41in
what is now identified as exon 10 (exon 3 in the Lam study).
Although our selection parameter would tag common variants
of the TGIF gene (MAF ? 0.1), we cannot exclude the possi-
bility that other rarer variants in this gene, not in linkage
disequilibrium with our tSNPs, might be associated with myo-
pia. It is plausible that SNPs with a minor allele frequency of
?10% could still have a major effect on a common trait, such
as myopia. There are currently two views on allelic frequencies
and common diseases: the common disease/common allele
hypothesis and the common disease/multiple rare allele hy-
pothesis. We have assessed the first hypothesis to check
whether common variants contribute to myopia susceptibility;
(r2) between each pair of SNPs with darker shades representing stronger linkage disequilibrium. Tag SNPs for the TGIF gene are shown in relation
to the four haplotype blocks, which were determined by the Haploview program and the HapMap database.
Linkage disequilibrium between the common tag variants (MAF ? 0.1) in HapMap CEPH trios. Each square represents the correlation
52 Pertile et al.
IOVS, January 2008, Vol. 49, No. 1
however, we cannot rule out the second hypothesis of alleles
with low population frequencies being responsible for suscep-
tibility to myopia.
Assessment of ocular biometric measures as quantitative
traits is a novel approach to assess association of SNPs from the
TGIF gene. Phenotypic definitions of myopia based on refrac-
tion vary greatly between studies, and defining myopia as
“high,” “moderate,” and “low” tends to limit statistical power
by defining myopia as a series of categories rather than as a
continuum. Furthermore, the underlying biology of refraction
suggests that it is probably influenced by both genes and
environmental factors, of which several traits including the
ocular biometric components of axial length, anterior chamber
depth, and corneal curvature are implicated. Although these
underlying components have been shown to be influenced by
a genetic component,10,11,15,16,52the exact genes underlying
each of these traits has so far not been identified.
In conclusion, this is the first case–control association study
to evaluate all ranges of refraction as well as ocular biometric
measures in a Caucasian population. The lack of significant
association with TGIF tSNPs suggests that TGIF is an unlikely
candidate gene for myopia and its underlying ocular biometric
determinants. We have also shown that sex is not a significant
covariate for ocular biometic traits which is in contrast to
previously published data.11,16Recent studies, however, have
implicated the hepatocyte growth factor gene (HGF) in high
myopia53as well as two collagen genes associated with myo-
pia.54,55The HGF gene was analyzed in a high-myopia family-
based association study of Han Chinese, the collagen type I
alpha 1 (COL1A1) gene with high myopia in a Japanese co-
hort54and the collagen type II alpha 1 (COL2A1) gene with
common forms of myopia in a predominantly Caucasian pop-
ulation.55These genes are implicated in eye growth and may
provide alternative candidate genes for further exploration in
the analysis of biometric traits and myopia. Future investiga-
tions in identifying myopia candidate genes should therefore
focus on genes located in the MYP2 region and other myopia-
linked regions as well as genes involved with eye growth, as
we have now shown that the likelihood that TGIF is a good
candidate gene for myopia is low.
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