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The Journal of Clinical Endocrinology & Metabolism 91(10):3821–3825
Copyright © 2006 by The Endocrine Society
doi: 10.1210/jc.2006-0348
Epistasis between Loci on Chromosomes 2 and 6
Influences Human Height
Yao-Zhong Liu, Yan-Fang Guo, Peng Xiao, Dong-Hai Xiong, Lan-Juan Zhao, Hui Shen, Yong-Jun Liu,
Volodymyr Dvornyk, Ji-Rong Long, Hong-Yi Deng, Jin-Long Li, and Hong-Wen Deng
Osteoporosis Research Center (Y.-Z.L., P.X., D.-H.X., L.-J.Z., H.S., Y.-J.L., V.D., J.-R.L., H.-Y.D., H.-W.D.), Creighton
University Medical Center, and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska 68131; The
Key Laboratory of Biomedical Information and Engineering (H.-W.D.), Ministry of Education, and Institute of Molecular
Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, People’s Republic of China;
Laboratory of Molecular and Statistical Genetics (Y.-F.G., H.-W.D.), College of Life Sciences, Hunan Normal University,
Changsha, Hunan 410081, People’s Republic of China; Department of Biological Sciences (V.D.), Kent State University,
Kent, Ohio 44242; and Seattle Biomedical Research Institute (J.-L.L.), Seattle, Washington 98109
Context: Human height is a typical and important complex trait,
which is determined by both actions and interactions of multiple
genes. Although an increasing number of genes or genomic regions
have been discovered for their independent effects on height variation, no study has been performed to identify genes or loci that interact to control the trait.
three regions, 9q22, 6p21, and 2q21, which achieved significant or
suggestive linkage signals for height in our recent whole genome scan.
Objective: This study aimed to search for potential genomic regions
that harbor interactive genes underlying human height.
Results: Significant genetic interaction between 6p21 and 2q21 was
detected, with 2q21 achieving a maximum LOD score of 3.21 (P ⫽
0.0035) under the epistatic model, compared with a maximum LOD
score of 1.63 under a two-locus additive model. Interestingly, 6p21
contains a cluster of candidate genes for skeletal growth, suggesting
a mechanism whereby 2q21 regulates height through 6p21.
Methods: Here with a sample containing 3726 Caucasians, the largest one ever obtained from a single population of the same ethnicity
among genetic linkage studies of human complex traits, we performed
variance component linkage analyses of height based on a two-locus
epistatic model. We examined pairwise genetic interaction among
Conclusion: By providing the first evidence for genetic interaction
underlying human height variation, this study further delineated the
genetic architecture of human height and contributed to the genetic
dissection of human complex traits in general. (J Clin Endocrinol
Metab 91: 3821–3825, 2006)
H
UMAN HEIGHT IS the result of linear growth during
development and childhood years, which is modulated by a variety of systemic and local factors, such as GH,
glucocorticoids, thyroid hormone, vitamin D, sex steroids,
IGF-I, Indian hedgehog, and PTHrP. Genetic mutations involving these factors may cause abnormal stature. It was
estimated in 1997 that there were more than 1 million children with idiopathic short stature and 24,000 with medically
defined short stature between the ages of 4 and 15 in the
United States (1).
In normal populations, the variation of height is characterized by high inheritance. The heritability,1 generally above
0.75 (2– 4), is higher than most other human complex traits,
such as body mass index and bone mineral density. Yet the
genetic factors underlying normal height variation are still
largely unknown. Association studies have identified quite
First Published Online July 18, 2005
Abbreviations: MLS, Maximum LOD score; SOLAR, sequential oligogenic linkage analysis routines.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
1
Phenotypic variation of a trait, such as height and body mass index,
in a population results from the joint effects of both environmental and
genetic factors. The proportion of phenotypic variation that is due to
genetic factors is the heritability of the trait.
a few candidate genes for height, such as the collagen I A1
gene (5), the GH-1 gene (6), the vitamin D receptor gene (7),
the peroxisome proliferator-activated receptor-␥ gene (8),
and the PTH/PTHrP receptor gene (9). Through a genomewide linkage2 approach, studies have suggested many
genomic regions linked to height (10 –17) [for a brief review
of identified regions linked to height, see Willemsen et al.
(14)]. Interestingly, the 7q31 region has been identified in
three independent studies (11, 13, 15), making it one of the
promising regions containing genes for human height. In a
series of three consecutive genome-wide linkage scans (10,
12, 18), we also identified 9q22 and Xq24 as two regions
showing consistent signals for linkage to height.
The likely underlying genetic model for height, as for other
complex traits/diseases,3 might involve multiple genes,
2
Two genetic loci are in linkage (or linked) if they are transmitted
together from parents to offspring more often than expected under
independent inheritance. Loci that are physically close to each other in
a chromosome are more likely to be in linkage than those that are more
far apart. Linkage mapping takes advantage of this phenomenon by
tracing the cosegregation of a genetic marker with a trait or a disease in
human families. Through linkage mapping with multiple markers,
genes underlying a trait or a disease may be localized to a relatively
narrow chromosomal region for additional fine mapping and positional
cloning.
3
A trait/disease is determined by actions and interactions of both
genetic and environmental factors. Therefore, genetically, a complex
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J Clin Endocrinol Metab, October 2006, 91(10):3821–3825
which work additively or interactively to contribute to the
trait. So far, genetic studies of height have mainly focused on
identification of genes for their independent (additive) effects on height variation. No study has been performed to
find genes or loci that interact to control height. Here with
a large sample containing 3726 Caucasians from 434 pedigrees, the largest one ever obtained in the field of linkage
studies of human complex traits, we attempted to identify
interactive genomic regions underlying human height. We
investigated genetic interaction between three loci, 9q22,
6p21, and 2q21. These three loci achieved relatively strong
linkage signals among all the regions on autosomes in our
recent whole-genome linkage study of height (19). We tested
their pairwise interaction based on a two-locus epistatic4
model. Interestingly, significant interaction between 6p21
and 2q21 was detected, making them the first set of identified
regions that may contain interactive genes for human height.
Subjects and Methods
Subjects
The study was approved by the Creighton University Institutional
Review Board. All the study subjects signed informed-consent documents before entering the project. The study subjects came from an
expanding database created for ongoing studies in the Osteoporosis
Research Center of Creighton University to search for genes underlying
common human complex traits, including height, body mass index, bone
mineral density, etc. The sampling scheme and exclusion criteria have
been detailed elsewhere (10). Briefly, patients with chronic diseases and
conditions that may potentially affect the development of human height
as well as other studied traits were excluded from the study. These
diseases/conditions included chronic disorders involving vital organs
(heart, lung, liver, kidney, and brain), serious metabolic diseases (diabetes, hypo- and hyperparathyroidism, hyperthyroidism, etc.), skeletal
diseases (Paget’s disease, osteogenesis imperfecta, rheumatoid arthritis,
etc.), chronic use of drugs affecting bone metabolism (corticosteroid
therapy, anticonvulsant drugs), and malnutrition conditions (chronic
diarrhea, chronic ulcerative colitis, etc.), etc.
All the study subjects were Caucasians of European origin. The sample contains a total of 4102 phenotyped subjects from 434 pedigrees (see
Table 1 for their basic characteristics), of whom 3726 subjects were
genotyped. The sample was mainly made up of pedigrees of median to
large size, i.e. with 10 – 451 genotyped subjects per family (see Table 2 for
the distribution of pedigree size). Such a structure of the sample was
advantageous by providing us a large number of relative pairs informative for linkage analyses, with a total of 158,456 (see Table 3 for the
number of relative pairs contained in the sample).
Genotyping
DNA extraction was performed according to a protocol in our previous whole-genome studies (10, 18). The 393 autosomal microsatellite
markers from the Marshfield screening set 14 were successfully genotyped by Marshfield Center for Medical Genetics, with a genotyping
error rate around 5%. The markers have an average population heterozygosity of 0.75 ⫾ 0.06 and spaced on average 8.9 cM. The detailed
description, including name, chromosomal location, heterozygosity, and
allele size range, of the whole panel of microsatellite markers genotyped
trait/disease may not follow strict Mendelian inheritance. Typical examples include human height, body mass index, diabetes, hypertension,
schizophrenia, and many types of cancers.
4
Epistasis, or gene-gene interaction, is broadly defined as the interaction between alleles of different loci in the human genome. Biologically, epistasis refers to the phenomenon where a gene’s effect is masked
by or dependent on another gene. For quantitative traits, such as height,
the term is defined as the deviation from additivity in the effects of alleles
of different loci with respect to their contribution to a phenotype.
Liu et al. • Epistasis Study of Human Height
TABLE 1. Basic characteristics of phenotyped subjects
Age groups (yr)
20 –29
Male
Female
30 –39
Male
Female
40 – 49
Male
Female
50 –59
Male
Female
60 – 69
Male
Female
70⫹
Male
Female
Height (cm)
Sample size
Mean
SD
180
166
6.8
6.1
250
355
180
166
7.4
6.5
279
489
179
165
6.5
6.5
383
633
177
163
6.9
5.7
309
412
176
161
7.1
6.1
204
312
174
158
6.4
6.9
200
276
In total, we have height information for 4102 subjects, who are all
included in the table. Among them, 3726 subjects were genotyped. The
subjects who were not genotyped are also listed here because their
information was also used for linkage analysis. Their phenotype information, along with that of the genotyped subjects, was used to build
polygenic models for adjustment of raw height data.
in our study is listed in the table accessible via the link http://research.
marshfieldclinic.org/genetics/sets/Set14FinalForWeb.xls. The detailed
protocol for genotyping is available at http://research.marshfieldclinic.
org/genetics/Lab_Methods/methods.html. A genetic database management system (GenoDB) (20) was employed to manage the phenotype
and genotype data for linkage analyses. GenoDB was also used for allele
binning (including setting up allele binning criteria and converting allele
sizes to distinct allele numbers), data quality control, and data formatting for PedCheck (21) and linkage analyses. PedCheck was performed
to ensure that the genotype data conform to a Mendelian inheritance
pattern at all the marker loci.
Statistical analyses
Variance component linkage analyses (22–24) for quantitative traits
were performed using sequential oligogenic linkage analysis routines
(SOLAR) (24). Multipoint and two-point LOD scores were calculated for
chromosomes 1–22. Tests for pairwise epistatic interactions between the
three loci, 9q22, 6p21, and 2q21, were performed in a series of three
models: 1) two separate single-locus models with marker effects due to
each marker locus individually, 2) a two-locus additive model with
marker effects for two loci simultaneously but without interaction term,
and 3) a two-locus epistatic model with marker effects for both loci as
well as an epistatic term. The significance associated with the increase
of LOD scores under the epistatic model over that under the additive
TABLE 2. Distribution of pedigree size
Pedigree size
(no. of subjects)
⬍10
10 –19
20 –29
30 –39
40⫹
Total
No. of families
No. of subjects
376
27
12
5
14
434
1568
335
304
168
1351
3726
Our sample is mainly made up of pedigrees of median to large size,
i.e. with 10 or more subjects per family and the largest pedigree
containing 451 genotyped subjects. Most pedigrees have more than
three generations. Given the complex structure of the pedigrees in our
sample, a large number of informative relative pairs are available for
linkage analysis (as shown in Table 3).
Liu et al. • Epistasis Study of Human Height
J Clin Endocrinol Metab, October 2006, 91(10):3821–3825
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Results
TABLE 3. Number of informative relative pairs
Relative pairs
No. of relative pairs
Sibling
Grandparent-grandchild
Avuncular
First cousin
First cousin, once removed
Second cousin
Second cousin, once removed
All relative pairs
5,729
4,988
9,111
14,274
19,473
25,969
23,630
158,456
The statistical power of a linkage study is directly related to the
number of informative relative pairs contained in the sample. The
large number of informative relative pairs in our sample as shown
here is a clear indication of high statistical power of our study.
model was determined by using a ␹2 test with 1 df. Twice the difference
in loge likelihoods of these two models yields a test statistic that is
asymptotically distributed as a 1/2:1/2 mixture of a ␹2 variable (1 df) and
a point mass at zero (25).
In linkage analyses, age, sex, and age-sex interaction were used as
covariates to adjust for raw height data.
According to SOLAR, the heritability of height in our sample
was 0.79 (se ⫽ 0.021). The height raw data, after being adjusted
with covariates (i.e. age, sex, and age ⫻ sex) using SOLAR, had
a kurtosis value of 0.54, therefore conforming to normality as
required by the variance component linkage analyses (26).
Based on a two-locus (i.e. 6p21 and 2q21) additive model, a
maximum LOD score (MLS) of 1.63 was achieved on 2p21. The
LOD score increased to 3.21 under the two-locus epistatic
model. According to a ␹2 test with 1 df, the nominal P value for
the epistatic effect is 0.0035. Figure 1 shows the linkage signals
on chromosome 2 under the single-locus, two-locus additive,
and two-locus epistatic models. No significant epistasis was
detected between 9q22 and 6p21 or between 9q22 and 2q21.
Discussion
The complexity of genetics of human complex traits/diseases can be largely attributed to epistasis or gene-gene in-
FIG. 1. Analysis of epistatic interaction between 6p21 and 2q21. The dotted line represents linkage signals for height under the single-locus
model, the dashed line linkage signals for height under the two-locus additive model, and the solid line linkage signals for height under the
two-locus epistatic model.
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J Clin Endocrinol Metab, October 2006, 91(10):3821–3825
teractions. Deciphering the interconnected networks of genes
and their relationship with trait variation or disease susceptibility is the key to the efficient genetic dissection of complex
traits/diseases. However, so far only a limited number of
studies have performed epistasis-based analyses in humans
(27–30). For human height, an important complex trait apparently under the control of multiple genes, no attempt has
been made to identify genes that interact to influence the
trait.
Our epistatic analyses for height were focused on three
regions, 9q22, 6p21, and 2q21. They represent important regions for height in our sample because they were the only
ones on autosomes that achieved significant or suggestive
linkage signals in our recent whole-genome study of height
(12). Limiting our study to the three regions may also help
minimize the problem of multiple testing.
Interestingly, epistasis was observed between 2q21 and
6q21, as evidenced by a considerable increase of MLS on 2q21
under the epistatic model compared with under the additive
model. The LOD increase, with a nominal P value of 0.0035,
was significant even after Bonferroni correction (in total,
three pairs of regions were tested for epistasis). According to
SOLAR, the fraction of height variation due to the epistasis
between the two regions is approximately 20%.
A clear advantage of our study is its large sample size. To
the best of our knowledge, in the field of genetic linkage
studies of complex traits, our study sample was the largest
one ever obtained from a single study population of the same
ethnicity. More importantly, the major structure of our sample is made up of large pedigrees (Table 2). As a result, our
sample contains a large number of relative pairs informative
for linkage analyses (Table 3), which may give our study
higher statistical power than most other linkage studies of
human complex traits. Because a linkage study of low statistical power may suffer from a low positive predictive
value, the likelihood that an observed linkage is true (31), the
high statistical power of our study ensures a high likelihood
that our findings for the epistatic effects between 6p21 and
2q21 are robust and reliable.
Interestingly, 6p21 contains a cluster of genes (e.g.
COL11A2, CCD, RUNX2, and RXRB) that are functionally
important to longitudinal growth or skeletal development.
The COL11A2 (collagen, type XI, ␣-2) gene (MIM 120290) is
involved in human cartilage development (32). Mutations of
the gene lead to chondrodysplasia or osteochondrodysplasia
(33, 34), common conditions causing short stature. The CCD
(cleidocranial dysplasia) gene (MIM 119600) is responsible
for syndromes characterized by generalized skeletal dysplasia and growth retardation (35). The RUNX2 (runt-related
transcription factor 2) gene (MIM 600211) encodes core-binding factor 1, a well-known transcription factor regulating
osteoblast differentiation (36). The factor is essential to osteogenesis by controlling the integration, organization, and
assembly of nucleic acids and regulatory factors for skeletal
gene expression (37). The RXRB gene (MIM 180246) encodes
retinoid X receptor-␤, which heterodimerizes with thyroid
hormone and vitamin D receptor, two important factors for
longitudinal growth, thereby increasing their DNA binding
and transcriptional function (38). Because 2q21 does not contain genes known to be directly involved in skeletal growth
Liu et al. • Epistasis Study of Human Height
and given the epistasis between 2q21 and 6p21 detected in
our study, it may be reasonable to hypothesize that 2q21 may
regulate human height mainly through its interaction with
6p21.
Noticeably, the region of 7q31 has been shown to be linked
to height in three previous studies (11, 13, 15) yet did not
achieve significant linkage signals in our study. Given the
high statistical power of our sample (12), the negative linkage
result of our study may indicate that the region’s effects on
height might be very weak in our study population. Indeed,
a recent linkage exclusion study by our group (39) has excluded the region for height at a relative effect size of 5% or
greater (P ⬍ 0.0018), suggesting that the region may contribute very little to height variation in our Caucasian population. Genetic heterogeneity may be one of the reasons
underlying the different results on the 7q31 region’s linkage
to height. This is supported by the fact that the study population in our work was made up of Caucasians from the
midwestern United States, whereas the samples for the studies by Hirschhorn et al. (11) and by Perola et al. (13), which
detected 7q31, were mainly from a northern European population, which is well known for its different genetic makeup
compared with the general population because of a long
history of genetic isolation. The study by Wu et al. (15) combined several samples for reanalysis of linkage to height.
Notably, the 7q31 region was not detected initially in any of
the samples alone. Combining the samples together made a
very large dataset containing 6752 subjects. Even with such
a huge sample size and, most likely, very high statistical
power, the linkage signals of the region (LOD ⫽ 2.46) did not
achieve the genome-wide significance level for linkage (i.e.
LOD ⱖ 3.0), suggesting that the region’s effects on height
indeed might be very small in size in the general population
(which is in fact consistent with what was implicated in our
study).
In summary, our study provided the first evidence for
significant genetic epistasis underlying human height. The
results demonstrated that taking into account epistasis in
linkage analyses of human complex traits may enhance linkage detection for regions that are otherwise insignificant in
regular linkage analyses. With two new interactive regions
for height identified, our study further delineated the genetic
basis of human height.
Acknowledgments
Received February 16, 2006. Accepted July 10, 2006.
Address all correspondence and requests for reprints to: Hong-Wen
Deng, Ph.D., Osteoporosis Research Center, Creighton University Medical Center, 601 North 30th Street, Suite 6787, Omaha, Nebraska 68131.
E-mail: [email protected].
Investigators of this work were partially supported by grants from
National Institutes of Health (K01 AR02170-01, R01 AR45349-01, and
R01 GM60402-01A1) and an LB595 grant from the State of Nebraska. The
study also benefited from grants from the National Science Foundation
of China, Huo Ying Dong Education Foundation, HuNan Province,
Xi’an Jiaotong University, and the Ministry of Education of China. The
genotyping experiment was performed by Marshfield Center for Medical Genetics and supported by National Heart, Lung, and Blood Institute Mammalian Genotyping Service (Contract No. HV48141).
Disclosure statement: The authors have nothing to disclose.
Liu et al. • Epistasis Study of Human Height
J Clin Endocrinol Metab, October 2006, 91(10):3821–3825
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