|Researchers Uncover New Piece to the Puzzle
of Human Height
Study Suggests Connection Between Genetic Basis of Height and
In studies involving more than 35,000 people and a survey across
the entire human genome, an international team supported in part
by the National Institutes of Health (NIH) has found evidence that
common genetic variants recently linked to osteoarthritis may also
play a minor role in human height. The findings were released today
in the advance online publication of the journal Nature Genetics.
The variants most strongly associated with height in the new genome-wide
association study lie in a region of the human genome thought to
influence expression of a gene for growth differentiation factor
5 (GDF5), which is a protein involved in the development of cartilage
in the legs and other long bones. Rare variants in the GDF5 gene
have been associated with disorders of skeletal development, and
more common variants recently have been tied to susceptibility
to osteoarthritis of the hip and knees in Asian and European populations.
"The common variants we identified are associated with both
short stature and, as described previously, increased risk of osteoarthritis," said
the study's senior author Karen L. Mohlke, Ph.D., of the University
of North Carolina, Chapel Hill. "Our findings suggest a link
between the genetic basis of height and osteoarthritis, potentially
mediated through alterations in bone growth and development."
Dr. Mohlke and her colleagues emphasized that the new variants
account for just a small fraction of the genetic basis of height,
which means much more research is needed before scientists can
paint a complete picture of this complex human trait.
A variety of factors, including genetics, prenatal environment
and diet, interact to determine how tall someone grows. It is currently
thought that genetic factors are responsible for at least 80 percent
of the variation in height among people. However, the new genetic
variants, together with another recently identified height-associated
genetic variant called HMGA2, account for less than 1 percent of
human height variation.
Specifically, the newly identified genetic variant is associated
with an average difference in height of about 0.4 centimeter (cm),
or a little more than an eighth of an inch. The exact effect ranged
from 0.3 cm to 1.4 cm (0.12 to 0.55 inches), depending upon the
population and whether an individual has one or two copies of the "taller" version
of the variant. No differences in the effect were detected between
males and females, nor did the variants appear to be associated
with weight or body mass index.
"Many of the genetic variants involved in height likely will
have only small effects, so it's going to take a lot of work involving
very large sample sets to uncover all of them," said National
Human Genome Research Institute (NHGRI) Director Francis S. Collins,
M.D., Ph.D., one of the study's co-authors and an investigator
in NHGRI's Genome Technology Branch. "But it is very exciting
to have powerful enough tools to succeed at this extremely difficult
work. Our findings show how understanding the factors involved
in human height may provide new insights into osteoarthritis and
other musculoskeletal diseases."
Osteoarthritis is by far the most common type of arthritis, affecting
nearly 21 million Americans. The degenerative joint disease, which
primarily affects cartilage, is seen mostly among older people.
The researchers speculate that genetic variants that reduce production
of the GDF5 protein may affect the amount of cartilage in the spine,
the proportion of limbs and/or the angles of joints, resulting
in a modest decrease in height and increased susceptibility to
To make their findings, researches used a genome-wide association
study, which is a relatively new, comprehensive strategies that
utilizes tools made possible by the sequencing of the human genome
and the mapping of human genetic variation. To conduct a genome-wide
association study on a quantitative trait such as height, researchers
survey each participant's complete set of DNA, or genome, looking
for strategically selected markers of genetic variation.
If average height differs for individuals with certain genetic
variants, this indicates that something in that chromosomal neighborhood
likely influences height. In this particular study, researchers
initially examined the effects of more than 2 million genetic variants.
The variants detected using this approach can accurately point
to the region of the genome involved, but may not themselves directly
influence the trait. This means researchers often need to take
additional steps, such as sequencing the DNA in that particular
region of the genome, to identify the exact genetic variant that
affects the trait.
The completion of the map of human genetic variation, or HapMap,
has fueled a surge in genome-wide association studies, with most
of the increase coming in the past 10 months. Researchers around
the globe have now associated more than 60 common DNA variants
with the risk of more than 20 common diseases or related traits.
"Genome-wide association studies often require the skills
of researchers from many different institutions and many different
disciplines. By working together in a collaborative manner, we
can tackle the complexities of common disease and quantitative
traits far more efficiently than we could working alone," said
Gonçalo R. Abecasis, D.Phil., a statistical geneticist of
the University of Michigan's School of Public Health, Ann Arbor,
who co-directed the study with Dr. Mohlke.
This latest work was accomplished as a result of innovative international
partnerships with scientists and study participants. Researchers
began by scanning the genomes of nearly 4,300 people from the Mediterranean
island of Sardinia and more than 2,300 people from Finland. The
initial findings were then validated by follow-up studies involving
more than 24,000 additional individuals of European ancestry and
nearly 4,000 African American individuals.
The Sardinians were participants in the SardiNIA project, a multidisciplinary,
longitudinal genetic study of complex traits and diseases in Sardinia
supported by the National Institute on Aging (NIA). The Finns were
participants in the Finland-United States Investigation Of Non-Insulin
Dependent Diabetes Mellitus Genetics (FUSION) study, which receives
support from the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK).
"It has been exciting to see how the SardiNIA and FUSION
investigators have productively combined results from a number
of populations to lead us to these current insights," noted
NIA Director Richard J. Hodes, M.D. "In these efforts, we
must also recognize the thousands of study participants for helping
to catalyze advances in our understanding of the genetic factors
of age-related disease."
NIDDK Director Griffin P. Rodgers, M.D., said, "This study is
an example of how an investment in studies originally designed
to evaluate specific diseases, such as diabetes, can lead to diverse
and unexpected findings."
The research received major support from NHGRI, NIA, NIDDK and
the National Heart, Lung and Blood Institute, all of which are
part of NIH.
In addition to the University of North Carolina, Chapel Hill;
University of Michigan, Ann Arbor; NHGRI; and NIA: other institutions
with researchers taking part in the study were: the C.N.R Institute
of Neurogenetics and Neuropharmacology, Monserrato, Italy; University
of Virginia School of Medicine, Charlottesville; University of
Maryland School of Medicine, Baltimore; University of Bristol,
England; the Broad Institute of MIT and Harvard, Cambridge, Mass.;
Johns Hopkins School of Medicine, Baltimore; London School of Hygiene
and Tropical Medicine, University of London; Keck School of Medicine,
University of Southern California, Los Angeles; Veterans Administration
Medical Center, Baltimore; University of Texas Health Science Center
at Houston; and the University of Helsinki and the National Public
Health Institute in Finland.
For the FUSION group, the laboratory analysis of genetic variants
was conducted by the Center for Inherited Disease Research, using
funding from NIH and The Johns Hopkins University in Baltimore.
For the SardiNIA group, the analysis was conducted by the ProgeNIA
team of the genetic laboratory in Lanusei, Sardinia. The analysis
of the Diabetes Genetics Initiative (DGI) follow-up samples was
primarily supported by funding from the Novartis Institutes for
Biomedical Research, Basel, Switzerland.
Also today, another NIH-supported genome-wide association study
involving the FUSION, SardiNIA and DGI groups was released in the
advance online publication of Nature Genetics. In that work, an
international team, which included many researchers from the height
study, identified seven new genetic variants associated with levels
of cholesterol and other fats in the blood and confirmed 11 others.
For more information about genome-wide association studies, go
For more information about osteoarthritis, go to: http://health.nih.gov/result.asp/485/27.
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