NUMBER OF GENES LINKED TO HEIGHT REVEALED
The largest
genome-wide association study (GWAS) to date, involving more than 300
institutions and more than 250,000 subjects, roughly doubles the number of
known gene regions influencing height to more than 400. The study, from the
international Genetic Investigation of Anthropometric Traits (GIANT)
Consortium, provides a better glimpse at the biology of height and offers a
model for investigating traits and diseases caused by many common gene changes
acting together. Findings were published online October 5 by Nature Genetics
Height is almost completely determined by genetics, but our
earlier studies were only able to explain about 10 percent of this genetic
influence," says Joel Hirschhorn, MD, PhD, of Boston Children's Hospital
and the Broad Institute of MIT and Harvard, leader of the GIANT Consortium and
co-senior investigator on the study. "Now, by doubling the number of
people in our study, we have a much more complete picture of how common genetic
variants affect height -- how many of them there are and how much they contribute."
The GIANT investigators, numbering in the hundreds, shared and
analyzed data from the genomes of 253,288 people. They checked about two
million common genetic variants (those that showed up in at least 5 percent of
their subjects). From this pool, they pinned down 697 (in 424 gene regions) as
being related to height, the largest number to date associated with any trait
or disease.
"We can now explain about 20 percent of the heritability of
height, up from about 12 percent where we were before," says co-first
author Tonu Esko, PhD, of Boston Children's Hospital, the Broad Institute and
the University of Tartu (Estonia).
"The study also narrows down the genomic regions that
contain a substantial proportion of remaining variation -- to be discovered with
even larger sample sizes," adds co-senior investigator Peter Visscher,
PhD, of the University of Queensland, Australia.
Greater size, greater power
Height is a model trait for understanding how human genetics
works -- especially for traits produced by not one gene, but many. Height is
easy to measure, and an estimated 80 percent of variation in height is genetic.
Previous large-scale genome-wide association studies (GWAS) have
indicated that a large number of genes influence height, and suggested that the
majority of heritability comes from common genetic variants, not rare ones.
Because sample sizes have not been large enough to draw definitive conclusions,
the GIANT team built the largest sample to date.
"When you double the sample size and increase your
statistical power, you can make new discoveries," says Hirschhorn.
"Our results prioritize many genes and pathways as important in skeletal
growth during childhood. Without a highly collaborative model, there's no way
we could get this work done."
The researchers believe their results answer critics of
population-scale GWAS, who have argued that increasing the sample size yields
diminishing returns or results that become meaningless.
"In 2007 we published the first paper that identified the
first common height gene, and we have now identified nearly 700 genetic
variants that are involved in determining height," says co-senior
investigator Timothy Frayling, PhD, of the University of Exeter, U.K. "We
believe that large genetic studies could yield similarly rich lists in a
variety of other traits."
The biology of height
Many of the 697 height-related genetic variants were located
near genes known to be involved in growth, but there were also plenty of
surprises.
"There were some pathways that we knew were important, but
had not come out in previous GWAS," says Hirschhorn, who is also an
endocrinologist at Boston Children's. "Many of the genes we identified are
likely to be important regulators of skeletal growth, but were not known to be
involved until now. Some may also be responsible for unexplained syndromes of
abnormal skeletal growth in children. As you increase the sample size, you get
more biology."
For example, the mTOR gene is well known to be involved in
cellular growth, but had not previously been connected with human skeletal
growth. Other genes confirmed as important include genes involved in metabolism
of collagen (a component of bone) and chondroitin sulfate (a component of
cartilage), as well as networks of genes active in growth plates, the area of
growing tissue near the ends of the long bones. Still other genes point to
biology whose relationship with height isn't yet known.
Among GIANT's future goals is to look at variants that occur at
lower than 5 percent frequency, and to look for variants in the
non-protein-coding portions of genes.
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