Height is the "poster child" of complex genetic
traits, meaning it is influenced by multiple genetic variants working
together. It's easy to measure, so makes a relatively simple model for
understanding traits produced by not one gene, but many.
83 new DNA changes that affect human height have been uncovered by the international Genetic
Investigation of Anthropometric Traits (GIANT) Consortium, the largest, deepest search to date. These changes are uncommon
or rare, but they have potent effects, with some of them adjusting
height by more than two cm (almost 8/10 of an inch).
‘83 new DNA changes that affect human height have been uncovered by the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium.’
700,000-plus-person study also found several genes pointing to
previously unknown biological pathways involved in skeletal growth.
Findings were published online by Nature
"While our last study identified common height-related changes in
the genome, this time we went for low-frequency and rare changes that
directly alter proteins and tend to have stronger effects," says Joel
Hirschhorn of Boston Children's Hospital and the Broad
Institute of MIT and Harvard, chair of the GIANT Consortium and
co-senior investigator on the study together with researchers at the
Montreal Heart Institute, Queen Mary University, the University of
Exeter, UK, and nearly 280 other research groups.
"To identify these
protein-altering changes, some of them very uncommon, required
tremendous statistical power, which we achieved thanks to a strong
Applying a new technology
In 2014, GIANT, studying roughly 250,000 people, brought the total
number of known genetic variants to nearly 700 -- in more than 400 spots
in the genome. This effort involved a powerful method called
genome-wide association study (GWAS), which rapidly scans across the
genomes of large populations for markers that track with a particular
trait. GWAS are good at finding common genetic variants, but nearly all
of the identified variants alter height by less than 1 mm (less than
1/20 of an inch).
GWAS studies are not as good at capturing uncommon
genetic variants, which can have larger effects. Finally, the common
variants that track with traits tend to lie mostly outside the
protein-coding parts of genes, making it harder to figure out which
genes they affect.
So in the new study, the GIANT investigators used a different
technology: the ExomeChip, which tested for a catalogue of nearly
200,000 known variants that are less common and that alter the function
of protein-coding genes. These variants point more directly to genes and
can be used as a shortcut to figuring out which genes are important for
a specific disease or trait. Most had not been assessed in prior
genetic studies of height.
Using ExomeChip data from a total of 711,428 adults (an initial
460,000 people and about 250,000 more to validate the findings), the
investigators identified 83 uncommon variants associated with adult
height: 51 "low-frequency" variants (found in less than 5% of
people) and 32 rare variants (found in less than 0.5%).
With these new findings, 27.4%of the heritability of height
is now accounted for (up from 20% in earlier studies), with most
heritability still explained by common variants.
24 of the newly discovered variants affect height by more
than 1 cm (4/10 of an inch), larger effects than typically seen with
common variants. "This finding matches a pattern seen in other genetic
studies, where the more potent variants are rarer in the population,"
says Hirschhorn, who is also an endocrinologist at Boston Children's and
a professor of pediatrics and genetics at Harvard Medical School.
Rare but potent clues to new biology
These rare variants not only had large effects but also pointed to
dozens of genes as important for skeletal growth. Some of these genes
were already known, but many (including SUSD5, GLT8D2, LOXL4, FIBIN, and
SFRP4) have not previously been connected with skeletal growth.
One gene of particular interest, STC2, had two different DNA changes
that both had larger effects on height. Though the variants are quite
rare (frequency of 0.1%), people with either of these changes
were 1-2 cm taller than non-carriers. Further investigations by
co-authors Troels R. Kjaer and Claus Oxvig of Aarhus University
(Denmark) suggested that the variants influence height by affecting the
availability of growth factors in the blood. "The STC2 protein serves as
a brake on human height, validating it as a potential drug target for
short stature," says Hirschhorn.
Height: A window into complex genetics
Why study height?
"Mastering the complex genetics of height may give us a blueprint
for studying multifactorial disorders that have eluded our complete
understanding, such as diabetes and heart disease," says Hirschhorn.
"This study has shown that rare protein-altering variants can be helpful
at finding some of the important genes, but also that even larger
sample sizes will be needed to completely understand the genetic and
biologic basis of human growth and other multifactorial diseases."
Indeed, the GIANT consortium is already embarking on a GWAS of
height with more than two million people, and other studies involving
sequencing data are underway. "We predict that these more comprehensive
studies will continue to enhance our understanding of human growth and
how best to attain the biological insights that will inform treatments
for common diseases," says Hirschhorn.