BioEd Online

A genetic survey of more than 34,000 people has revealed the first gene known to have a decisive effect on height in people of average stature. A change to just a single letter of genetic code is linked to a height boost of almost a centimetre in a healthy person, all other things being equal.

Although up to 90% of variation in people's height is thought to be down to genetics, identifying the genes involved is difficult because there are thought to be hundreds of them, each with an almost imperceptible effect.

Researchers therefore combed through almost the entire genome of nearly 5,000 volunteers in search of tiny changes, called polymorphisms, that correspond to variations in height. Eventually they found a single-letter DNA substitution, buried in a gene called HMGA2, that influences height.

People with two copies of the 'tall' variant of HMGA2 are, on average, almost a centimetre taller than those with two copies of the 'short' version. Those with one copy of each are somewhere in the middle. Follow-up testing of some 29,000 people confirmed that HMGA2 does indeed affect height, the research group reports in Nature Genetics¹.

The height of medicine

"It doesn't explain why one person is six foot five and another is four foot ten — in terms of the variation it is about 1%," explains Timothy Frayling of Peninsula Medical School in Exeter, UK, who led the international research consortium. "But there are possibly several hundred more polymorphisms that also influence height."

It's also not exactly clear how HMGA2 influences height, despite the fact that rare severe mutations in the gene are already known to alter body size in both mice and humans. The gene is involved in unravelling the protein-rich structure, called chromatin, in which chromosomes are packaged, leading Frayling to speculate that the gene may influence the speed at which DNA is replicated during cell division, thus affecting overall body growth.

Nevertheless, simply knowing which genes help to determine height could help doctors decide whether small kids have naturally 'short' genes, or whether they are suffering from a medical condition that stunts growth. "For a lot of children who perhaps are a bit behind their growth chart, there is a pressure for doctors to treat them or find something wrong with them," Frayling says. "If we can find 50 or 100 height genes, we could look at them and say 'this is entirely in keeping with your height profile'."

Short on evidence

The discovery could also help to piece together the genetic framework of diseases such as diabetes and cancer, suggests another member of the research group, Joel Hirschhorn of the MIT Broad Institute and the Children's Hospital, both in Boston, Massachusetts.

There is some evidence that slightly shorter-than-average people are susceptible to diabetes, although this may be for socio-economic reasons. Conversely, taller people tend to be more prone to cancer, perhaps because they simply have more growing cells in which the disease can arise.

Discovering the genes that govern height would allow geneticists to examine whether different versions of these genes are linked to increased rates of various diseases, and could even help them work out the mechanisms involved.

In the meantime, however, Frayling and his colleagues are searching for yet more genes that influence height. "We won't expose all of the genetic basis of height, but over the next couple of years, we might find several hundred [genes] — perhaps 50% of the variation," Frayling says.

In theory, it's simply a question of getting DNA samples from as many people as possible, so that the tiny statistical effects of individual genes can be teased out. "Unlike most other complex traits, height is something that can be easily defined and measured in very large numbers of people," Hirschhorn says.