A thousand points of height

Study finds heaps of genetic variants influencing stature

Geneticists are getting to the long and short of the genes that control how tall a person will grow. The short answer is that at least 180 different common genetic variants are involved; the long, that more than 600 variants may control human height.

Scanning the genetic blueprints of more than 100,000 people, scientists have turned up at least 180 different genetic variants involved in determining human height, the researchers report online September 29 in Nature. That may sound impressive, but each of the genes involved has a small effect, and researchers are still able to account for only about 10 percent of the genetic contributions that give rise to the wide variation in height.

“It’s a lot more complicated than we originally thought, and there may be thousands of variants with subtle effects,” says Michael Weedon, a geneticist at Peninsula College of Medicine & Dentistry in Exeter, England. Weedon is one of 293 coauthors of the new study, which reanalyzed data from more than 50 previous genome-wide association studies to find genes that affect growth in people.

Larger studies might uncover even more genetic variants associated with height. Assuming all variants have the same modest effects as the ones in this study — each affecting height by a millimeter or so — the researchers calculate that between 483 and 1,040 different variants may be involved, accounting for almost 20 percent of the genetic components that determine height. Scientists are still debating where the remaining genetic components are likely to be found.

Nutrition and other environmental factors may also play a role, says Aravinda Chakravarti, a human geneticist at Johns Hopkins University School of Medicine in Baltimore. The children of immigrants are often taller than their parents, presumably due to better nutrition, he says. Studies like this one might eventually help researchers predict how much improved nutrition might make a person grow, perhaps providing an alternative to growth hormone for treating children with short stature.

While height itself is usually not of great medical significance, the new study may give researchers insight into how many genes may influence development of diseases, says Jeffrey Barrett, a statistical geneticist at the Wellcome Trust Sanger Institute near Cambridge, England. “This tells us something about the architecture of other human traits,” he says.

In particular, such studies pinpoint regions of the genome where important genes may be located. But the studies don’t indicate whether height or other characteristics are influenced by lots of common genetic variants with small effects or by rare variants with more dramatic influences.

“It doesn’t tell us that the causal variants in the region are rare. It doesn’t tell us if they are common. It just doesn’t tell us,” says David Goldstein, a human geneticist at Duke University in Durham, N.C. When scientists begin sequencing complete human genomes to find variations that actually cause disease, Goldstein says, the genetic markers used in genome-wide association studies will be helpful in making sense of the data.

Such genome-wide studies can help scientists uncover biological processes involved in causing or protecting against diseases, Chakravarti adds.

Some of the genes pinpointed in the new study were already known to affect height, but some implicated genes are involved in biological processes that were not previously suspected to control growth.

Many biologists have suspected that synergistic interactions between genes could produce stronger effects on traits than the action of any single gene. But the new study did not detect any such interactions that contribute to height. “There was no evidence of anything greater than we would expect by chance,” says study coauthor Joel Hirschhorn, a human geneticist at Children’s Hospital Boston, Harvard Medical School and the Broad Institute in Cambridge, Mass.

That doesn’t mean that interactions between genes aren’t important, says Chakravarti, just that such studies are not good at detecting them.
Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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