The Genetic Dimension of Height and Health

From Danny Devito to Yao Ming, the world is filled with short people and tall people and everyone in between. While factors such as nutrition influence height differences, much of that variation depends on genes. After all, both of Ming’s parents were basketball stars, and Devito’s were not.

But the genes that made Ming grow to 7 feet 6 inches and Devito stop growing several feet shorter could be important for more than sports. Changes in how height genes work could not only add or subtract a few centimeters from leg length, but could also affect underlying cell biology in ways that can lead to disease, recent research suggests.

Statistical studies find that shorter people are more likely to get heart disease, diabetes and osteoarthritis. Other studies show that the same genes that make healthy cells multiply to make a person grow taller can also make cancer cells proliferate in tumors. On the other hand, genes that make bones grow longer can form extra cartilage in joints, protecting them from the ravages of osteoarthritis.

The long and short of it is that height genes might affect health as well as height — although scientists don’t completely understand how.

Some genes that have been implicated in determining height have been well-studied for their connections to particular diseases, but not as well-studied for how they affect height. And while statistical links between height and disease are robustly documented, scientists don’t completely understand if or how the same genes could set the foundation for both height and disease.

Pinning down that connection could have payoffs for treating disease and ensuring health.

“When you take a kid to the pediatrician, the first thing they do is measure the child’s height,” says geneticist Guillaume Lettre of Children’s Hospital Boston and of the Broad Institute, in Cambridge, Mass. He is coauthor of a study that identified several genes associated with height.

Growing too fast or too slow could be a sign of health problems such as hormone imbalances. But if the genes controlling height were well known, pediatricians could easily determine whether a short-for-their-age child simply inherited the gene variants that denote a more diminutive stature, or actually has a more serious condition, Lettre says.

Linking height genes to health is difficult, though, because details of the genetic pathway to height are complex. Many genes work together to create normal variations in height. So far, the suspicion that height genes affect health is supported mostly by statistical studies.

In 2001, for instance, epidemiologist David Gunnell of the University of Bristol in England and colleagues found that taller people can face a 20 to 60 percent greater risk for various cancers, including of the breast, prostate and colon.

Last year, epidemiologist Luisa Zuccolo, also of Bristol, followed up on Gunnell’s work with a study focused on the link between height and prostate cancer. The risk of developing prostate cancer increased by 6 percent for every 10 centimeters over the median height of the 1,357 men in the study, Zuccolo and colleagues reported in Cancer Epidemiology, Biomarkers & Prevention. Despite the link, height was still less of a risk factor than age and family history, but “understanding why height is associated with prostate cancer could help us to understand its causes,” Zuccolo says.

One molecule that taller people have in abundance compared with shorter people is insulin-like growth factor 1, or IGF-1. The insulin-like molecule stimulates the growth of cells and tissues, and higher levels of the molecule have also been linked to the incidence and progression of several different types of cancer. IGF-1 can bind to the tumors of cancers of the breast, prostate and bladder, stimulating the growth of tumor cells. Zuccolo speculates that the IGF-1 gene could link height and prostate cancer.

Stimulating growth

IGF-1 is a protein that binds to receptor molecules on other cells, triggering a cascade of events that eventually stimulate cell growth.

A study reported in 2007 in Science found that variations in the IGF-1 gene were one reason that Chihuahuas don’t grow as large as Great Danes. Geneticist Nathan Sutter, then at the National Human Genome Research Institute in Bethesda, Md., and colleagues found that small dog breeds had one particular variant of the gene for IGF-1, but almost all giant breeds had a different version of the gene.

A 1993 study by Michael Ranke and colleagues at University Children’s Hospital in Tübingen, Germany, found that shorter children had lower levels of IGF-1. Ranke and his colleagues speculate that lower levels of IGF-1 could cause a reduction in growth in early childhood.

In 2001, Gunnell and colleagues reported that leg length is the height component most strongly associated with coronary heart disease and with insulin resistance, a condition that can lead to type 2 diabetes. After measuring leg length and trunk length in 2,429 men and tracking coronary heart disease over 15 years, the team found that insulin resistance and heart disease were more frequent in men with shorter legs, while trunk length showed less association.

But it’s not height itself that makes people sick, researchers say. The ratio of leg length to trunk length could signal IGF-1 levels and thus, possibly, a likelihood for certain diseases. Small variations in the amount of IGF-1 produced can affect growth during childhood, and also alter the incidence of disease later in life.

Lower levels of IGF-1 may have other effects. One study found that individuals with the lowest IGF-1 levels had a twofold increase in heart disease incidence, epidemiologist Torben Jørgensen of the University of Copenhagen and colleagues reported in 2002 in Circulation.

In a 2004 study of IGF-1, height and disease, Gunnell and his colleagues found that shorter stature is linked to heart disease and to insulin resistance.

Researchers aren’t sure why, but large amounts of the IGF-1 protein increase insulin sensitivity, which can reduce a person’s risk for heart problems. Insensitivity to insulin, or insulin resistance, associated with type 2 diabetes is linked to the inflammation that leads to heart disease, but the mechanism of this link is not known.

More evidence of an IGF-1–heart disease link comes from a 2007 finding that IGF-1 injections lowered the incidence of heart disease in mice fed a high-fat diet. The study, by Patrice Delafontaine of Tulane University School of Medicine in New Orleans and colleagues, was published in Arteriosclerosis, Thrombosis, and Vascular Biology. The researchers think that increased IGF-1 reduces the inflammation that can cause heart disease.

But while IGF-1 is known to function in both disease and height, it’s not yet known exactly how the two intersect.

A height and cancer suspect

Genome-wide association studies offer one way to sift through the human genome by comparing genomes of thousands of people for variations associated with a specific trait. To hunt for height genes, researchers try to identify genetic variations that crop up more often in shorter people or taller people.

So far, several studies have related about 40 different genes to height. But more genes are likely to be found, says Gonçalo Abecasis, a statistical geneticist at the University of Michigan in Ann Arbor who collaborated on two of the studies. “There are lots of different genes that each only make a small contribution to height,” he says.

The researchers expect that the list of height genes will run into the hundreds. “We’re making progress, but there are many more height genes to find,” says geneticist Michael Weedon of the Peninsula Medical School in Exeter, England.

Weedon and his colleagues used genome-wide association studies to identify height gene candidates and found that the gene at the top of their list is also a well-known cancer gene. Variants of the high-mobility group A2 gene, called HMGA2, correlated with small variations in height within a population of just over 19,000 people, the researchers reported in Nature Genetics in 2007. That study was the first evidence that small variations in the gene could produce normal height differences among people.

“Sometimes it’s hard to link the gene you find to a height-related function — but this one was easy,” says Lettre, a coauthor on the study.

Scientists already knew that rare HMGA2 mutations could have severe effects on body size. Take 13-year-old Brenden Adams of Ellensburg, Wash., for example. An average-sized newborn, Adams began growing faster than anyone could explain and now stands 7 feet and 3 inches.

At first, doctors couldn’t figure out why. Then they took a look at his chromosomes. A portion of one copy of Adams’ chromosome 12 is inverted, as if a piece of the chromosome had broken off, flipped around and then reattached. The genes on this inverted section seemed to be undamaged — except for where the chromosome broke, which turned out to be at HMGA2.

Azra Ligon and Brad Quade of Brigham and Women’s Hospital and Harvard Medical School in Boston studied Adams’ case. They aren’t sure exactly how the change to HMGA2 is making Adams grow so much, but they speculate that the chromosome inversion disrupted the normal regulation of the gene.

The HMGA2 gene encodes a protein that activates other genes by rearranging how DNA is stored. To package huge amounts of DNA inside each cell, the DNA is twisted and coiled into the chromosomes, then compacted in an orderly fashion so that the correct section is easily available when needed. The HMGA2 protein recognizes and binds to specific twists in chromosomes in order to activate the genes needed for a wide array of biological processes, including the growth and proliferation of cells.

Weedon and colleagues speculate that mutations in the HMGA2 gene can affect how much of the protein is produced.

Previous work also showed that the HMGA2 gene is active only during embryo development in both mice and people. In mature tissues, gene 
activity was almost undetectable, a sign that the gene may not have much effect on the later stages of growth and 
development.

“It seems that the contribution of this gene is laid down early in life,” says geneticist Peter Visscher of the Queensland Institute of Medical Research in Brisbane, Australia.
But the gene does get turned on at later stages in cancerous cells. HMGA2 proteins are found in the tumors of several different types of cancer, including those of the breast, pancreas and lung, suggesting that the gene may help cancer cells grow and proliferate. But scientists don’t know whether the increased risk of cancer in taller people has anything to do with differences in the HMGA2 gene. While HMGA2 is implicated in both cancer and height, “the mechanistic dots have not yet been connected,” says Lettre.

“Right now, we fall short of explaining exactly how HMGA2 controls height,” he says. “We don’t know exactly how variations in HMGA2 that correlate with height could affect how the gene works.”

And while genes such as HMGA2 are already well-characterized because of their roles in disease or development, little is known about many of the height genes that the statistical studies turn up.

Figuring out what these genes do could explain the links between height and disease. “We’re not there yet,” says Abecasis. “But when you start looking at all these different genes, you find that they are linked to lots of different things.”

Adds Lettre: “We’re interested in learning more about how genes control height. But we’re hoping that some of the height genes will have other effects on health too.” That would help the scientists gain insights into the biological processes of growth. “Time will tell, but that is certainly a hope.”

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The short path to osteoarthritis
Taller people may be at a higher statistical risk of cancer, but short people face height-related disease risks too.

A gene called growth differentiation factor 5, or GDF5, is related to height; it encodes a protein important for bone and cartilage growth and skeletal development. Geneticist Karen Mohlke of the University of North Carolina at Chapel Hill and her colleagues found that slight differences in the GDF5 gene caused differences of about 0.3 to 0.7 centimeters in height. The people on the shorter end of these differences were more likely to have the particular GDF5 variant associated with osteoarthritis, a type of arthritis caused by the breakdown of cartilage in joints.

People with lower levels of the GDF5 protein have shorter bones and less cartilage in their joints. Shorter people are more susceptible to osteoarthritis because they have less cartilage to wear down.

“It makes sense that a reduction in GDF5 would decrease bone growth and lead to reduced height,” says Gonçalo Abecasis, a statistical geneticist at the University of Michigan in Ann Arbor and a coauthor of the study, which was published in Nature Genetics in 2008. “And as well as this, there would be less cartilage in the joints, which could increase susceptibility to osteoarthritis,” he says.