Clinical Context

Although height is not typically considered a disease risk factor, it is linked to numerous diseases. High heritability of height plus recent advances clarifying its genetic basis now allow use of genetic tools to examine pathophysiologic relationships between height and clinical traits.

A Mendelian randomization-phenome-wide association study can identify such novel, hypothesis-generating associations. Phenome-wide evaluation of clinical traits associated with measured and genetic height could identify the full scope of diseases associated with height as a risk or protective factor.

Study Synopsis and Perspective

A person's "genetic" height, or the height they are predicted to reach independent of environmental influences, may be an underappreciated risk factor for a wide range of chronic conditions, according to a study published in PLOS Genetics.

Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk for cardiovascular disease. It has been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person's reaching their expected height based on their genes.

This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic data set of a national health care system biobank. Mendelian randomization uses "genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures," the authors explain. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions, as well as revealing new associations with several other conditions.

The results confirmed that being tall is linked to a higher risk for atrial fibrillation and varicose veins and a lower risk for coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk for peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.

The meta-analysis "identified five additional traits associated with genetically-predicted height," wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. "Two were genitourinary conditions--erectile dysfunction and urinary retention--that can be associated with neuropathy, and a third was a phecode for non-specific skin disorders that may be related to skin infections--consistent with the race/ethnicity stratified results."

F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Connecticut, who was not involved in the study, said that the findings were not particularly surprising overall, but it is striking that the researchers had "such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes." He also noted the study's strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person's measured height.

"This is key, since lots of things affect actual height; nutrition is an important one that could certainly be linked to disease as well," Dr Wilson said. "By using genetic height, the authors remove these potential confounders. Since genetic height is 'assigned' at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done."

The study relied on data from the US Veteran Affairs Million Veteran Program, with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants.

In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person's actual measured height. They also determined that including body mass index as a covariate had little effect on the results.

Genetically predicted height predicted a reduced risk for hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk for atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk for varicose veins in the legs and deep vein thrombosis.

Another novel association uncovered by the analysis was between women's genetically predicted height and both asthma and nonspecific peripheral nerve disorders. "Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women," the authors write. "In sum, our results suggest that an individual's height may warrant consideration as a non-modifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature."

"Genetic height is in your genes--there is nothing to be done about it--so it is more of academic interest than clinical interest," Dr Wilson said. It is not even clear whether incorporating a person's height (actual or genetically predicted, if it could be easily determined for each person) into risk calculators. "To know whether it would be beneficial to use height (or genetic height) as a risk factor, you'd need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction," Dr Wilson said For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant."

In contrast, the fact that height in general has any potential influence at all on disease risk may inspire members of the health care team to consider other risk factors in especially tall individuals.

"Physicians and members of the health care team may find it interesting that we have some confirmation that height does increase the risk of certain conditions," Dr Wilson said. "While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients."

The research was funded by the US Department of Veteran Affairs, the Boettcher Foundation's Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award.

Clinical Implications

• Height may be an underrecognized, nonmodifiable, biologically plausible risk factor for several common conditions in adults.
• The findings have implications for risk stratification and disease surveillance.
• Implications for the Health Care Team: Height is a risk factor that can be associated with cardiovascular disease traits: being tall was linked to higher risk for atrial fibrillation, varicose veins, and deep vein thrombosis and lower risk for coronary heart disease, hypertension, and hyperlipidemia, this associations can affect the care of common chronic diseases.

Earn Credit