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Scientists have identified a key genetic factor that helps explain why men are typically five inches taller than women. This difference is attributed to a gene called SHOX that operates differently between the sexes due to variations in chromosome structure.
A new study, published on May 19 in the Proceedings of the National Academy of Sciences, analyzed genetic data from nearly one million people across three large biobanks in the U.S. and the UK. Researchers found the SHOX gene accounts for approximately one-quarter—or 25%—of the average height difference between men and women.
The research team, led by Matthew Oetjens, assistant professor in Geisinger's Department of Developmental Medicine, focused on individuals with abnormal numbers of sex chromosomes to understand how gene dosage affects height. Men typically average about 13 centimeters (five inches) taller than women globally, but the biological mechanisms behind this sexual dimorphism have remained poorly understood.
"Because height shows a large and reproducible difference between sexes and is widely measured, it serves as a valuable model for investigating the genomic factors underlying sex differences," Oetjens told The New York Times.
The SHOX gene, short for short stature homeobox, is located on both X and Y chromosomes in a region called the pseudoautosomal region. Unlike most genes that are unique to either the X or Y chromosome, genes in this region are present on both chromosomes, meaning both males and females normally have two functional copies.
In women, one of the two X chromosomes undergoes a process called X-inactivation, where most genes on that chromosome are silenced to prevent complications from having duplicate genetic material. However, the SHOX gene is located near the tip of the X chromosome in a region where some genes escape this silencing process, though not completely. This partial escape results in reduced SHOX gene activity in women compared to men.
Men have one fully active SHOX gene on their X chromosome and another fully active copy on their Y chromosome. This gives males a higher overall dose of SHOX gene expression, which researchers determined contributes to increased height.
The study examined people with rare conditions involving extra or missing sex chromosomes, which provided researchers a unique opportunity to assess how additional copies of the SHOX gene affect height. They discovered individuals with an extra Y chromosome were taller than those with an extra X chromosome, demonstrating that the SHOX gene has a stronger effect when located on the Y chromosome.
By incorporating data from people with abnormal numbers of sex chromosomes into their height model, researchers determined exchanging an X chromosome for a Y chromosome increases height by 3.1 centimeters independent of other sex-related factors, including hormonal differences. This suggests approximately 23% of the average height difference between men and women results from increased expression of shared genes on the Y chromosome relative to the X chromosome.
Eric Schadt, a genetics expert at Mount Sinai in New York City, called the findings "definitely cool." He noted that while the gene effect is modest, it explains about 20% of the height difference between sexes. "It is a great use of these biobanks to uncover what is still somewhat of a mystery," Schadt said.
The SHOX gene produces a protein that regulates the activity of other genes and plays an essential role in skeletal development, particularly affecting the growth and maturation of bones in the arms and legs. The gene belongs to a family of homeobox genes that control the formation of body structures during early embryonic development.
Mutations or deletions in the SHOX gene can cause various growth disorders, including Leri-Weill dyschondrosteosis and idiopathic short stature. The gene's importance in height regulation has been recognized since its discovery during research into short stature in women with Turner syndrome, a condition where genetic material from the X chromosome is missing.
The remaining three-quarters of the height difference between men and women likely stems from other genetic factors and male sex hormones, Oetjens noted. The research team analyzed data from Geisinger's MyCode Community Health Initiative, the National Institutes of Health's All of Us cohort, and the UK Biobank, identifying 1,225 participants with sex chromosome aneuploidies among the nearly one million participants in total.
While the SHOX gene does not fully explain why men are taller than women, it provides important insight into the complex genetic mechanisms underlying human growth patterns. The remaining height difference is attributed to testosterone and other male sex hormones, along with additional genetic and environmental factors.
