Geisinger Scientists Uncover Genetic Basis for Sex-Based Height Variation

A study by Geisinger examined the genetic basis of height differences between adult males and females. It found that Y chromosome genes contribute more to height than their X chromosome counterparts, regardless of male sex. The study was published in Proceedings of the National Academy of Sciences.

Males typically have one X and one Y chromosome, while females usually have two X chromosomes. On average, adult males are about 13 centimeters (approximately 5 inches) taller than adult females. This height difference cannot be fully explained by differences in sex hormones alone, suggesting that genetic factors linked to the X and Y chromosomes also play a role.

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.

Matthew Oetjens, Ph.D., Assistant Professor and Study Lead, Department of Developmental Medicine, Geisinger Health System

The Geisinger research team investigated the influence of sex-related genetic factors on human height by studying individuals with an atypical number of X or Y chromosomes, a genetic condition referred to as sex chromosome aneuploidy.

They analyzed clinical and genetic data from nearly one million participants in the UK Biobank, the National Institutes of Health’s All of Us cohort, and Geisinger’s MyCode Community Health Initiative. Of these, approximately 1,225 individuals had an aneuploidy involving one of the sex chromosomes.

By including individuals with more or fewer than two sex chromosomes in a height model, the researchers found that replacing an X chromosome with a Y chromosome increased height by an average of 3.1 cm (1.25 inches), independent of other sex-related factors such as hormonal differences.

The results suggest that increased expression of certain genes on the Y chromosome, compared to those on the X chromosome, accounts for approximately 23 % of the average height difference between males and females.

Beyond its implications for understanding human height, this study provides broader insights into how sex chromosome aneuploidy research can uncover the mechanisms behind observed sex differences in various medical conditions.

Alexander Berry, Ph.D., Bioinformatics Scientist and Study Co-Lead, Geisinger Health System

SHOX, a gene found on both the X and Y chromosomes, is known to influence human height. However, because both males and females typically have two copies of this gene, it has not been considered a major contributor to the height difference between the sexes.

Recent research suggests that SHOX is partially silenced on the second X chromosome in individuals with two or more X chromosomes. The findings from the Geisinger study support the idea that reduced SHOX expression in females contributes to the observed height difference between males and females.