Beyond hormones: Geisinger researchers define X and Y chromosome contributions to height

DANVILLE, Pa. – A Geisinger study provides new insight into height differences between adult men and women, demonstrating that Y chromosome genes contribute more to height than their X chromosome counterparts, independent of male sex determination. The results were published this week in the Proceedings of the National Academy of Sciences.

Typical females have two X chromosomes, while typical males have one X and one Y chromosome. The differences between the X and Y chromosomes cause hormonal differences between males and females, but these differences have been insufficient to explain the average 13-centimeter (~5-inch) height difference between the sexes.

“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,” said Matthew Oetjens, Ph.D., assistant professor in Geisinger’s Department of Developmental Medicine and one of the study leads.

The Geisinger research team sought to determine the effects of sex-related factors on human height by examining height in people with an abnormal number of X or Y chromosomes, a genetic condition known as sex chromosome aneuploidy. 

The team analyzed genetic and clinical data on nearly one million participants enrolled in Geisinger’s MyCode Community Health Initiative, the National Institutes of Health’s All of Us cohort and the UK Biobank. Of these participants, 1,225 had a sex chromosome aneuploidy. By incorporating people with more or fewer than two sex chromosomes into a model of height, they found that exchanging an X for a Y chromosome increased height by 3.1 centimeters (1.25 inches) independent of other sex-related factors, including hormonal differences. This result suggests that an estimated 23% of the average difference in height between men and women is explained by increased expression of shared genes on the Y chromosome relative to the X chromosome.

“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,” said Alexander Berry, Ph.D., bioinformatics scientist and study co-lead.

SHOX, a gene found on both the X and Y chromosomes, is a known contributor to human height, but because two copies are found in both men and women, it has not been considered a likely contributor to the sex difference in height. However, recent studies have shown that SHOX is partially silenced on the second X chromosome in individuals with two or more X chromosomes. The Geisinger study’s results are consistent with the hypothesis that reduced SHOX expression in females results in a net difference in height between the sexes.

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