Alexander S. F. Berry, Brenda M. Finucane, Scott M. Myers, Christa L. Martin, David H. Ledbetter, Huntington F. Willard, and Matthew T. Oetjens

PNAS May 19 2025; 122 (22) e2503039122; https://doi.org/10.1073/pnas.2503039122

Significance

Human stature is one of many physical phenotypes that vary between the sexes. On average, adult males are taller than females. However, the underlying biological mechanisms that explain this dimorphism are not entirely understood. Here, we compared heights in three large population-based cohorts that included 1,225 adults with sex chromosome aneuploidies (SCAs). Having an extra Y chromosome conferred a larger increase in height than that observed with an additional X chromosome, independent of male hormonal effects. We conclude that differential expression of height-related pseudoautosomal genes on the X and Y chromosomes contributes to sexual dimorphism for stature. Beyond height, future SCA research may elucidate mechanisms underlying observed sex differences in the prevalence of autoimmune, neuropsychiatric, and other medical disorders.

Abstract

Many human phenotypic traits vary between the sexes, including adult height for which males are, on average, 13 cm taller than females. The biological mechanisms for this sexual dimorphism are not entirely understood. One hypothesis to explain the sexual dimorphism in height relates to differential expression in males and females of SHOX, a height-related gene in the pseudoautosomal region 1 (PAR1) on the X and Y sex chromosomes. SHOX expression is reduced on the inactive X chromosome (Xi), compared to the active X in females. Sex chromosome aneuploidies (SCAs), characterized by an atypical number of X and/or Y chromosomes, serve as informative models for investigating PAR1-related gene dosage effects. Here, we leveraged three large biobanks to study 928,605 individuals, including 1,225 adults with SCAs: 45,X (n = 95), 47,XXY (n = 505), 47,XYY (n = 290), and 47,XXX (n = 335). By modeling height across individuals with various sex chromosome complements, we quantified the contributions of five sex-related genomic contributors to height, including Xi chromosome dosage, Y chromosome dosage, male sex hormones, and effects of Klinefelter and Turner syndromes. We found that a unit increase in Y chromosome dosage confers 3.1cm (95% CI, 1.9 to 4.3) more to height than a unit increase in Xi chromosome dosage, independent of hormonal variables. The larger increase in height conferred by the Y chromosome explained 22.6% of the observed difference in height between 46,XY males and 46,XX females. This finding is consistent with the hypothesis that reduced SHOX expression in females results in a net difference in height between the sexes.

See: https://www.pnas.org/doi/10.1073/pnas.2503039122

Figure 1

Height distribution by sex chromosome complement across cohorts. Mean heights of each sex chromosome complement are shown and indicated with dotted vertical lines. Analyses of 45,X height were not performed for the All of Us cohort because data cannot be reported for groups containing fewer than 20 individuals.