Sex-related variations in medical phenotypes like autism spectrum disorder and autoimmune conditions are complex and need a structured framework to understand their underlying causes. Height is a well-suited model to investigate the genomic basis of sex differences, as it is a normally distributed trait in the general population. On average, adult males are approximately 13 cm taller than females, but the molecular mechanisms of this sexual dimorphism are not fully understood this sexual dimorphism.
Human sex chromosomes, specifically the SHOX gene located in the pseudoautosomal region (PAR1), are known to influence height. Transcription of the SHOX gene and other PAR1 genes is decreased on the inactive X chromosomes (Xi) compared to the active X. It indicated that a reduction in SHOX expression on the Xi chromosome, in contrast to the Y chromosome, may be a critical factor contributing to sex-related differences in height.
This study uses a large population-based dataset to investigate the adult height dimorphism in individuals with both atypical and typical sex chromosome complements. Individuals with sex chromosome aneuploidies (SCAs) serve as valuable models for studying the genetic and hormonal contributors to height variation. The analysis compared the height of people with a range of sex chromosome complements from 3 large biobanks, to assess the effect of sex hormone dosage on height, independent of male sex hormone exposure. The dataset included 928,605 individuals of whom 1225 had SCAs: 47, XYY (n = 290), 47, XXY (n = 505), 47, XXX (n = 335) and 45, X (n = 95).
Participants were drawn from Geisinger’s MyCode Community Health Initiative, NIH’s All of Us (version 7) cohort, and the UK Biobank. The genetic ancestry was determined by using a principal component analysis (PCA) of genotype data and divided into European (EUR), Ad Mixed American (AMR), African (AFR), South Asian (SAS), and East Asian (EAS) groups based on the 1000 Genomes Project classification. Â
The study was limited to adults aged 18 years or older with documented height data and high-quality genotyping arrays. SCAs were identified based on log R ratios (LRR) of the genotype probes from X and Y chromosomes. Sex chromosome complement was analysed using the LRRy: LRRx ratio compared against defined thresholds. Chromosomal sex was analysed based on the absence (female) or presence (male) of the Y chromosome.
Height phenotypes were examined between sex chromosome complements by using electronic health record (EHR)-derived height data. Participants were grouped by sex chromosome complement, and the individual contributions of each sex-related genomic component to height were assessed. A linear regression model was used to estimate the height differences while adjusting for age and the first 10 major components of ancestry. Cross-cohort meta-analyses were used for comparisons involving at least two cohorts.
The study examined the link between height and sex chromosome complement in adults across ancestry groups. In both EUR and AFR cohorts, individuals with a 46, XY complement were, on average, 13.72 cm taller than those with a 46, XX complement. Notably, the presence of an extra Y chromosome had a greater impact on height than an extra X chromosome.
This study found that there are 5 sex-related genetic factors to height, which include Y chromosome dosage, Xi chromosome dosage, effects of Turner (45, X) and Klinefelter (47, XXY) syndromes, and male sex hormones. A unit increase in the Y chromosome dose contributed to an average increase of 3.1 cm (95 % Confidence interval [CI] 1.9 to 4.3), which was greater than a unit increase in the Xi chromosome dosage.
The larger contribution of the Y chromosome accounted for 22.6% of the observed height difference between 46, XY males and 46, XX females. These findings support the hypothesis that reduced SHOX expression on the Xi chromosome contributes to the sex-based height differences.
Reference: Berry ASF, Finucane BM, Myers SM, et al. X and Y gene dosage effects are primary contributors to human sexual dimorphism: The case of height. Proc Natl Acad Sci U S A. 2025;122(22):e2503039122. doi:10.1073/pnas.2503039122
