Researchers at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, have carried out the largest-scale genome-wide investigation to date of the X chromosome, a chromosome often neglected in genetic studies. By combining data from over 340,00 UK Biobank participants with over 410,000 FinnGen participants, the team examined 48 quantitative traits ranging from body measurements, such as height and blood pressure, to blood biomarkers.
The results of the study, demonstrating the importance of including X-chromosome in all genetic analyses, were published in the American Journal of Human Genetics on 12 May, 2025.
Their analysis demonstrates that, on average, X-linked variants explain about 3% of the heritability of complex traits. This figure is almost exactly what would be expected from the chromosome’s share of common genetic variation in the human genome.
In mammals, including humans, males carry only one copy of the X, and females effectively do the same because one copy is shut down in each cell to keep the dose the same as in males. This phenomenon is called X-chromosome inactivation (XCI) and is expected to result in a pronounced male bias in X-linked heritability, which has been observed in this study for most traits. However, a sizable number of genes escape inactivation in females — a phenomenon shown in this study to be reflected in height genetics and may contribute to sex differences in height.
Yet dosage compensation does not end there: compared with equivalent variants on the autosomes, the study demonstrated that active alleles on the X exert effects that are about 1.6-times larger, providing a chromosome-wide “boost” that partially makes up for having only one active copy in every cell.
“Our results showed that genetic data can reflect both facets of dosage compensation, which until now were mainly explored through gene-expression studies,” says first author Yu Fu, a doctoral researcher at FIMM.
“Interestingly, we find that the mechanisms act together so that sex differences in how the X chromosome contributes to complex trait variation remain but are confined to a manageable range.”
Senior author Taru Tukiainen, a former FIMM Group Leader, adds:
“By finally putting the X chromosome on equal footing with the rest of the genome, we expose a richer landscape of human genetics. Our findings make a strong case for including the X chromosome in genome-wide studies. Doing so will not only sharpen our view of disease biology but also elaborate on the role of the sex chromosome complement in shaping sex differences.”
Original publication:
Role of X chromosome and dosage-compensation mechanisms in complex trait genetics, The American Journal of Human Genetics, DOI: 10.1016/j.ajhg.2025.04.004