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The effect of X-linked dosage compensation on complex trait variation

By Julia Sidorenko, Irfahan Kassam, Kathryn Kemper, Jian Zeng, Luke Lloyd-Jones, Grant W. Montgomery, Greg Gibson, Andres Metspalu, Tonu Esko, Jian Yang, Allan F. McRae, Peter M. Visscher

Posted 03 Oct 2018
bioRxiv DOI: 10.1101/433870 (published DOI: 10.1038/s41467-019-10598-y)

Quantitative genetics theory predicts that X-chromosome dosage compensation between sexes will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of dosage compensation in complex trait variation in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and in 1,600 gene expression traits from a sample of 2,000 individuals as well as across-tissue gene expression from the GTEx resource. We find, on average, twice as much genetic variation for complex traits due to X-linked loci in males compared to females, consistent with a negligible effect of predicted escape from X-inactivation on complex trait variation across traits and also detect biologically relevant X-linked heterogeneity between the sexes for a number of complex traits.

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