Role of X chromosome and dosage-compensation mechanisms in complex trait genetics.

The X chromosome (chrX) is often excluded from genome-wide association studies due to its unique biology complicating the analysis and interpretation of genetic data. Consequently, the influence of chrX on human complex traits remains debated. Here, we systematically assessed the relevance of chrX and the effect of its biology on complex traits by analyzing 48 quantitative traits in 343,695 individuals in UK Biobank with replication in 412,181 individuals from FinnGen. We show that, in the general population, chrX contributes to complex trait heritability at a rate of 3% of the autosomal heritability, consistent with the amount of genetic variation observed in chrX. We find that a pronounced male bias in chrX heritability supports the presence of near-complete dosage compensation between sexes through X chromosome inactivation (XCI). However, we also find subtle yet plausible evidence of escape from XCI contributing to human height. Assuming full XCI, the observed chrX contribution to complex trait heritability in both sexes is greater than expected given the presence of only a single active copy of chrX, mirroring potential dosage compensation between chrX and the autosomes. We find this enhanced contribution attributable to systematically larger active allele effects from chrX compared to autosomes in both sexes, independent of allele frequency and variant deleteriousness. Together, these findings support a model in which the two dosage-compensation mechanisms work in concert to balance the influence of chrX across the population while preserving sex-specific differences at a manageable level. Overall, our study advocates for more comprehensive locus discovery efforts in chrX.