Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.01.16.633321

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

Fu, Y.·Kenttamies, A.·Ruotsalainen, S. E.·Pirinen, M.·Tukiainen, T.
View original source ↗Export metadata ↓

Abstract

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 to 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 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 where the two dosage compensation mechanisms work in concert to balance the influence of the 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.

Source connections

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Fu, Y., Kenttamies, A., Ruotsalainen, S. E., Pirinen, M., Tukiainen, T.. 2025-01-17. Role of X chromosome and dosage compensation mechanisms in complex trait genetics. https://doi.org/10.1101/2025.01.16.633321

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Large language model-based bibliometric evaluation of population descriptors in human genetics

As the use of population descriptors such as race, ethnicity, and ancestry have become increasingly common in modern genetics research, there have been growing calls to critically examine their use. Most notably, in 2023, the National Academies of Science, Engineering, and Medicine (NASEM) published a report titled Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field, which included eight specific and actionable recommendations for researchers to implement the ethical and accurate use of population descriptors in genetic research. Here, we use the 2023 NASEM report as a benchmark to analyze the use of population descriptors in genome-wide association studies (GWAS). We develop a general toolkit for large language model-based bibliometrics, operationalize the report's recommendations into an evaluation framework, and apply this framework to evaluate all 4,007 papers from the GWAS Catalog published between 2007 and 2025 with full text available on PubMedCentral. We find significant improvements in adherence to NASEM report recommendations over time. However, most improvements predate the publication of the NASEM report itself, suggesting the report functioned primarily as a synthesis of existing best practices rather than a catalyst for change. We conclude by highlighting opportunities for growth in the field of human genetics.

genetics↗
bioRxiv2026

Mitigating biases of rescaling in forward-in-time population genetic simulations

Forward-in-time population genetic simulations are widely used in evolutionary analyses, but simulating large populations and long genomic regions remains computationally demanding. To reduce this cost, parameter rescaling is widely employed, in which the original evolutionary process is approximated by one with a smaller population size and fewer generations. Recently, several studies using the SLiM simulator have raised concerns about the accuracy of this rescaling approach. In this study, we show that many of the biases reported in these studies can be mitigated by using a different simulation algorithm. These results reveal that the accuracy of parameter rescaling depends on how well the simulation algorithm preserves diffusion-limit properties under rescaling.

genetics↗
bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗