Dataset Information

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects.

ABSTRACT: Purpose:The purpose of this study was to identify genetic variants on chromosome X associated with intraocular pressure (IOP) and determine if they possess any sex-specific effects. Methods:Association analyses were performed across chromosome X using 102,407 participants from the UK Biobank. Replication and validation analyses were conducted in an additional 6599 participants from the EPIC-Norfolk cohort, and an independent 331,682 participants from the UK Biobank. Results:We identified three loci associated with IOP at genomewide significance (P < 5 × 10-8), located within or near the following genes: MXRA5 (rs2107482, P = 7.1 × 10-11), GPM6B (rs66819623, P = 6.9 × 10-10), NDP, and EFHC2 (rs12558081, P = 4.9 × 10-11). Alleles associated with increased IOP were also associated with increased risk for primary open-angle glaucoma in an independent sample. Finally, our results indicate that chromosome X genetics most likely do not illicit sex-specific effects on IOP. Conclusions:In this study, we report the results of genomewide levels of association of three loci on chromosome X with IOP, and provide a framework to include chromosome X in large-scale genomewide association analyses for complex phenotypes.

SUBMITTER: Simcoe MJ

PROVIDER: S-EPMC7490223 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects.

Simcoe Mark J MJ Khawaja Anthony P AP Mahroo Omar A OA Hammond Christopher J CJ Hysi Pirro G PG

Investigative ophthalmology & visual science 20200901 11

<h4>Purpose</h4>The purpose of this study was to identify genetic variants on chromosome X associated with intraocular pressure (IOP) and determine if they possess any sex-specific effects.<h4>Methods</h4>Association analyses were performed across chromosome X using 102,407 participants from the UK Biobank. Replication and validation analyses were conducted in an additional 6599 participants from the EPIC-Norfolk cohort, and an independent 331,682 participants from the UK Biobank.<h4>Results</h4 ...[more]

PMID: 32926103

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Project description:The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change.

Dataset Information

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects.

Publications

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects.

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