Why Does the X Chromosome Lag Behind Autosomes in GWAS Findings?

Authors

Ivan P Gorlov
Christopher I Amos

Publication Date

2-1-2023

Journal

PLoS Genetics

DOI

10.1371/journal.pgen.1010472

PMID

36848382

PMCID

PMC9997976

PubMedCentral® Posted Date

2-27-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Male, Female, Humans, Genome-Wide Association Study, X Chromosome, Polymorphism, Single Nucleotide

Abstract

The X-chromosome is among the largest human chromosomes. It differs from autosomes by a number of important features including hemizygosity in males, an almost complete inactivation of one copy in females, and unique patterns of recombination. We used data from the Catalog of Published Genome Wide Association Studies to compare densities of the GWAS-detected SNPs on the X-chromosome and autosomes. The density of GWAS-detected SNPs on the X-chromosome is 6-fold lower compared to the density of the GWAS-detected SNPs on autosomes. Differences between the X-chromosome and autosomes cannot be explained by differences in the overall SNP density, lower X-chromosome coverage by genotyping platforms or low call rate of X-chromosomal SNPs. Similar differences in the density of GWAS-detected SNPs were found in female-only GWASs (e.g. ovarian cancer GWASs). We hypothesized that the lower density of GWAS-detected SNPs on the X-chromosome compared to autosomes is not a result of a methodological bias, e.g. differences in coverage or call rates, but has a real underlying biological reason-a lower density of functional SNPs on the X-chromosome versus autosomes. This hypothesis is supported by the observation that (i) the overall SNP density of X-chromosome is lower compared to the SNP density on autosomes and that (ii) the density of genic SNPs on the X-chromosome is lower compared to autosomes while densities of intergenic SNPs are similar.

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