Major sex differences in allele frequencies for X chromosomal variants in both the 1000 Genomes Project and gnomAD

Author summaryThe human X chromosome contains over 800 genes and is the 8(th) largest human chromosome. Genome-wide associations studies have generally failed to examine variants on the X chromosome for association with diseases and traits, partly due to complexities of the data analysis, and challenges with genotype imputation. We examined X chromosomal variants from the 1000 Genomes Project for sex differences in allele frequency and found that many variants showed significant differences. These variants cluster at the centromeric parts of the pseudoautosomal regions 1 and 2, as well as the putative pseudo-autosomal region 3 (also termed X-transposed region). This pattern was observed in high coverage whole genome sequence data from the same subjects that was aligned to GRCh38, suggesting that is not an artefact of low coverage sequencing or problems specific to GRCh37. In addition, we replicated this phenomenon in high coverage whole genome sequence aligned to GRCh38 from the gnomAD database in both the non-Finnish European and African/African American samples. These findings have implications for the analysis of X chromosomal variants for disease and trait associations. An unexpectedly high proportion of SNPs on the X chromosome in the 1000 Genomes Project phase 3 data were identified with significant sex differences in minor allele frequencies (sdMAF). sdMAF persisted for many of these SNPs in the recently released high coverage whole genome sequence of the 1000 Genomes Project that was aligned to GRCh38, and it was consistent between the five super-populations. Among the 245,825 common (MAF>5%) biallelic X-chromosomal SNPs in the phase 3 data presumed to be of high quality, 2,039 have genome-wide significant sdMAF (p-value <5e-8). sdMAF varied by location: non-pseudo-autosomal region (NPR) = 0.83%, pseudo-autosomal regions (PAR1) = 0.29%, PAR2 = 13.1%, and X-transposed region (XTR)/PAR3 = 0.85% of SNPs had sdMAF, and they were clustered at the NPR-PAR boundaries, among others. sdMAF at the NPR-PAR boundaries are biologically expected due to sex-linkage, but have generally been ignored in association studies. For comparison, similar analyses found only 6, 1 and 0 SNPs with significant sdMAF on chromosomes 1, 7 and 22, respectively. Similar sdMAF results for the X chromosome were obtained from the high coverage whole genome sequence data from gnomAD V 3.1.2 for both the non-Finnish European and African/African American samples. Future X chromosome analyses need to take sdMAF into account.

Automated summary

This study found significant sex differences in genetic variations on the X chromosome, which has important implications for disease and trait associations. Variations in pseudoautosomal regions and X-transposed regions showed larger differences compared to non-pseudoautosomal regions. These findings need to be taken into account in X chromosome analyses.