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

Abstract

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.