The Challenges of Chromosome Y Analysis and the Implications for Chronic Kidney Disease

Abstract

The role of chromosome Y in chronic kidney disease (CKD) remains unknown, as chromosome Y is typically excluded from genetic analysis in CKD. The complex, sex-specific presentation of CKD could be influenced by chromosome Y genetic variation, but there is limited published research available to confirm or reject this hypothesis. Although traditionally thought to be associated with male-specific disease, evidence linking chromosome Y genetic variation to common complex disorders highlights a potential gap in CKD research. Chromosome Y variation has been associated with cardiovascular disease, a condition closely linked to CKD and one with a very similar sexual dimorphism. Relatively few sources of genetic variation in chromosome Y have been examined in CKD. The association between chromosome Y aneuploidy and CKD has never been explored comprehensively, while analyses of microdeletions, copy number variation, and single-nucleotide polymorphisms in CKD have been largely limited to the autosomes or chromosome X. In many studies, it is unclear whether the analyses excluded chromosome Y or simply did not report negative results. Lack of imputation, poor cross-study comparability, and requirement for separate or additional analyses in comparison with autosomal chromosomes means that chromosome Y is under-investigated in the context of CKD. Limitations in genotyping arrays could be overcome through use of whole-chromosome sequencing of chromosome Y that may allow analysis of many different types of genetic variation across the chromosome to determine if chromosome Y genetic variation is associated with CKD.

Keywords: LOY; chromosome Y; chronic kidney disease; genome-wide association; genotyping arrays; haplogroup; imputation; microdeletion.

Figure 1

Comparison of whole-genome (top) and chromosome Y (bottom) SNPs between different commonly used genotyping platforms. Dark grey-shaded boxes indicate the total number of either whole-genome or chromosome Y SNPs present on each array. The percentages that chromosome Y SNPs make up of their respective arrays are shown in brackets in the dark grey-shaded boxes. The light grey-shaded box is the percentage chromosome Y SNPs in the entire genome, for comparison. Pink-shaded boxes show the number of SNPs common between all arrays for either whole genome (top) or chromosome Y SNPs (bottom). The Affymetrix 500K array has been excluded from the chromosome Y section (bottom), as it contains zero chromosome Y SNPs.

Figure 2

Positions of chromosome Y SNPs on each array in relation to chromosome Y genes from the UCSC database (Kent et al., 2002). “Combined” track contains all SNPs from the six individual array tracks (n SNPs = 4344). Chromosome Y SNPs from the pseudoautosomal regions are not included here, explaining the lack of gene coverage at the start and the end of the chromosome.