Y chromosome variation and complex traits: the Ygen consortium

The genetics of complex traits have been studied in great detail using Genome-Wide Association Studies (GWAS), leading to substantive insights regarding the genetic determinants of quantitative traits and disease mechanisms. However, there remain significant parts of the genome which are not routinely assayed in GWA studies, the largest of which is the Y Chromosome. Only carried by men and constitutively haploid, the Y Chromosome totals about 25 Mb of sequenceable DNA containing 27 genes or gene families, including genes known to be implicated in Mendelian conditions such as infertility and deafness. Nevertheless, the Y Chromosome has been almost completed neglected in the context of complex traits and diseases, until a recent study that associated Y Chromosome variants and risk of coronary artery disease. Here we present Ygen, an international consortium that gathers together a large number of collaborating population-based cohorts. Ygen allows us to investigate the role of the Y chromosome in complex traits for the first time in an adequately powered setting. In the project more than 30 diverse traits of public health or evolutionary interest are considered, including anthropometric measures, haematological counts, cardiovascular risk factors, metabolic markers, inflammatory response and fertility. The study uses 70 SNPs included in the Illumina HumanExome Beadchip that were specifically designed to represent Y Chromosome diversity across the world. Genotypes are used to define haplogroups which in turn provide information on Y Chromosome lineages, thus increasing the number of SNPs tested. These are analysed using a single-SNP association approach and results combined in a meta-analysis. We will present results of the ongoing study which already includes more than 10,000 men. This will include an overview of quality control, focusing on genealogical consistency and SNP performance in haplogroup estimation, and the results of the association study.