Using Y chromosomal haplogroups in genetic association studies and suggested implications

Y chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits (including cardio-metabolic traits) have been reported. In apparently homogeneous populations, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing associations between autosomal SNPs and phenotypes will yield difference in association. For proof of concept, we derived Y-DNA haplogroups from 6,537 males from two epidemiological cohorts, ALSPAC (N=5,080, 816 Y-DNA SNPs) and 1958 Birth Cohort (N=1,457, 1,849 Y-DNA SNPs). For illustration, we studied well-known associations between 32 SNPs and body mass index (BMI), including associations involving FTO SNPs. Overall, no association was replicated in both cohorts when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little evidence of differences in phenotype or gene association by Y-DNA structure. Further studies using other traits, Phenome-wide association studies (PheWAS), haplogroups and/or autosomal SNPs are required to test the generalisability of this approach.