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Limited Effect of Y Chromosome Variation on Coronary Artery Disease and Mortality in UK Biobank—Brief Report


The effect of genetic variation in the male-specific region of the Y chromosome (MSY) on coronary artery disease and cardiovascular risk factors has been disputed. In this study, we systematically assessed the association of MSY genetic variation on these traits using a kin-cohort analysis of family disease history in the largest sample to date.

We tested 90 MSY haplogroups against coronary artery disease, hypertension, blood pressure, classical lipid levels, and all-cause mortality in up to 152 186 unrelated, genomically British individuals from UK Biobank. Unlike previous studies, we did not adjust for heritable lifestyle factors (to avoid collider bias) and instead adjusted for geographic variables and socioeconomic deprivation, given the link between MSY haplogroups and geography. For family history traits, subject MSY haplogroups were tested against father and mother disease as validation and negative control, respectively.

Our models find little evidence for an effect of any MSY haplogroup on cardiovascular risk in participants. Parental models confirm these findings.

Kin-cohort analysis of the Y chromosome uniquely allows for discoveries in subjects to be validated using family history data. Despite our large sample size, improved models, and parental validation, there is little evidence to suggest cardiovascular risk in UK Biobank is influenced by genetic variation in MSY.
N=223513 . Robust!

Identification of Y Haplogroups
"Phylogenetic analysis was performed on all male-inferred UK Biobank participants (N=223 513) using yhaplo v1.1.2.23 Among the 13 569 reference SNPs (single nucleotide polymorphisms) provided by yhaplo, 232 were genotyped on both UK Biobank arrays. SNPs with a call rate of <95% (n=39) and monomorphic SNPs (n=27) were removed, leaving 166 SNPs for haplogroup inference. Eighty-nine haplogroups were reported directly by yhaplo, and a further 38 were defined through combinations of derived groups to increase statistical power of rarer haplogroups and to detect effects arising from deeper nodes in the Y chromosome genealogy (Table S1)." (...)

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