Detection and characterization of male sex chromosome abnormalities in the UK Biobank study
PURPOSE: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. METHODS: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. RESULTS: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 × 10-8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10-6). CONCLUSION: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. ; Y.Z., E.J.G., M.P., M.K., R.Y.J., H.L.A., F.R.D., C.L., J.R.B.P. and K.K.O. are supported by the Medical Research Council (Unit programs: MC_UU_00006/1 and MC_UU_00006/2). M.K. is supported by a Gates Fellowship. A.R.W. and J.T. hold Academy of Medical Sciences (AMS) Springboard awards [SBF004\1079 and SBF006\1134], which are supported by the AMS, the Wellcome Trust, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK. R.N.B. and A.M. are supported by the Medical Research Council (MR/T00200X/1). K.S.R. is supported by Cancer Research ...