Detection and characterization of male sex chromosome abnormalities in the UK Biobank study.
Genetics in medicine : official journal of the American College of Medical Genetics 2022
Zhao Y, Gardner EJ, Tuke MA, Zhang H, Pietzner M, Koprulu M, Jia RY, Ruth KS, Wood AR, Beaumont RN, Tyrrell J, Jones SE, Lango Allen H, Day FR, Langenberg C, Frayling TM, Weedon MN, Perry JRB, Ong KK, Murray A
PubMed ID : 35687092
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.
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.
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), 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).
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.
Sex chromosomes determine our biological sex. Men have one X and one Y chromosome (XY), and women have two X’s (XX). However, some men also have an extra X or Y chromosome (XXY or XYY) - this is typically picked up on investigations of men with delayed puberty and infertility. New research now shows that having an extra X or Y chromosome also increases risks for several other diseases, including Type 2 diabetes and thrombosis. However, most men with XXY or XYY are unaware that they have this condition.
Researchers from the Universities of Cambridge and Exeter analysed genetic data collected on over 200K UK men aged 40-70. They identified 213 men with an extra X chromosome (XXY) and 143 men with an extra Y chromosome (XYY). Remarkably, only 23% of men with XXY and only 1% with XYY reported knowing they had a diagnosis of abnormal chromosomes.
By linking genetic data to routine health records, they found that men with XXY have substantially higher chances of reproductive problems, including a 3-fold higher risk of delayed puberty and 4-fold higher risk to be childless, as well as significantly lower blood concentrations of the natural male hormone, testosterone. Although men with XYY appeared to have a normal reproductive function, men with either XXY or XYY had higher risks of several other health conditions, including a 3-fold higher risk of Type 2 diabetes, 6-fold higher risk of venous thrombosis, 3-fold higher risk of pulmonary embolism, and 4-fold higher risk of chronic obstructive pulmonary disease.
“Men with extra sex chromosomes were mostly unaware of this but as a result they have substantially higher risks of metabolic, vascular, and respiratory diseases, which may be preventable.
It might be helpful if XXY and XYY were more widely tested for in men who present to their doctor with a relevant health concern. Future studies could also assess the possible value of wider screening for unusual chromosomes in the general population so that early interventions can be started to avoid the related diseases”.
Their paper, Detection and characterisation of male sex chromosome abnormalities in the UK Biobank study, was published in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG). MRC Epidemiology Unit PhD student, Yajie Zhao, is the first author. Prof Ken Ong from the University of Cambridge and Dr Anna Murray from the University of Exeter are the senior authors.