Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

Yajie Zhao; Eugene J. Gardner; Marcus A Tuke; Huairen Zhang; Maik  Pietzner; Mine Koprulu; Raina Y. Jia; Katherine S Ruth; Andrew R Wood; Robin N Beaumont; Jessica Tyrrell; Samuel E Jones; Hana Lango Allen; Felix R Day; Claudia Langenberg; Timothy Frayling; Michael N Weedon; John R.B. Perry; Ken K Ong; Anna Murray

doi:10.1016/j.gim.2022.05.011

Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

Yajie Zhao, Eugene J. Gardner, Marcus A Tuke, Huairen Zhang, Maik Pietzner, Mine Koprulu, Raina Y. Jia , Katherine S Ruth, Andrew R Wood, Robin N Beaumont, Jessica Tyrrell, Samuel E Jones, Hana Lango Allen, Felix R Day, Claudia Langenberg, Timothy Frayling, Michael N Weedon, John R.B. Perry, Ken K Ong^*, Anna Murray^*

^*Corresponding author for this work

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

31 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1909-1919
Journal	Genetics in Medicine
Volume	24
Issue number	9
Early online date	9 Jun 2022
DOIs	https://doi.org/10.1016/j.gim.2022.05.011
Publication status	Published - 2 Sept 2022

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

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Zhao, Y., Gardner, E. J., Tuke, M. A., Zhang, H., Pietzner, M., Koprulu, M., Jia , R. Y., Ruth, K. S., Wood, A. R., Beaumont, R. N., Tyrrell, J., Jones, S. E., Lango Allen, H., Day, F. R., Langenberg, C., Frayling, T., Weedon, M. N., Perry, J. R. B., Ong, K. K., & Murray, A. (2022). Detection and characterization of male sex chromosome abnormalities in the UK Biobank study. Genetics in Medicine, 24(9), 1909-1919. https://doi.org/10.1016/j.gim.2022.05.011

@article{079760983882428b9d986b5ba125813b,

title = "Detection and characterization of male sex chromosome abnormalities in the UK Biobank study",

abstract = "PurposeThe 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.MethodsWe 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.ResultsOnly 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).ConclusionKS 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.",

author = "Yajie Zhao and Gardner, {Eugene J.} and Tuke, {Marcus A} and Huairen Zhang and Maik Pietzner and Mine Koprulu and Jia, {Raina Y.} and Ruth, {Katherine S} and Wood, {Andrew R} and Beaumont, {Robin N} and Jessica Tyrrell and Jones, {Samuel E} and {Lango Allen}, Hana and Day, {Felix R} and Claudia Langenberg and Timothy Frayling and Weedon, {Michael N} and Perry, {John R.B.} and Ong, {Ken K} and Anna Murray",

year = "2022",

month = sep,

day = "2",

doi = "10.1016/j.gim.2022.05.011",

language = "English",

volume = "24",

pages = "1909--1919",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "9",

}

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, T, Weedon, MN, Perry, JRB, Ong, KK & Murray, A 2022, 'Detection and characterization of male sex chromosome abnormalities in the UK Biobank study', Genetics in Medicine, vol. 24, no. 9, pp. 1909-1919. https://doi.org/10.1016/j.gim.2022.05.011

TY - JOUR

T1 - Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

AU - Zhao, Yajie

AU - Gardner, Eugene J.

AU - Tuke, Marcus A

AU - Zhang, Huairen

AU - Pietzner, Maik

AU - Koprulu, Mine

AU - Jia , Raina Y.

AU - Ruth, Katherine S

AU - Wood, Andrew R

AU - Beaumont, Robin N

AU - Tyrrell, Jessica

AU - Jones, Samuel E

AU - Lango Allen, Hana

AU - Day, Felix R

AU - Langenberg, Claudia

AU - Frayling, Timothy

AU - Weedon, Michael N

AU - Perry, John R.B.

AU - Ong, Ken K

AU - Murray, Anna

PY - 2022/9/2

Y1 - 2022/9/2

N2 - PurposeThe 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.MethodsWe 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.ResultsOnly 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).ConclusionKS 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.

AB - PurposeThe 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.MethodsWe 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.ResultsOnly 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).ConclusionKS 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.

U2 - 10.1016/j.gim.2022.05.011

DO - 10.1016/j.gim.2022.05.011

M3 - Article (Academic Journal)

C2 - 35687092

SN - 1098-3600

VL - 24

SP - 1909

EP - 1919

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 9

ER -

Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

Cite this