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The genetics of testosterone contributes to “femaleness/maleness” of cardiometabolic traits and type 2 diabetes

Abstract

The genetic architecture of testosterone is highly distinct between sexes. Moreover, obesity is associated with higher testosterone in females but lower testosterone in males. Here, we ask whether male-specific testosterone variants are associated with a male pattern of obesity and type 2 diabetes (T2D) in females, and vice versa. In the UK Biobank, we conducted sex-specific genome-wide association studies and computed polygenic scores for total (PGSTT) and bioavailable testosterone (PGSBT). We tested sex-congruent and sex-incongruent associations between sex-specific PGSTs and metabolic traits, as well as T2D diagnosis. Female-specific PGSBT was associated with an elevated cardiometabolic risk and probability of T2D, in both sexes. Male-specific PGSTT was associated with traits conferring a lower cardiometabolic risk and probability of T2D, in both sexes. We demonstrate the value in considering polygenic testosterone as sex-related continuous traits, in each sex.

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Fig. 1: Testosterone polygenic scores and cardiometabolic traits.

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Acknowledgements

This research has been funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Foundation for Innovation, and National Institutes for Health. The research has been conducted using the UK Biobank Resource under Application Number 43688. The corresponding author, Dr. Tomáš Paus, is the guarantor.

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DEV contributed to the project conception, analyses, figure, and manuscript writing and revision. NP and JS contributed to the analyses and manuscript revision. ZP and TP contributed to the project conception and manuscript writing and revision. All authors approved the final version and are accountable for the work.

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Correspondence to Tomáš Paus.

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Vosberg, D.E., Parker, N., Shin, J. et al. The genetics of testosterone contributes to “femaleness/maleness” of cardiometabolic traits and type 2 diabetes. Int J Obes (2021). https://doi.org/10.1038/s41366-021-00960-w

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