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

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 (PGS_TT) and bioavailable testosterone (PGS_BT). We tested sex-congruent and sex-incongruent associations between sex-specific PGS_Ts and metabolic traits, as well as T2D diagnosis. Female-specific PGS_BT was associated with an elevated cardiometabolic risk and probability of T2D, in both sexes. Male-specific PGS_TT 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.

Doi: https://doi.org/10.1038/s41366-021-00960-w