Sex-specific genetic influence on thyroid-stimulating hormone and free thyroxine levels, and interactions between measurements: KNHANES 2013–2015

BACKGROUND: Although a wide range of genetic influences on thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels have been reported, sex differences in the genetic influences have not been well described. METHODS: We assessed TSH and fT4 levels in 2,250 subjects without thyroid peroxidase antibody, with data obtained from the Korea National Health and Nutrition Examination Surveys (KNHANES) conducted from 2013 to 2015. Using variance decomposition methods, the variation of TSH and fT4 levels was divided into genetic and environmental components common to both sexes, and to males and females separately. The genetic correlation between TSH and fT4 levels was also assessed in both sexes, and in males and females separately. RESULTS: Narrow-sense heritability for TSH and fT4 were 54% and 56%, respectively. Sex-specific heritability for TSH levels was significantly higher in females than in males (75% and 41%, respectively; p = 0.037). Heritability for fT4 levels was not significantly different between males and females (62% and 52%, respectively; p = 0.335). TSH and fT4 levels showed a negative genetic correlation in females (ρ(g) = -0.347, p = 0.040) after regressing out the influences of environmental covariates, but this correlation was not present in males (ρ(g) = -0.160, p = 0.391). CONCLUSIONS: The genetic influences on individual TSH levels were more prominent in females than in males. In addition, female-specific pleiotropy between TSH and fT4 might be a clue that this stronger genetic influences in females would mainly affect thyroid function per se, rather than other TSH-related factors that do not primarily trigger the negative feedback loop between TSH and fT4.