In a unique prospective birth cohort study, we observed that a common genetic variant in LIN28B
that confers earlier puberty was associated with a prolonged increase in BMI during adolescence and early to mid-adulthood in women only. This variant was also associated with a constant reduction in height. Although this variant has only relatively small effects on pubertal timing (1
) and BMI, our findings allow us to make inferences about the causal relationships between these outcomes.
The main strength of this study was the availability of longitudinal data on weight and height across childhood, adolescence, and adulthood up to age 53 yr, which allowed a unique exploration of life-course genetic associations with body size. Our longitudinal analyses make full use of all available outcome data under the assumption that missing data are missing at random. This is a reasonable assumption given that the DNA was collected at the most recent contact with participants, and hence the sample represents those still alive and in the study at age 53 yr.
We recently described rs314276 in LIN28B
to be the first common genetic determinant of the timing of puberty (1
). This locus was also identified in three other studies of menarche timing (2
is homologous to the heterochronic gene lin-28
in Caenorhabditis elegans
and encodes a potent and specific regulator of preprocessing of the let-7
family of micro-RNAs (15
). In contrast to its consistent association with pubertal timing, our earlier studies showed that rs314276 was not associated with obesity risk in older adults; in a large cross-sectional analysis of 10,166 women and 9,840 men aged 40–75 yr, rs314276 showed no association with BMI, waist circum-ference, or body fat (1
). Together with our current findings, these observations suggest that the rs314276 C allele is associated with greater weight and BMI during adolescence and early adult life in women, but its effects become gradually attenuated from around ages 30–40 yr onward, suggesting that different genetic or lifestyle factors contribute to the ongoing rise in adult BMI.
The relevance of this prolonged but transient increase in BMI on disease risk is uncertain. He et al.
) described that the association between earlier menarche and increased type 2 diabetes risk was stronger in women aged under 45 yr, and in the Bogalusa Heart Study (16
), childhood and adolescent BMI predicted carotid intimal thickness in young adults. Therefore, elevated adiposity even during adolescence and early to mid-adult life are important for metabolic disease outcomes.
Surprisingly, given that rs314276 is related to pubertal timing in both boys and girls (1
), no associations were seen with weight or BMI in men. There is a marked sexual divergence in body composition during puberty; girls show preferential accumulation of fat mass over fat-free mass (17
) in parallel with changes in estrogen levels (18
), whereas boys gain relatively more fat-free mass (17
), likely driven by changes in androgen levels (19
). It is therefore possible that early puberty has different effects on adiposity according to sex. Furthermore, although we confirmed the rs314276 C allele association with shorter adult height, there was no evidence to support our earlier hypothesis that this is due to accelerated gains in childhood height followed by earlier growth cessation (1
). Instead, the association with shorter height was constant throughout childhood and adult life in both sexes.
Although it is well established that earlier pubertal maturation in girls is related to increased body weight, the causal direction is unclear. There are plausible biological mechanisms to explain why girls who are already over-weight before puberty could have earlier pubertal onset and progression (20
). Conversely, earlier puberty in girls could also have a direct influence on adiposity, for example due to longer exposure to estrogens. The lack of any clear association between rs314276 and BMI or weight during young childhood (before age 7–8 yr) in either our current or earlier studies (1
) needs further confirmation but leads us to infer that the current associations with this variant illustrate the direct effects of early pubertal timing on adolescent and early adult BMI. However, further studies are needed to exclude pleiotropic effects of this SNP on the timing of puberty and energy homeostasis.
In conclusion, genetic variation in LIN28B that confers earlier puberty was associated with a prolonged increase in BMI in women during adolescence and early to mid-adulthood.