Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.
Methods and findings
MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12–14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10−5) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10−4), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.
This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.
Why was this study done?
- Worldwide there has been a shift towards earlier puberty over time, possibly due to changes in childhood lifestyle and levels of adiposity.
- Early puberty has been linked to an increased risk of asthma in women, but findings are inconsistent across studies, and little research has been done in men.
- There is some suggestion that late puberty might also increase the risk of asthma.
- Studies performed so far have some methodological limitations that make it difficult to distinguish true effects from spurious findings.
What did the researchers do and find?
- We studied the effect of age at puberty on asthma in women and men using Mendelian randomisation, an approach that exploits genetic data to overcome some limitations of classical observational studies.
- From the UK Biobank study, we analysed data on approximately 240,000 women and approximately 190,000 men with available genetic data and self-reported information on asthma and age at puberty (menarche for women and voice breaking for men).
- We found that women and men with early puberty had an increased risk of asthma of 8% and 7%, respectively.
- We found no evidence of a detrimental effect of late puberty on asthma.
What do these findings mean?
- These findings, together with suggestions of other detrimental effects of early puberty on health, emphasise the importance of evaluating the overall evidence on health effects of early puberty.
- The similarity of findings in females and males might be explained by common biological or psychological factors related to early puberty, but further research is needed to investigate this.