The risk of developing MS reportedly increases with early puberty, particularly in women. This leads to interesting hypotheses around the effect of hormones on the maturation of the immune system. But what if there was another equally plausible reason for this finding? For instance, having more body fat at childhood leads to earlier puberty, which in turn is also associated with an increased risk of MS. Could a high BMI (body mass index) therefore be the missing link?
In a large genetic screening study of women from European ancestry Harroud et al. selected single-nucleotide polymorphisms (SNPs) associated with age at menarche. The effects of these SNPs on MS susceptibility was then tested in people from the International Multiple Sclerosis Genetics Consortium that includes 14,802 MS cases and 26703 controls.
In essence, the effect of each SNP on MS susceptibility was weighted by its effect on age at puberty. To account for the effect of weight status, they looked at the effects of the same puberty-associated SNPs on adult and childhood BMI. To exclude the effect of reverse causation, they also looked at whether genetically increased risk of MS influenced pubertal timing.
So what did they find?
They found that genetically predicted later puberty was linked to a protective effect on MS susceptibility. The effect size was that every 1 year increase in the age at puberty decreased the odds of developing MS by 8%. But there is a but, this effect was not independent of BMI and the magnitude of association was dependent on the extent of obesity.
Could obesity therefore be the missing link in the rising cases of MS in the Western world?
Neurology. 2019 Mar 20. pii: 10.1212/WNL.0000000000007325. doi: 10.1212/WNL.0000000000007325. [Epub ahead of print
Effect of age at puberty on risk of multiple sclerosis: A mendelian randomization study.
Harroud A, Morris JA, Forgetta V, Mitchell R, Smith GD, Sawcer SJ, Richards JB
Objective: To investigate the potential for a causal effect of age at puberty on multiple sclerosis (MS) susceptibility using a mendelian randomization (MR) approach.
Methods: We used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) involving 329,245 women. The genetic architecture of pubertal timing across both sexes is highly correlated (genetic correlation [r g] = 0.75, p = 1.2 × 10-79), allowing these variants to provide reliable insight into pubertal timing in males as well. The effect of pubertal timing on risk of MS was measured with summary statistics from a GWAS of 14,802 cases with MS and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. Multivariable MR controlling for effects of body mass index (BMI) using genetic data from additional consortia investigated whether pubertal effects on MS were dependent on weight status.
Results: A 1-year increase in genetically predicted age at puberty decreased odds of MS by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86-0.99, p = 0.03). However, multivariable MR analysis showed that after accounting for effects on adult BMI, the association of age at puberty with MS susceptibility attenuated (OR 0.96, 95% CI 0.88-1.04, p = 0.36). Similar results were obtained when childhood BMI was incorporated. Sensitivity analyses provided no evidence of major bias from genetic pleiotropy.
Conclusions: We found support for an association between higher age at puberty and decreased risk of MS with a magnitude comparable to that reported in observational studies. This effect appears to be largely mediated by the strong association between age at puberty and obesity. A large causal effect of pubertal timing independent of BMI is unlikely.