MS susceptibility is it puberty, or is it something else?

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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?

ABSTRACT

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.

About the author

Neuro Doc Gnanapavan

10 comments

  • My mother died of aggressive ms. I now have it too. Both of us very skinny. Both of us late menarche. This research doesn’t ring true to me.

    • This is not a direct cause. So BMI affects something else. You may have something else that has the same effect by by a different route. So BMI, sun exposure and genetics affect vitamin d levels during childhood. You can have low vitamin d with a normal BMI because of your genes or because you avoid the sun. Or you can have a high BMI and normal vitamin d because of genetics or sun exposure. Only when you look at large numbers of people do you see an effect of BMI on vitamin d levels. At an individual level it is not visible.

      This is an example I am not saying low vitamin d in childhood causes MS.

  • “effect of hormones ”

    Fewer reproductive years in women linked to an increased risk of dementia

    Women who start their period later, go through menopause earlier or have a hysterectomy may have a greater risk of developing dementia, according to a new study published in the March 27, 2019, online issue of Neurology, the medical journal of the American Academy of Neurology. The study found a link between increased risk of dementia and fewer total reproductive years when women are exposed to higher levels of estrogen hormones.

    https://medicalxpress.com/news/2019-03-reproductive-years-women-linked-dementia.html

  • I have always been ideal BMI to marginally underweight. I have always been active, cycling etc. I have never smoked. But I started slow PPMS in early 20s. I’m a female with excellent general health, no comorbidities. I so often fail to fit the generalisations presented about MS. But I know, I am but an anecdote.

  • Do they comment on what age? I was always told I started menstrating quite early, but was just my mother ad grandmother commenting. I too wonder about the confounding factor with BMI. I have few other factors always mentioned: birth month (November), never had EBV as far as I know, etc.

    While the “data” may be strong, it feels like a stretch,

    • They don’t comment on the specific age in the paper because it is continuous variable, the older the person is the greater the risk.

      I have been reading the comments from others also. It is important to understand that the methodology of this work; first the genetic contribution to the age at puberty (both men and women), followed by the effect of genetically predicted pubertal timing on MS susceptibility. That is these are MS risk genetic data sets, they would not be able to inform us about the other sizable environmental contributions that are not genetically attributable.

      If you wanted to examine other risk factors that have a plausible genetic association then you could ask that from this data set, but you’d have to have a good idea as to what you’re looking at.

      • Thank you as always for your insightful reply. Makes a little more sense now. A chart or 2 would have helped here as well. I still believe there are a number of both genetic and environmental effects over time which lead to the condition we know and see as MS.

  • Same feedback as MSINTHEUS
    Skinny always, diagnosed with MS at age 12, periods began late (at over 14)….
    So I find these conclusions hard to believe

    Perhaps the BMI typically corresponds to some other factor that really does play a role in MS. For example, the relevant factor may be something diet-related. Most people on that diet may have a high BMI

  • I was a skinny, tan child. Played outside, lived in many different places due to a military father. Started menses at 12. I’ve always been scrawny and I’ve never smoked, and to my knowledge to EB. Diagnosed with MS at 48.

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