Study results indicate that multiple sclerosis (MS) is approximately three times more common among women than men, suggesting that sexual steroid hormones may play a role in MS development, with longer exposure to these hormones due to earlier puberty possibly leading to higher risk of MS. Evidence also suggests that MS incidence has increased in recent years while age at puberty has declined. “If age at puberty does in fact have an effect on risk of MS, it could help explain this increase in incidence,” says Adil Harroud, MD. “It could also account for the increase in the female to male sex ratio, as the decline in age at puberty has been more pronounced for girls.” In light of these findings and the widespread understanding that onset of MS before puberty is particularly rare, Dr. Harroud and colleagues conducted a study to better understand this link.
Moving Beyond Prior Research
Previous observational studies suggesting that earlier age at puberty may be associated with increased risk of MS are susceptible to bias from confounding and reverse causation, explains Dr. Harroud. “To address some of these limitations, we conducted a Mendelian randomization study, where we used genetic variants associated with age at puberty as a proxy for that risk factor,” he adds. “These genetic variants are much less likely to be associated with common confounders.”
The study team used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) of 329,245 women. As the genetic architecture of pubertal timing across both sexes is highly correlated, these variants were able to provide reliable insight into pubertal timing in males as well. The effect of a 1-year increase in genetically predicted age at puberty on the risk of MS was then assessed using another GWAS that included 14,802 people with MS and 26,703 controls. “As children with higher body weight tend to enter puberty earlier, and increased BMI is also linked to a greater risk of MS, we also wanted to investigate whether pubertal effects on MS were dependent on weight status,” says Dr. Harroud. “So, we performed a similar analysis while accounting for genetic effects on BMI.”
Confirming the Link
The study team found that earlier puberty was, indeed, associated with an increased risk of MS, with a 1-year decrease in genetically predicted at a puberty linked to an 8% higher risk of MS (Figure). “Most importantly, however, we also found that this association is influenced by weight status, as the effect of age at puberty on the risk of MS was attenuated significantly once we accounted for changes in BMI,” notes Dr. Harroud. “Our findings do not support a substantial role for the timing of puberty on the risk of MS independent of BMI. These results rather suggest that the current obesity epidemic might explain in part why the incidence of MS is increasing.”
Puberty-related variants not associated with BMI had no influence on MS risk, while puberty-related variants that are associated with BMI did influence MS risk, suggesting that effects specific to pubertal timing, such as longer duration of exposure to sex hormones, do not have large effects on MS susceptibility. “Prevention strategies should therefore be aimed at decreasing rates of obesity,” adds Dr. Harroud.
Sensitivity analyses were performed as part of the study to assess for the presence of pleiotropy, a potential source of bias in Mendelian randomization studies. Reinforcing the validity of the study findings, these analyses did not find evidence of pleiotropy—situations in which the genetic variants affected MS risk through pathways other than age at puberty or BMI.
Urgency to Control Weight
Dr. Harroud says the findings are important because obesity is a modifiable risk factor. “This means that decreasing rates of obesity could help to reduce the prevalence of MS,” he says. “Neurologists and pediatricians have an important role to play in this by counselling individuals at high risk of MS, such as those who have first-degree relatives with the disease. Also, most of the complications linked to obesity tend to manifest only late in life, but MS is a condition that often starts when people are in their 20s and 30s. This provides more urgency for us to help young individuals control their weight.”
Dr. Harroud explains that although much has been learned in the last few years about the genetic variants that influence MS risk, little is known regarding how these and other genes might influence the course of the disease. “There is a growing body of evidence showing that obesity contributes to the development of MS as well as other autoimmune diseases,” he says. “However, the mechanisms behind this remain unclear. Uncovering these mechanisms could lead to new therapeutic strategies.”
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