The link between puberty age and multiple sclerosis (MS) risk appeared to be largely mediated by obesity, a Mendelian randomization study suggested.
While genetically-predicted age at puberty was tied to odds of MS, this relationship was attenuated after accounting for genetic effects on body mass index (BMI), reported J. Brent Richards, MD, MSc, of McGill University in Montreal, and co-authors in Neurology.
“Previous studies have shown that children with higher body weight tend to enter puberty earlier than children with normal body weight, and increased BMI is also linked to a greater risk of MS,” Richards said in a statement. “It appears that earlier age at puberty is associated with an increased risk of MS, but this association is influenced by BMI.”
“Our findings do not support a substantial role for the effect of the timing of puberty on the risk of MS independent of BMI,” he added.
Epidemiological studies have shown an increased risk of MS with earlier pubertal age, especially in women. Higher adiposity in childhood has been tied to earlier puberty, which has been tied to higher adult BMI.
“Striking changes in the demographic pattern of MS, with increasing prevalence and incidence over time, especially in women, strongly indicate an influence of modifiable exposures on the disease,” observed An Goris, PhD, and Benedicte Dubois, MD, PhD, both of KU Leuven in Belgium, in an accompanying editorial. “In understanding these important clues, it is difficult to pinpoint which of the many environmental, lifestyle, and socio-demographic changes that have occurred over the past decades, such as higher smoking and obesity rates and earlier age at puberty, are responsible.”
Mendelian randomization correlates genetic predispositions randomly assigned at conception with health outcomes later in life. “Through the Mendel laws, nature generates random genetic differences between individuals,” Goris and Dubois said. “This leads to a range of naturally occurring genetic predispositions for a risk factor, mimicking the biological effect of a modifiable exposure.” Previously, Mendelian randomization has been used to show associations between vitamin D and MS.
In this analysis, Richards and colleagues used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) of 329,245 women of European ancestry. The genetic architecture of pubertal timing across both sexes is highly correlated and these variants provided reliable insights about pubertal timing in males as well, they noted.
To assess the effect of puberty age on MS risk, they used a GWAS of 14,802 MS cases and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. They determined that a 1-year increase in genetically predicted age at puberty decreased the odds of MS by 8% (OR 0.92, 95% CI 0.86–0.99, P=0.03).
After accounting for genetic effects on adult BMI, the effect of puberty age on MS attenuated (OR 0.96, 95% CI 0.88–1.04, P=0.36). Adjusting for genetic effects on childhood BMI yielded similar results (OR 0.97, 95% CI 0.89-1.05, P=0.40). Puberty-related variants not associated with BMI had no detectable influence on MS risk, while puberty-related variants associated with BMI did influence MS risk.
“BMI is associated with a broad range of biological, lifestyle, and socio-demographic aspects, shifting the BMI-MS question to the next, mechanistic level,” Goris and Dubois wrote. Prior research has excluded one mechanistic hypothesis by demonstrating that adiponectin, an anti-inflammatory cytokine negatively correlated with BMI, did not drive MS risk, they noted.
“Other alternative mechanisms include pro-inflammatory cytokines such as interleukin-6 that are positively associated with BMI,” they added. “Studies on the genetic architecture of the immune system will provide appropriate genetic instruments for future use in Mendelian randomization.”
The analysis had several limitations, Richards and colleagues noted. Summary-level statistics from the International Multiple Sclerosis Genetics Consortium precluded separate analyses of male and female cases. And while some genetic variants may relate to MS risk through pathways other than pubertal timing or BMI, the researchers took several steps to reduce the likelihood of pleiotropy.
“More research is needed to determine whether decreasing rates of obesity could help to reduce the prevalence of MS,” Richards added. “If so, this could be another important reason for public health initiatives to focus on lowering obesity rates.”
The Richards laboratory is supported by the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and the Fonds de Recherche Sante Quebec (FRQS). Richards is supported by a FRQS Clinical Research Scholarship and received research support from the National MS Society and the MS Society of Canada. TwinsUK is funded by the Wellcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research–funded BioResource, Clinical Research Facility, and the Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London.
Researchers reported relationships with Precision Analytics, Merck Sharp & Dohme, Eli Lilly and Company, and GlaxoSmithKline.
Editorialists reported relationships with Biogen Idec, Sanoﬁ-Aventis, Teva, Merck, Novartis, and Roche.