MS Speaks

Multiple Sclerosis => MS - RESEARCH AND NEWS => Topic started by: agate on May 26, 2018, 01:34:43 pm

Title: (AAN abst.) Effect of age at puberty on risk of MS...
Post by: agate on May 26, 2018, 01:34:43 pm

Presented at the annual AAN conference (April 27, 2018):
Effect of Age at Puberty on Risk of Multiple Sclerosis: A Mendelian Randomization Study

Adil Harroud1,5, John A. Morris2,5, Vincenzo Forgetta2,5, Ruth Mitchell6,7, George Davey Smith6,7, Stephen Sawcer8 , J. Brent Richards2,3,4,5,9

1 Department of Neurology, 2 Department of Human Genetics, 3 Department of Medicine, 4 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 5 Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 6 MRC Integrative Epidemiology Unit, 7 School of Social and Community Medicine, University of Bristol, 8 Department of Clinical Neurosciences, University of Cambridge, 9 Department of Twin Research and Genetic Epidemiology, King's College London


To investigate the potential for a causal effect of age at puberty on MS susceptibility and whether such effects are mediated by obesity using Mendelian randomization (MR).


Several observational studies have reported an increased risk of MS with earlier age at puberty, although others found no association, or an opposite effect. These studies are subject to residual confounding from factors such as obesity which are associated with both puberty timing and MS susceptibility.


We used genetic variants strongly associated with age at menarche in a genome wide association study (GWAS) involving 329,245 women. The genetic architecture of puberty timing across both sexes is highly correlated (rgenetic correlation=0.75, p=1.2x10-79), allowing these variants to provide insight into puberty timing in males as well. The effect of puberty timing on risk of MS was measured by conventional MR methods using the latest International MS Genetics Consortium (IMSGC) meta-analysis (14,802 cases, 26,703 controls).

To test whether puberty effects on MS were mediated by body mass index (BMI), we conducted a multivariable MR using summary-level statistics from a BMI GWAS of 87,048 individuals.


We selected 375 independent autosomal non-HLA variants associated with puberty timing at genomewide significance. Of those, 372 were ascertained either directly (n=345) or through a proxy (n=27, median r2=0.995) in the IMSGC meta-analysis. The main analysis revealed that a 1 year decrease in the age at puberty increased odds of MS by 8% (OR=1.08, 95% CI 1.01-1.16, p=0.03). Multivariable MR analysis showed that this effect was greatly attenuated after accounting for mediating effects of BMI (OR=1.04, 95% CI 0.96-1.12, p=0.36).


This study found support for an inverse association between age at puberty and MS susceptibility. This effect is largely mediated by the strong association between age at puberty and obesity. A large causal effect of puberty timing independent of BMI is unlikely.