PT  - JOURNAL ARTICLE
AU  - Harroud, Adil
AU  - Morris, John A.
AU  - Forgetta, Vincenzo
AU  - Mitchell, Ruth
AU  - Smith, George Davey
AU  - Sawcer, Stephen J.
AU  - Richards, J. Brent
TI  - Effect of age at puberty on risk of multiple sclerosis
AID  - 10.1212/WNL.0000000000007325
DP  - 2019 Apr 16
TA  - Neurology
PG  - e1803--e1810
VI  - 92
IP  - 16
4099  - http://n.neurology.org/content/92/16/e1803.short
4100  - http://n.neurology.org/content/92/16/e1803.full
SO  - Neurology2019 Apr 16; 92
AB  - 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 [rg] = 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.BMI=body mass index; CI=confidence interval; EGG=Early Growth Genetics; ENGAGE=European Network for Genetic and Genomic Epidemiology; GWAS=genome-wide association study; HLA=human leukocyte antigen; IMSGC=International Multiple Sclerosis Genetics Consortium; MR=mendelian randomization; MS=multiple sclerosis; OR=odds ratio; ReproGen=Reproductive Genetics; SNP=single-nucleotide polymorphism