Adil Harroud1, John A Morris1, Vincenzo Forgetta1, Ruth Mitchell1, George Davey Smith1, Stephen J Sawcer1, J Brent Richards2. 1. From the Department of Neurology and Neurosurgery (A.H.), Department of Human Genetics (J.A.M., V.F., J.B.R.), Department of Medicine (J.B.R.), and Department of Epidemiology, Biostatistics and Occupational Health (J.B.R.), McGill University; Centre for Clinical Epidemiology (A.H., J.A.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; MRC Integrative Epidemiology Unit (R.M., G.D.S.), School of Social and Community Medicine, and Population Health Sciences (R.M., G.D.S., S.J.S.), Bristol Medical School, University of Bristol; Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK. 2. From the Department of Neurology and Neurosurgery (A.H.), Department of Human Genetics (J.A.M., V.F., J.B.R.), Department of Medicine (J.B.R.), and Department of Epidemiology, Biostatistics and Occupational Health (J.B.R.), McGill University; Centre for Clinical Epidemiology (A.H., J.A.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; MRC Integrative Epidemiology Unit (R.M., G.D.S.), School of Social and Community Medicine, and Population Health Sciences (R.M., G.D.S., S.J.S.), Bristol Medical School, University of Bristol; Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK. brent.richards@mcgill.ca.
Abstract
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.
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.
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Authors: Ruth E Mitchell; Kirsty Bates; Robyn E Wootton; Adil Harroud; J Brent Richards; George Davey Smith; Marcus R Munafò Journal: PLoS Biol Date: 2020-11-30 Impact factor: 8.029