Milena A Gianfrancesco1, Pernilla Stridh1, Brooke Rhead1, Xiaorong Shao1, Edison Xu1, Jennifer S Graves1, Tanuja Chitnis1, Amy Waldman1, Timothy Lotze1, Teri Schreiner1, Anita Belman1, Benjamin Greenberg1, Bianca Weinstock-Guttman1, Gregory Aaen1, Jan M Tillema1, Janace Hart1, Stacy Caillier1, Jayne Ness1, Yolanda Harris1, Jennifer Rubin1, Meghan Candee1, Lauren Krupp1, Mark Gorman1, Leslie Benson1, Moses Rodriguez1, Soe Mar1, Ilana Kahn1, John Rose1, Shelly Roalstad1, T Charles Casper1, Ling Shen1, Hong Quach1, Diana Quach1, Jan Hillert1, Maria Bäärnhielm1, Anna Hedstrom1, Tomas Olsson1, Ingrid Kockum1, Lars Alfredsson1, Catherine Metayer1, Catherine Schaefer1, Lisa F Barcellos1, Emmanuelle Waubant2. 1. From the Division of Epidemiology, School of Public Health (M.A.G., X.S., E.X., H.Q., D.Q., C.M., L.F.B.), and Computational Biology Graduate Group (B.R.), University of California, Berkeley; Department of Clinical Neuroscience and Center for Molecular Medicine (P.S.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (J.S.G., E.W.) and Regional Pediatric MS Center, Neurology (J.H., S.C.), University of California, San Francisco; Partners Pediatric Multiple Sclerosis Center (T.C.), Massachusetts General Hospital for Children, Boston; Division of Neurology (A.W.), Children's Hospital of Philadelphia, PA; Blue Bird Circle Multiple Sclerosis Center (T.L.), Baylor College of Medicine, Houston, TX; Children's Hospital Colorado (T.S.), University of Colorado, Denver; Lourie Center for Pediatric Multiple Sclerosis (A.B., L.K.), Stony Brook Children's Hospital, NY; Department of Neurology (B.G.), University of Texas Southwestern, Dallas; Pediatric Multiple Sclerosis Center (B.W.-G.), Jacobs Neurological Institute, SUNY Buffalo, NY; Pediatric MS Center at Loma Linda University Children's Hospital (G.A.), CA; Mayo Clinic's Pediatric Multiple Sclerosis Center (J.M.T., M.R.), Rochester, MN; University of Alabama Center for Pediatric-onset Demyelinating Disease (J.N., Y.H.), Children's Hospital of Alabama, Birmingham; Department of Pediatric Neurology (J.R.), Northwestern Feinberg School of Medicine, Chicago, IL; Primary Children's Hospital (M.C.), University of Utah, Salt Lake City; Boston Children's Hospital (M.G., L.B.), MA; Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center (S.M.), St. Louis Children's Hospital, Washington University School of Medicine, MO; Children's National Medical Center (I.K.), Washington, DC; Departments of Neurology (J.R.) and Pediatrics (S.R., T.C.C.), University of Utah School of Medicine, Salt Lake City; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Oakland, CA; Institute of Environmental Medicine (J.H., M.B., A.H., T.O., I.K., L.A.), Karolinska Institutet; Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Stockholm, Sweden; and Research Program on Genes, Environment and Health (C.S.), Kaiser Permanente, Oakland, CA. 2. From the Division of Epidemiology, School of Public Health (M.A.G., X.S., E.X., H.Q., D.Q., C.M., L.F.B.), and Computational Biology Graduate Group (B.R.), University of California, Berkeley; Department of Clinical Neuroscience and Center for Molecular Medicine (P.S.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (J.S.G., E.W.) and Regional Pediatric MS Center, Neurology (J.H., S.C.), University of California, San Francisco; Partners Pediatric Multiple Sclerosis Center (T.C.), Massachusetts General Hospital for Children, Boston; Division of Neurology (A.W.), Children's Hospital of Philadelphia, PA; Blue Bird Circle Multiple Sclerosis Center (T.L.), Baylor College of Medicine, Houston, TX; Children's Hospital Colorado (T.S.), University of Colorado, Denver; Lourie Center for Pediatric Multiple Sclerosis (A.B., L.K.), Stony Brook Children's Hospital, NY; Department of Neurology (B.G.), University of Texas Southwestern, Dallas; Pediatric Multiple Sclerosis Center (B.W.-G.), Jacobs Neurological Institute, SUNY Buffalo, NY; Pediatric MS Center at Loma Linda University Children's Hospital (G.A.), CA; Mayo Clinic's Pediatric Multiple Sclerosis Center (J.M.T., M.R.), Rochester, MN; University of Alabama Center for Pediatric-onset Demyelinating Disease (J.N., Y.H.), Children's Hospital of Alabama, Birmingham; Department of Pediatric Neurology (J.R.), Northwestern Feinberg School of Medicine, Chicago, IL; Primary Children's Hospital (M.C.), University of Utah, Salt Lake City; Boston Children's Hospital (M.G., L.B.), MA; Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center (S.M.), St. Louis Children's Hospital, Washington University School of Medicine, MO; Children's National Medical Center (I.K.), Washington, DC; Departments of Neurology (J.R.) and Pediatrics (S.R., T.C.C.), University of Utah School of Medicine, Salt Lake City; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Oakland, CA; Institute of Environmental Medicine (J.H., M.B., A.H., T.O., I.K., L.A.), Karolinska Institutet; Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Stockholm, Sweden; and Research Program on Genes, Environment and Health (C.S.), Kaiser Permanente, Oakland, CA. emmanuelle.waubant@ucsf.edu.
Abstract
OBJECTIVE: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). METHODS: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). RESULTS: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. CONCLUSIONS: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.
OBJECTIVE: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). METHODS: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). RESULTS: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. CONCLUSIONS: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.
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