Abstract
Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.
Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18–20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.
Results: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64–0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76–0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76–0.94). No association was observed for age at onset or disease severity.
Conclusions: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.
GLOSSARY
- CI=
- confidence interval;
- EHR=
- electronic health record;
- EIMS=
- Epidemiological Investigation of Multiple Sclerosis;
- GERA=
- Genetic Epidemiology Research on Adult Health and Aging;
- GEMS=
- Genes and Environment in Multiple Sclerosis;
- GWAS=
- genome-wide association study;
- HWE=
- Hardy-Weinberg equilibrium;
- ICD-9=
- International Classification of Diseases, 9th Revision;
- IV=
- instrumental variable;
- KPNC=
- Kaiser Permanente in Northern California;
- LD=
- linkage disequilibrium;
- MAF=
- minor allele frequency;
- MDS=
- multidimensional scaling;
- MR=
- mendelian randomization;
- MS=
- multiple sclerosis;
- MSSS=
- Multiple Sclerosis Severity Scores;
- SNP=
- single nucleotide polymorphism;
- VDRE=
- vitamin D response element;
- wGRS=
- weighted genetic risk score
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors.
↵* These authors contributed equally to the article.
Supplemental data at Neurology.org/ng
- Received June 8, 2016.
- Accepted in final form July 12, 2016.
- © 2016 American Academy of Neurology
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