Format

Send to

Choose Destination
Neurol Genet. 2016 Sep 13;2(5):e97. doi: 10.1212/NXG.0000000000000097. eCollection 2016 Oct.

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

Author information

1
Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.

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.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center