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Cited by 445Multiple Sclerosis Research StudiesVitamin D Research StudiesGenetic Associations and Epidemiology

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Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study

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Mokry, Lauren E., Ross, Stephanie, Ahmad, Omar S., Forgetta, Vincenzo, Smith, George Davey, Leong, Aaron, Greenwood, Celia M. T., Thanassoulis, George, Richards, J. Brent·2015·PLOS Medicine
DOI 10.1371/journal.pmed.1001866PMC PMC4549308
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Abstract

BACKGROUND: Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS. METHODS AND FINDINGS: We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely. CONCLUSIONS: A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

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Crossref · 10.1371/journal.pmed.1001866

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Fig 1 Schematic representation of Mendelian randomization analysis. The leftmost box lists SNPs that were genome-wide significant for 25OHD level in SUNLIGHT (n = 33,996). The blue arrow represents the effect of SNPs on multiply adjusted natural-log-transformed 25OHD level using data from CaMos (n = 2,347). The green arrow represents the causal association of decreased 25OHD level with the risk of MS using data from the largest genetic association study to date for MS (the IMSGC Immunochip study, up to 14,498 cases and 24,091 healthy controls).
Fig 1 Schematic representation of Mendelian randomization analysis. The leftmost box lists SNPs that were genome-wide significant for 25OHD level in SUNLIGHT (n = 33,996). The blue arrow represents the effect of SNPs on multiply adjusted natural-log-transformed 25OHD level using data from CaMos (n = 2,347). The green arrow represents the causal association of decreased 25OHD level with the risk of MS using data from the largest genetic association study to date for MS (the IMSGC Immunochip study, up to 14,498 cases and 24,091 healthy controls).CC BY · PubMed Central
Fig 2 Vitamin D pathway. In blue are the genes containing, or in proximity to, SNPs that were genome-wide significant for 25OHD level in SUNLIGHT (n = 33,996). The p-values for the association with 25OHD level were 1.9 × 10−109 for GC, 2.1 × 10−27 for DHCR7, 3.3 × 10−20 for CYP2R1, and 6.0 × 10−10 for CYP24A1. Note that each gene plays an independent role in modulating the level of 25OHD. Kidney and liver images credit: https://openclipart.org/.
Fig 2 Vitamin D pathway. In blue are the genes containing, or in proximity to, SNPs that were genome-wide significant for 25OHD level in SUNLIGHT (n = 33,996). The p-values for the association with 25OHD level were 1.9 × 10−109 for GC, 2.1 × 10−27 for DHCR7, 3.3 × 10−20 for CYP2R1, and 6.0 × 10−10 for CYP24A1. Note that each gene plays an independent role in modulating the level of 25OHD. Kidney and liver images credit: https://openclipart.org/.CC BY · PubMed Central
Fig 3 25OHD level by number of 25OHD-decreasing alleles in the CaMos cohort. Here we show the box-plot of natural-log-transformed 25OHD by the count of 25OHD-decreasing alleles in the CaMos population. A count of zero represents individuals with no 25OHD-decreasing alleles (or homozygous at each loci for the 25OHD-increasing allele), and a count of six represents an individual with six 25OHD-decreasing alleles. No individuals with a count of seven or more 25OHD-decreasing alleles were observed in this cohort. The center line and error bars represent the mean level of natural-log-transformed 25OHD and its 95% CI for each respective allele count. Note a negative trend between allele count and mean natural-log-transformed 25OHD.
Fig 3 25OHD level by number of 25OHD-decreasing alleles in the CaMos cohort. Here we show the box-plot of natural-log-transformed 25OHD by the count of 25OHD-decreasing alleles in the CaMos population. A count of zero represents individuals with no 25OHD-decreasing alleles (or homozygous at each loci for the 25OHD-increasing allele), and a count of six represents an individual with six 25OHD-decreasing alleles. No individuals with a count of seven or more 25OHD-decreasing alleles were observed in this cohort. The center line and error bars represent the mean level of natural-log-transformed 25OHD and its 95% CI for each respective allele count. Note a negative trend between allele count and mean natural-log-transformed 25OHD.CC BY · PubMed Central
Fig 4 Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis. Estimates obtained using a fixed-effects model.
Fig 4 Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis. Estimates obtained using a fixed-effects model.CC BY · PubMed Central
Fig 5 Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding the DHCR7 locus. Estimates obtained using a fixed-effects model.
Fig 5 Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding the DHCR7 locus. Estimates obtained using a fixed-effects model.CC BY · PubMed Central

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Authors
Mokry, L. E., Ross, S., Ahmad, O. S., Forgetta, V., Smith, G. D., Leong, A., Greenwood, C. M. T., Thanassoulis, G., & Richards, J. B.
Affiliations
  • Jewish General Hospital (CA)
  • University of Bristol (GB)
  • Harvard University (US)
  • McGill University Health Centre (CA)
  • King's College London (GB)
Corresponding author
Richards, J. Brent
ORCID
Venue
PLOS Medicine
Publisher
Public Library of Science (PLoS)
Published
2015-08-25
Volume
12
Issue
8
Pages
e1001866
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.1001866
PMC
PMC4549308
OpenAlex
W2152795085
Cited by
445
References
61
Citations by year
2026: 15 · 2025: 21 · 2024: 29 · 2023: 48 · 2022: 54 · 2021: 35 · 2020: 45 · 2019: 43 · 2018: 57 · 2017: 49 · 2016: 42 · 2015: 5
FWCI
40.47
Type
journal article
Language
en
Update notices
correction (2016-03-02)
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Explore Bristol Research (publishedVersion, cc-by)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship@McGill (McGill) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Heart and Stroke Foundation of Canada
  • Canadian Diabetes Association
  • Jewish General Hospital
  • Servier
  • Canadian Institutes of Health Research (119462_1)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
multiple sclerosis, vitamin D, 25-hydroxyvitamin D, causal relationship, sun exposure, single nucleotide polymorphisms, pleiotropy, population stratification, vitamin D supplementation, disease risk factors
MeSH terms
Europe, Humans, Multiple Sclerosis, Risk Factors, Vitamin D Deficiency, Linkage Disequilibrium, Risk Assessment, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis

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