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

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. J. Brent Richards and colleagues assess whether genetically predicted vitamin D levels associate with risk of multiple sclerosis.Background: Multiple sclerosis (MS) is a debilitating neurological disorder that affects the nerves in the brain and spinal cord and that usually presents between the ages of 20 and 40 years. It is an autoimmune disease—a disease in which the body’s immune system attacks healthy tissues. In the case of MS, the immune system attacks myelin, the fatty tissue that forms an insulating sheath around nerves fibers. Multiple areas of scarring (sclerosis) in the myelin are produced by immune attack, and the damage slows down or blocks the transmission of electrical signals along the nerves to and from the brain and causes symptoms such as loss of vision, muscle stiffness, and daytime fatigue. For most affected individuals, MS initially follows a relapsing–remitting course characterized by periods lasting days or weeks during which symptoms flare up, followed by periods during which symptoms becomes milder or disappear. Half of people with relapsing–remitting MS eventually develop secondary progressive MS, in which their symptoms inexorably worsen. There is currently no cure for MS, but some treatments can relieve its symptoms or reduce the number of relapses. Why Was This Study Done?: Why the immune system attacks myelin to cause MS is unclear but probably involves both genetic and environmental risk factors. One potential environmental risk factor is reduced levels of vitamin D. Circulating levels of 25-hydroxyvitamin D (25OHD; the clinical determinant of vitamin D status) are determined in part by exposure to sunlight, and MS is more common at higher latitudes, where exposure to sunlight is decreased. Other epidemiological studies (investigations that examine disease patterns in populations) also suggest an association between lower vitamin D level and an increased risk of MS but cannot prove that a decreased vitamin D level actually causes MS. Individuals who develop MS might share another unknown characteristic that increases their risk of MS (confounding), or individuals who have MS might spend less time outdoors and, as a result, have lower circulating vitamin D levels (reverse causation). It is important to know whether a decreased vitamin D level increases the risk of MS because vitamin D insufficiency is becoming increasingly common. Here, the researchers undertake a Mendelian randomization study to determine whether circulating vitamin D level has a causal effect on MS susceptibility. Because gene variants are inherited randomly, they are not prone to confounding. Reverse causation is also prevented since MS does not change genetic variants. So, if vitamin D level actually affects MS risk, genetic variants that affect vitamin D level should be associated with altered susceptibility to MS. What Did the Researchers Do and Find?: The researchers first ascertained the effect on 25OHD level among participants in the Canadian Multicentre Osteoporosis Study of four single nucleotide polymorphisms (SNPs, a type of genetic variant) that were associated with 25OHD level in a genome-wide association study (SUNLIGHT). Each of the SNPs explained an important proportion of the population-level variance in 25OHD level in the Canadian Multicentre Osteoporosis Study. The researchers then used the SNPs to examine whether there was an association between genetically reduced 25OHD level and susceptibility to MS among participants in the International Multiple Sclerosis Genetics Consortium study, a genome-wide association study involving up to 14,498 people with MS and 24,091 healthy controls. They found that a genetic decrease in the natural-log-transformed 25OHD level by one standard deviation was associated with a 2-fold increased risk of MS. In practical terms, this finding means that increasing an individual’s circulating 25OHD level by approximately 1.5-fold decreases their odds of developing MS by 50%. What Do These Findings Mean?: These findings show that, among the participants of the International Multiple Sclerosis Genetics Consortium study, all of whom were of European ancestry, genetically lowered 25OHD level was strongly associated with increased susceptibility to MS. Although the Mendelian randomization approach used here largely avoids the possibility of confounding or reverse causation, the reliability of these findings may be limited by some of the assumptions made by the researchers during their analysis. Moreover, although these findings support a role for vitamin D in MS susceptibility, they provide no information about whether vitamin D modulates the course of MS after its onset, and they may not apply to people of non-European ancestry. Nevertheless, these findings provide a strong rationale for undertaking randomized controlled trials to investigate whether vitamin D supplementation can prevent the onset and/or progression of MS. Additional Information: This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001866.