Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans

Abstract

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.

Keywords: genetics; multiple sclerosis; vitamin D.

Fig. 1.

(A) Representation of the vitamin D pathway. (B) Example of a VDR binding variant (VDR-BV) location within a VDR binding region. VDR-BVs are single-nucleotide polymorphisms associated with increased or decreased VDR binding at a VDR binding region. (C) Directed acyclic graph depicting our MR analyses. Genetic variants associated with altered VDR binding at a locus (GIV_VDR-BV) are used to estimate association between VDR-Binding at a locus and MS susceptibility within our MS case–control datasets. Genetic variants from genome-wide association studies on serum vitamin D levels (GIV_25(OH)D) are used to estimate the association between VDR binding and MS unbiased by horizontal pleiotropy (dashed-line).

Fig. 2.

Results from meta-analyses of association between 25(OH)D genetic instrumental variables (GIV_25OHD) and VDR-BV rs2881514 and MS. GIVs_25OHD calculated using summary statistics from genome-wide association studies on serum 25(OH)D levels. (A) GIVs_25OHD calculated using summary statistics from Jiang et al. (13); (B) GIVs_25OHD calculated using summary statistics from Revez et al. (12). (C) Meta-analysis results for association between GIV_25(OH)D rs2881514 and MS and (D) evidence of interaction between rs2881514 and Jiang et al. 25(OH)D GIV. ${\tau }^2$ = estimate of between study heterogeneity; I² = proportion of variance due to heterogeneity; and P = P-value for Cochran’s Q test of heterogeneity.