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

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D)
42 serum levels and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding
43 in MS is unknown. Here, we leveraged previously identified variants associated with allele
44 imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol45 stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association
46 studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more
47 genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and
48 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the
49 relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for
50 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern
51 California, Swedish MS studies, and the UK Biobank were included. We estimated the
52 association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV
53 and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS
54 unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs
55 (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of
56 interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association
57 between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR
58 binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases
59 in which vitamin D plays a role