Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease

Gallone, Giuseppe, Haerty, Wilfried ORCID:, Disanto, Giulio, Ramagopalan, Sreeram V., Ponting, Chris P. and Berlanga-Taylor, Antonio J. (2017) Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease. Human Molecular Genetics, 26 (11). pp. 2164-2176. ISSN 0964-6906

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Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (> 2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.

Item Type: Article
Additional Information: Funding Information: We thank Mark Gerstein, Jieming Chen, Joel Rozowsky, Alexej Abyzov, Ekta Khurana and Yao Fu for precious help and technical insight on the AlleleSeq, CNVnator and Funseq2 platforms. We also thank Matthew Stephens and Yongtao Guan for help and insight on the PIMASS and BIMBAM platforms. We thank Gosia Trynka and Kamil Slowikowksi for providing r2-based LD block data; Yuchun Guo and David Gifford for precious help and technical insight on the GEM peak caller; Gerton Lunter for help on the STAMPY platform; Andreas Heger for help and technical insight on the GAT software and genomic randomization testing; Rory Stark and Simon Anders for insight on differential analysis of ChIP-seq data; Laura Clarke for help with the 1000 Genomes data and Daniel Gaffney for providing helpful pointers regarding the GEUVADIS QTLs calls; We thank Li Shen and Ning-Yi Shao (Icahn School of Medicine at Mount Sinai) for insight into NGSplot utilisation; and Oscar Bedoya Reina and Christoffer Nellaker for helpful discussions. Medical Research Council [to GG, AJBT, WH, CPP: MC_UU_12008/1, MC_UU_12021/1, MC_EX_G1000902]; Wellcome Trust and Genzyme [to SVR]; the Multiple Sclerosis Society UK [grant number 915/09] and the Council for Science and Technology (CONACyT) Mexico [grant number 211990 to AJBT]. Funding to pay the Open Access publication charges for this article was provided by the Research Councils UK (RCUK) open access fund. Publisher Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved.
Uncontrolled Keywords: molecular biology,genetics,genetics(clinical) ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
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Depositing User: LivePure Connector
Date Deposited: 15 Sep 2022 14:30
Last Modified: 18 Apr 2023 20:31
DOI: 10.1093/hmg/ddx092

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