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Published February 19, 2015 | public
Journal Article Open

Genetic and epigenetic fine mapping of causal autoimmune disease variants


Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T cells, CD8+ T cells, B cells, and monocytes. We find that ~90% of causal variants are non-coding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

Additional Information

© 2014 Macmillan Publishers Limited. Received 11 February 2014. Accepted 04 September 2014. Published online 29 October 2014. We thank members of the NIH Epigenomics Consortium, M. Greenberg, H. Chang and G. Haliburton for constructive comments. We also thank IIBDGC and P. Sullivan for sharing data pre-publication, and G. Cvetanovich, S. Bhela, C. Hartnick, F. Preffer, D. Dombkowski and the Brigham and Women's Hospital PhenoGenetic Project for assistance with data collection. This research was supported by the NIH Common Fund (ES017155), the National Human Genome Research Institute (HG004570), the National Institute of Allergy and Infectious Disease (AI045757, AI046130, AI070352, AI039671), the National Institute of Neurological Disorders and Stroke (NS24247, NS067305), the National Institute of General Medical Sciences (GM093080), the National Multiple Sclerosis Society (CA1061-A-18), the UCSF Sandler Fellowship, a gift from Jake Aronov, the Penates Foundation, the Nancy Taylor Foundation, and the Howard Hughes Medical Institute. Author Contributions: A.M., D.A.H. and B.E.B. designed the study. K.K.F. performed genetic analysis, PICS development and integration. M.J.D. supervised genetic analysis. J.Z., M.K., W.J.H., S.B., N.S., H.W., R.J.H.R., A.A.S., M.H., M.J.C.-A., D.M., C.J.L., V.K.K. and C.B.E. contributed to data collection and analysis. N.A.P. and P.L.D.J. contributed multiple sclerosis genotyping data. K.K.F., A.M., D.A.H. and B.E.B. wrote the manuscript.

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Supplemental Material - nature13835-s1.xls

Accepted Version - nihms626180.pdf


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August 20, 2023
August 20, 2023