CaltechAUTHORS
  A Caltech Library Service

Genetic and epigenetic fine mapping of causal autoimmune disease variants

Farh, Kyle Kai-How and Marson, Alexander and Zhu, Jiang and Kleinewietfeld, Markus and Housley, William J. and Beik, Samantha and Shoresh, Noam and Whitton, Holly and Ryan, Russell J. H. and Shishkin, Alexander A. and Hatan, Meital and Carrasco-Alfonso, Marlene-J. and Mayer, Dita and Luckey, C. John and Patsopoulos, Nikolaos A. and De Jager, Philip L. and Kuchroo, Vijay K. and Epstein, Charles B. and Daly, Mark J. and Hafler, David A. and Bernstein, Bradley E. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature, 518 (7539). pp. 337-343. ISSN 0028-0836. PMCID PMC4336207. http://resolver.caltech.edu/CaltechAUTHORS:20141110-102139773

[img] PDF - Accepted Version
See Usage Policy.

3553Kb
[img] MS Excel (Supplementary Table 1) - Supplemental Material
See Usage Policy.

3460Kb

Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:20141110-102139773

Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13835.htmlPublisherArticle
http://dx.doi.org/10.1038/nature13835DOIArticle
http://rdcu.be/cmmTPublisherFree ReadCube access
http://www.nature.com/nature/journal/v518/n7539/extref/nature13835-s1.xlsPublisherSupplementary Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336207PubMed CentralArticle
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.
Funders:
Funding AgencyGrant Number
NIHES017155
National Human Genome Research InstituteHG004570
National Institute of Allergy and Infectious DiseaseAI045757
National Institute of Allergy and Infectious DiseaseAI046130
National Institute of Allergy and Infectious DiseaseAI070352
National Institute of Allergy and Infectious DiseaseAI039671
National Institute of Neurological Disorders and StrokeNS24247
National Institute of Neurological Disorders and StrokeNS067305
National Institute of General Medical SciencesGM093080
National Multiple Sclerosis SocietyCA1061-A-18
UCSF Sandler FellowshipUNSPECIFIED
Penates FoundationUNSPECIFIED
Nancy Taylor FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
PubMed Central ID:PMC4336207
Record Number:CaltechAUTHORS:20141110-102139773
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20141110-102139773
Official Citation:Genetic and epigenetic fine mapping of causal autoimmune disease variants Kyle Kai-How Farh, Alexander Marson, Jiang Zhu, Markus Kleinewietfeld, William J. Housley, + et al. Nature doi:10.1038/nature13835
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:51496
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:10 Nov 2014 19:43
Last Modified:21 Jul 2017 23:03

Repository Staff Only: item control page