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Nature DOI:10.1038/nature13835

Genetic and epigenetic fine mapping of causal autoimmune disease variants.

Publication TypeJournal Article
Year of Publication2015
AuthorsFarh, KKai-How, Marson, A, Zhu, J, Kleinewietfeld, M, Housley, WJ, Beik, S, Shoresh, N, Whitton, H, Ryan, RJH, Shishkin, AA, Hatan, M, Carrasco-Alfonso, MJ, Mayer, D, C Luckey, J, Patsopoulos, NA, De Jager, PL, Kuchroo, VK, Epstein, CB, Daly, MJ, Hafler, DA, Bernstein, BE
JournalNature
Volume518
Issue7539
Pages337-43
Date Published2015 Feb 19
ISSN1476-4687
KeywordsAutoimmune Diseases, Base Sequence, Chromatin, Consensus Sequence, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genome-Wide Association Study, Humans, Nucleotide Motifs, Organ Specificity, Polymorphism, Single Nucleotide, T-Lymphocytes, Transcription Factors
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.

URLhttp://dx.doi.org/10.1038/nature13835
DOI10.1038/nature13835
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25363779?dopt=Abstract

Alternate JournalNature
PubMed ID25363779
PubMed Central IDPMC4336207
Grant ListAI039671 / AI / NIAID NIH HHS / United States
U54 HG006991 / HG / NHGRI NIH HHS / United States
T32 AI007019 / AI / NIAID NIH HHS / United States
P30 DK063720 / DK / NIDDK NIH HHS / United States
AI045757 / AI / NIAID NIH HHS / United States
U19 AI070352 / AI / NIAID NIH HHS / United States
AI070352 / AI / NIAID NIH HHS / United States
NS24247 / NS / NINDS NIH HHS / United States
12-0089 / / Worldwide Cancer Research / United Kingdom
R37 NS024247 / NS / NINDS NIH HHS / United States
R01 NS067305 / NS / NINDS NIH HHS / United States
R01 NS024247 / NS / NINDS NIH HHS / United States
NS067305 / NS / NINDS NIH HHS / United States
ES017155 / ES / NIEHS NIH HHS / United States
P01 AI039671 / AI / NIAID NIH HHS / United States
HG004570 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
P01 AI045757 / AI / NIAID NIH HHS / United States
AI046130 / AI / NIAID NIH HHS / United States
U19 AI046130 / AI / NIAID NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
GM093080 / GM / NIGMS NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States