Genetic and epigenetic fine mapping of causal autoimmune disease variants

KKH Farh, A Marson, J Zhu, M Kleinewietfeld… - Nature, 2015 - nature.com
KKH Farh, A Marson, J Zhu, M Kleinewietfeld, WJ Housley, S Beik, N Shoresh, H Whitton…
Nature, 2015nature.com
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 …
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.
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