Genetic and epigenetic fine mapping of causal autoimmune disease variants

Article

关键词: GENOME-WIDE ASSOCIATION;    REGULATORY T-CELLS;    SUSCEPTIBILITY LOCI;    TRANSCRIPTION FACTORS;    ENHANCER LANDSCAPE;    FOXP3 OCCUPANCY;    READ ALIGNMENT;    RISK LOCI;    EXPRESSION;    COMMON;   

DOI  :  10.1038/nature13835

来源: SCIE

【 摘 要 】

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 similar to 90% of causal variants are non-coding, with similar to 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, mostnon-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

【 授权许可】

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