A study published in Nature (2015) investigates the genetic and epigenetic fine-mapping of causal variants for 21 autoimmune diseases. The researchers developed a novel algorithm, PICS, to identify candidate causal variants from genotyping data. They integrated these predictions with transcription and cis-regulatory element annotations derived from RNA and chromatin mapping in primary immune cells, including CD4+ T-cells, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. The study found that ~90% of causal variants are noncoding, 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. Most noncoding risk variants affect non-canonical sequence determinants not well-explained by current gene regulatory models. The study also found that ~60% of likely causal variants map to enhancer-like elements, with preferential correspondence to stimulus-dependent CD4+ T-cell enhancers that respond to immune activation by increasing histone acetylation and transcribing noncoding RNAs. These enhancers frequently reside within extended clusters, but their distinct regulatory patterns and phenotypic associations suggest they represent independent functional units. Causal SNPs are enriched near binding sites for immune-related TFs, but rarely alter their cognate motifs. The study provides a unique resource for the study of autoimmunity, links causal disease variants with high probability to context-specific immune enhancers, and suggests that most non-coding causal variants act by altering non-canonical regulatory sequence rather than recognizable consensus TF motifs. The study also found that the majority of causal variants map to enhancers and frequently coincide with nucleosome-depleted sites bound by immune-related TFs. The resulting resource highlights specific TFs, target loci and pathways with disease-specific or general roles in autoimmunity. However, only a fraction of causal noncoding variants alter recognizable TF sequence motifs. Disease variants have a distinct functional distribution and infrequently overlap peripheral blood eQTLs, which suggests that they exert highly contextual regulatory effects. The study also found that many causal noncoding SNPs modulate TF-dependent enhancer activity (and confer disease risk) by altering adjacent DNA bases whose mechanistic roles are not readily explained by existing gene regulatory models. The study provides a comprehensive understanding of the genetic and epigenetic architecture of autoimmune diseases and highlights the importance of integrating genetic and epigenetic data to identify causal variants.A study published in Nature (2015) investigates the genetic and epigenetic fine-mapping of causal variants for 21 autoimmune diseases. The researchers developed a novel algorithm, PICS, to identify candidate causal variants from genotyping data. They integrated these predictions with transcription and cis-regulatory element annotations derived from RNA and chromatin mapping in primary immune cells, including CD4+ T-cells, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. The study found that ~90% of causal variants are noncoding, 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. Most noncoding risk variants affect non-canonical sequence determinants not well-explained by current gene regulatory models. The study also found that ~60% of likely causal variants map to enhancer-like elements, with preferential correspondence to stimulus-dependent CD4+ T-cell enhancers that respond to immune activation by increasing histone acetylation and transcribing noncoding RNAs. These enhancers frequently reside within extended clusters, but their distinct regulatory patterns and phenotypic associations suggest they represent independent functional units. Causal SNPs are enriched near binding sites for immune-related TFs, but rarely alter their cognate motifs. The study provides a unique resource for the study of autoimmunity, links causal disease variants with high probability to context-specific immune enhancers, and suggests that most non-coding causal variants act by altering non-canonical regulatory sequence rather than recognizable consensus TF motifs. The study also found that the majority of causal variants map to enhancers and frequently coincide with nucleosome-depleted sites bound by immune-related TFs. The resulting resource highlights specific TFs, target loci and pathways with disease-specific or general roles in autoimmunity. However, only a fraction of causal noncoding variants alter recognizable TF sequence motifs. Disease variants have a distinct functional distribution and infrequently overlap peripheral blood eQTLs, which suggests that they exert highly contextual regulatory effects. The study also found that many causal noncoding SNPs modulate TF-dependent enhancer activity (and confer disease risk) by altering adjacent DNA bases whose mechanistic roles are not readily explained by existing gene regulatory models. The study provides a comprehensive understanding of the genetic and epigenetic architecture of autoimmune diseases and highlights the importance of integrating genetic and epigenetic data to identify causal variants.