Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry

SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association stud...

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Published inNature genetics Vol. 48; no. 11; pp. 1313 - 1320
Main Authors Corradin, Olivia, Cohen, Andrea J, Luppino, Jennifer M, Bayles, Ian M, Schumacher, Fredrick R, Scacheri, Peter C
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.11.2016
Subjects
Autoimmune diseases
Chromatin - genetics
Cooperation
Disease
Gene expression
Gene Expression Regulation
Genetic aspects
Genetic Predisposition to Disease
Genetic research
Genetic susceptibility
Genetic Variation
Genome-wide association studies
Genome-Wide Association Study
Genomes
Haplotypes
Health aspects
Heritability
Humans
Hypotheses
Identification and classification
Influence
Inheritance Patterns
Linkage Disequilibrium
Lupus
Methods
Multiple sclerosis
Regulatory Elements, Transcriptional
Risk Assessment
Single nucleotide polymorphisms
Studies
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Summary:SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs. Additionally, the clinical risk associated with GWAS SNPs is considerably modified by the genotype of outside variants. Collectively, these findings suggest a potential model in which outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability for complex traits.
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ISSN:1061-4036
1546-1718
DOI:10.1038/ng.3674