Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits
Open accessAbstract
DNA variants (SNPs) that predispose to common traits often localize within noncoding regulatory elements such as enhancers. Moreover, loci identified by genome-wide association studies (GWAS) often contain multiple SNPs in linkage disequilibrium (LD), any of which may be causal. Thus, determining the effect of these multiple variant SNPs on target transcript levels has been a major challenge. Here, we provide evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the GWAS association arises from multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type. This finding suggests a “multiple enhancer variant” hypothesis for common traits, where several variants in LD impact multiple enhancers and cooperatively affect gene expression. Using a novel method to delineate enhancer–gene interactions, we show that multiple enhancer variants within a given locus typically target the same gene. Using available data from HapMap and B lymphoblasts as a model system, we provide evidence at numerous loci that multiple enhancer variants cooperatively contribute to altered expression of their gene targets. The effects on target transcript levels tend to be modest and can be either gain- or loss-of-function. Additionally, the genes associated with multiple enhancer variants encode proteins that are often functionally related and enriched in common pathways. Overall, the multiple enhancer variant hypothesis offers a new paradigm by which noncoding variants can confer susceptibility to common traits.
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If multiple GWAS hits exist in the same module, their cumulative presence can significantly contribute to disease development.
“If multiple Genome-Wide Association Study (GWAS) hits exist in the same module, their cumulative presence can significantly contribute to disease development [120, 163, 164].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [164]
The Results section (‘Common disease loci often involve multiple enhancer variants in LD’; page unavailable) proposes that multiple variants at one GWAS locus collectively contribute to the association signal and predisposition to common disease. The paper does not establish the broader claim about multiple GWAS hits in the same module: its finding concerns variants in linkage disequilibrium affecting enhancers of the same gene. (LLM, conf=0.85)
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- Authors
- Corradin, O., Saiakhova, A., Akhtar-Zaidi, B., Myeroff, L., Willis, J., Cowper-Sal·lari, R., Lupien, M., Markowitz, S., & Scacheri, P. C.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center (US)
- University Health Network (CA)
- Corresponding author
- Scacheri, Peter C.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-11-06
- Volume
- 24
- Issue
- 1
- Pages
- 1-13
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3875850
- OpenAlex
- W2010789111
- Cited by
- 366
- References
- 43
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 16 · 2023: 20 · 2022: 25 · 2021: 28 · 2020: 29 · 2019: 26 · 2018: 34 · 2017: 55 · 2016: 56 · 2015: 37 · 2014: 20
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA160356, R01CA155004, P50CA150964)
- National Institute of General Medical Sciences (T32GM008056)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- linkage disequilibrium, enhancer variants, gene expression regulation, enhancer-gene interactions, autoimmune disease susceptibility, rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, ulcerative colitis, single nucleotide polymorphisms, B lymphoblasts, HapMap
- MeSH terms
- Arthritis, Rheumatoid, Autoimmune Diseases, Celiac Disease, Colitis, Ulcerative, Crohn Disease, Enhancer Elements, Genetic, Humans, Lupus Erythematosus, Systemic, Multiple Sclerosis, Phenotype, Genetic Variation, Linkage Disequilibrium, Gene Expression, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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