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Cited by 241Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyChromatin Remodeling and Cancer

Enhancer variants: evaluating functions in common disease

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Corradin, Olivia, Scacheri, Peter C·2014·Genome Medicine
DOI 10.1186/s13073-014-0085-3PMC PMC4254432
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Abstract

Gene enhancer elements are noncoding segments of DNA that play a central role in regulating transcriptional programs that control development, cell identity, and evolutionary processes. Recent studies have shown that noncoding single nucleotide polymorphisms (SNPs) that have been associated with risk for numerous common diseases through genome-wide association studies frequently lie in cell-type-specific enhancer elements. These enhancer variants probably influence transcriptional output, thereby offering a mechanistic basis to explain their association with risk for many common diseases. This review focuses on the identification and interpretation of disease-susceptibility variants that influence enhancer function. We discuss strategies for prioritizing the study of functional enhancer SNPs over those likely to be benign, review experimental and computational approaches to identifying the gene targets of enhancer variants, and highlight efforts to quantify the impact of enhancer variants on target transcript levels and cellular phenotypes. These studies are beginning to provide insights into the mechanistic basis of many common diseases, as well as into how we might translate this knowledge for improved disease diagnosis, prevention and treatments. Finally, we highlight five major challenges often associated with interpreting enhancer variants, and discuss recent technical advances that may help to surmount these challenges.

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  • GWAS-detected genetic variants associated with complex traits and diseases are typically non-coding, non-promoter associated and highly enriched in enhancers.

    “The importance of enhancer variation in human pathology has been further highlighted by genome-wide association studies (GWAS), since GWAS-detected genetic variants associated with complex traits and diseases are typically non-coding, non-promoter associated and highly enriched in enhancers [184, 208, 209].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [208]

  • The majority of sentinel SNPs and their proxies lie within non-coding regions of the genome, and may not necessarily influence the expression of the nearest gene; instead, they likely modulate distal regulatory elements such as enhancers, which regulate distal gene expression.

    “Furthermore, the majority of these sentinel SNPs and their associated proxies lie within non-coding regions of the genome, and may not necessarily influence the expression of the nearest gene. Instead, these variants likely modulate the activity of distal regulatory elements, such as enhancers, which in turn regulate distal gene expression16, which is frequently not the nearest gene.”

    From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [16]

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Authors
Corradin, O., & Scacheri, P. C.
Affiliations
  • Case Western Reserve University (US)
  • Case Comprehensive Cancer Center (US)
Corresponding author
Scacheri, Peter C
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-10-28
Volume
6
Issue
10
Pages
85-85
ISSN
1756-994X (ISSN-L)
DOI
10.1186/s13073-014-0085-3
PMC
PMC4254432
OpenAlex
W2115717891
Cited by
241
References
20
Citations by year
2026: 10 · 2025: 16 · 2024: 31 · 2023: 16 · 2022: 31 · 2021: 31 · 2020: 30 · 2019: 22 · 2018: 23 · 2017: 11 · 2016: 16 · 2015: 4
FWCI
4.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Case Western Reserve University (T32 GM 008056)
  • National Institutes of Health
  • National Cancer Institute (R01CA160356)
  • National Institute on Deafness and Other Communication Disorders (R01DC009410)
  • National Institute of General Medical Sciences (T32GM008056)
  • National Institute of Dental and Craniofacial Research (R01DE018470)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
enhancer variants, cell type-specific enhancers, enhancer function, transcriptional regulation, mRNA levels, disease risk variants

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