Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay
Open accessAbstract
Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA's capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology.
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The plasmid reporter assay included a positive control variant rs9283753 from Tewhey et al. 2016 to ensure effectiveness and reproducibility.
“To ensure the effectiveness and reproducibility of our design, we also included a positive control variant (rs9283753) from Tewhey et al. 2016 [45].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [45]
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- Authors
- Tewhey, R., Kotliar, D., Park, D. S., Liu, B., Winnicki, S., Reilly, S. K., Andersen, K. G., Mikkelsen, T. S., Lander, E. S., Schaffner, S. F., & Sabeti, P. C.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Tewhey, Ryan
- Sabeti, Pardis C.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 165
- Issue
- 6
- Pages
- 1519-1529
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4957403
- OpenAlex
- W2412481123
- Cited by
- 480
- References
- 37
- Citations by year
- 2026: 39 · 2025: 50 · 2024: 66 · 2023: 39 · 2022: 42 · 2021: 46 · 2020: 53 · 2019: 51 · 2018: 39 · 2017: 42 · 2016: 13
- FWCI
- 39.05
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-02-22)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1dp2od006514-01)
- National Human Genome Research Institute (F32HG009226, K99HG008179, R01HG006785)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Allergy and Infectious Diseases (U19AI110818, R01AI114855)
- 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
- massively parallel reporter assay, cis-eQTL, non-coding variants, gene expression regulation, regulatory function, ankylosing spondylitis, non-coding polymorphisms
- MeSH terms
- Alleles, Gene Expression Regulation, Genetic Techniques, Humans, Sensitivity and Specificity, Spondylitis, Ankylosing, Genetic Variation, Gene Library, Genes, Reporter, Genetic Diseases, Inborn, Quantitative Trait Loci, Hep G2 Cells
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