Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits
Open accessAbstract
Genome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneously screen 2,756 variants in strong linkage disequilibrium with 75 sentinel variants associated with red blood cell traits. We show that this assay identifies elements with endogenous erythroid regulatory activity. Across 23 sentinel variants, we conservatively identified 32 MPRA functional variants (MFVs). We used targeted genome editing to demonstrate endogenous enhancer activity across 3 MFVs that predominantly affect the transcription of SMIM1, RBM38, and CD164. Functional follow-up of RBM38 delineates a key role for this gene in the alternative splicing program occurring during terminal erythropoiesis. Finally, we provide evidence for how common GWAS-nominated variants can disrupt cell-type-specific transcriptional regulatory pathways.
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MPRAs have been applied to assess biochemically annotated candidate enhancers, candidate enhancers harbouring variants that potentially mediate eQTLs, and even scans of the entire human genome.
“MPRAs have been applied to assess biochemically annotated candidate enhancers77,176-178, candidate enhancers harbouring variants that potentially mediate eQTLs179-182, and even scans of the entire human genome108,183.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [179]
The Introduction and Experimental Procedures describe an MPRA screening variants linked to red-blood-cell GWAS hits, and the Discussion reports that some tested variants lie within endogenous enhancers. The paper does not say these candidates were selected because they might mediate eQTLs; it mentions eQTL studies in the Introduction as a separate way to identify target genes. This verdict concerns the enhancer-variant clause to which this source is attached, not the separately cited whole-genome scans. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFunctional assessments of red blood cell trait-associated variants have revealed common mechanisms by which the activity of the master transcription factor GATA1 might be affected by genetic variants.
“For instance, functional assessments of red blood cell trait-associated variants have revealed common mechanisms by which the activity of the master TF GATA1 might be affected by genetic variants (Ulirsch et al., 2016).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Ulirsch et al., 2016
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- Authors
- Ulirsch, J. C., Nandakumar, S. K., Wang, L., Giani, F. C., Zhang, X., Rogov, P., Melnikov, A., McDonel, P., Do, R., Mikkelsen, T. S., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Sankaran, Vijay G.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 165
- Issue
- 6
- Pages
- 1530-1545
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4893171
- OpenAlex
- W2413629639
- Cited by
- 328
- References
- 57
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 23 · 2023: 24 · 2022: 24 · 2021: 28 · 2020: 44 · 2019: 46 · 2018: 34 · 2017: 38 · 2016: 18
- FWCI
- 36.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Broad Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R33HL120791, R21HL120791)
- National Human Genome Research Institute (R01HG006785)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103794)
- 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
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- red blood cell traits, common genetic variants, massively parallel reporter assay, functional variants, linkage disequilibrium, RBM38, CD164, alternative splicing, terminal erythropoiesis, non-coding variants
- MeSH terms
- Cell Line, Erythrocytes, Erythropoiesis, Genetic Techniques, Humans, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Genetic Variation, Gene Library, Alternative Splicing, Genes, Reporter, Cell Lineage
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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