TY - JOUR
T1 - Systematic functional dissection of common genetic variation affecting red blood cell traits
AU - Ulirsch, Jacob C.
AU - Nandakumar, Satish K.
AU - Wang, Li
AU - Giani, Felix C.
AU - Zhang, Xiaolan
AU - Rogov, Peter
AU - Melnikov, Alexandre
AU - McDonel, Patrick
AU - Do, Ron
AU - Mikkelsen, Tarjei S.
AU - Sankaran, Vijay G.
N1 - Funding Information:
We would like to thank members of the Sankaran Lab and numerous colleagues for valuable comments and discussions. This work was supported by a Broad Institute/Boston Children’s Hospital collaborative grant and by the National Institutes of Health grants R01 DK103794, R21 HL120791 (to V.G.S.), and R01 HG006785 (to T.S.M.).
Funding Information:
We would like to thank members of the Sankaran Lab and numerous colleagues for valuable comments and discussions. This work was supported by a Broad Institute/Boston Children's Hospital collaborative grant and by the National Institutes of Health grants R01 DK103794, R21 HL120791 (to V.G.S.), and R01 HG006785 (to T.S.M.).
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016/6/2
Y1 - 2016/6/2
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2016.04.048
DO - 10.1016/j.cell.2016.04.048
M3 - Article
C2 - 27259154
AN - SCOPUS:84971578930
SN - 0092-8674
VL - 165
SP - 1530
EP - 1545
JO - Cell
JF - Cell
IS - 6
ER -
