Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits.

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2016
Journal
Cell
Volume
165
Issue
6
Pages
1530-45
Date Published
2016 Jun 02
ISSN
1097-4172
DOI
10.1016/j.cell.2016.04.048
PubMed ID
27259154
PubMed Central ID
PMC4893171
Links
Grant list
R01 DK103794 / DK / NIDDK NIH HHS / United States
R01 HG006785 / HG / NHGRI NIH HHS / United States
R21 HL120791 / HL / NHLBI NIH HHS / United States
R33 HL120791 / HL / NHLBI NIH HHS / United States