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

被引：222

作者：

Ulirsch, Jacob C. ^{[1
,2
,3
]}

Nandakumar, Satish K. ^{[1
,2
,3
]}

Wang, Li ^{[3
]}

Giani, Felix C. ^{[1
,2
,3
,4
]}

Zhang, Xiaolan ^{[3
]}

Rogov, Peter ^{[3
]}

Melnikov, Alexandre ^{[3
]}

McDonel, Patrick ^{[3
]}

Do, Ron ^{[5
,6
]}

Mikkelsen, Tarjei S. ^{[3
,7
]}

Sankaran, Vijay G. ^{[1
,2
,3
,7
]}

机构：

[1] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] Charite, D-10117 Berlin, Germany

[5] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[7] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

来源：

CELL | 2016年 / 165卷 / 06期

基金：

美国国家卫生研究院;

关键词：

DIAMOND-BLACKFAN ANEMIA; GENOME-WIDE ASSOCIATION; IN-VIVO; TERMINAL ERYTHROPOIESIS; SIDEROBLASTIC ANEMIA; MAMMALIAN ENHANCERS; HUMAN HEMATOPOIESIS; NONCODING VARIANTS; DNA-SEQUENCE; EXPRESSION;

D O I：

10.1016/j.cell.2016.04.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1530 / 1545

页数：16

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