Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

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http://hdl.handle.net/10138/232542

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Guo , M H , Nandakumar , S K , Ulirsch , J C , Zekavat , S M , Buenrostro , J D , Natarajan , P , Salem , R M , Chiarle , R , Mitt , M , Kals , M , Pärn , K , Fischer , K , Milani , L , Magi , R , Palta , P , Gabriel , S B , Metspalu , A , Lander , E S , Kathiresan , S , Hirschhorn , J N , Esko , T & Sankaran , V G 2017 , ' Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 114 , no. 3 , pp. E327-E336 . https://doi.org/10.1073/pnas.1619052114

Titel: Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms
Författare: Guo, Michael H.; Nandakumar, Satish K.; Ulirsch, Jacob C.; Zekavat, Seyedeh M.; Buenrostro, Jason D.; Natarajan, Pradeep; Salem, Rany M.; Chiarle, Roberto; Mitt, Mario; Kals, Mart; Pärn, Kalle; Fischer, Krista; Milani, Lili; Magi, Reedik; Palta, Priit; Gabriel, Stacey B.; Metspalu, Andres; Lander, Eric S.; Kathiresan, Sekar; Hirschhorn, Joel N.; Esko, Tonu; Sankaran, Vijay G.
Upphovmannens organisation: Institute for Molecular Medicine Finland
Genomics of Neurological and Neuropsychiatric Disorders
Datum: 2017-01-17
Språk: eng
Sidantal: 10
Tillhör serie: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
DOI: https://doi.org/10.1073/pnas.1619052114
Permanenta länken (URI): http://hdl.handle.net/10138/232542
Abstrakt: Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.
Subject: genome sequencing
GWAS
basophils
hematopoiesis
CEBPA
INFLAMMATORY-BOWEL-DISEASE
RARE-VARIANT ASSOCIATION
FETAL-HEMOGLOBIN LEVELS
COPY NUMBER VARIATIONS
BLOOD-CELL TRAITS
WIDE ASSOCIATION
MAST-CELL
GENETIC-VARIATION
C/EBP-ALPHA
PARTITIONING HERITABILITY
3111 Biomedicine
Referentgranskad: Ja
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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