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

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dc.contributor.author Guo, Michael H.
dc.contributor.author Nandakumar, Satish K.
dc.contributor.author Ulirsch, Jacob C.
dc.contributor.author Zekavat, Seyedeh M.
dc.contributor.author Buenrostro, Jason D.
dc.contributor.author Natarajan, Pradeep
dc.contributor.author Salem, Rany M.
dc.contributor.author Chiarle, Roberto
dc.contributor.author Mitt, Mario
dc.contributor.author Kals, Mart
dc.contributor.author Pärn, Kalle
dc.contributor.author Fischer, Krista
dc.contributor.author Milani, Lili
dc.contributor.author Magi, Reedik
dc.contributor.author Palta, Priit
dc.contributor.author Gabriel, Stacey B.
dc.contributor.author Metspalu, Andres
dc.contributor.author Lander, Eric S.
dc.contributor.author Kathiresan, Sekar
dc.contributor.author Hirschhorn, Joel N.
dc.contributor.author Esko, Tonu
dc.contributor.author Sankaran, Vijay G.
dc.date.accessioned 2018-02-16T22:09:42Z
dc.date.available 2021-12-17T18:49:27Z
dc.date.issued 2017-01-17
dc.identifier.citation 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
dc.identifier.other PURE: 80031390
dc.identifier.other PURE UUID: 61ab282e-bfde-410f-970c-2208c642a2d4
dc.identifier.other WOS: 000392095800009
dc.identifier.other Scopus: 85009756476
dc.identifier.other ORCID: /0000-0001-9320-7008/work/30434482
dc.identifier.uri http://hdl.handle.net/10138/232542
dc.description.abstract 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. en
dc.format.extent 10
dc.language.iso eng
dc.relation.ispartof Proceedings of the National Academy of Sciences of the United States of America
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject genome sequencing
dc.subject GWAS
dc.subject basophils
dc.subject hematopoiesis
dc.subject CEBPA
dc.subject INFLAMMATORY-BOWEL-DISEASE
dc.subject RARE-VARIANT ASSOCIATION
dc.subject FETAL-HEMOGLOBIN LEVELS
dc.subject COPY NUMBER VARIATIONS
dc.subject BLOOD-CELL TRAITS
dc.subject WIDE ASSOCIATION
dc.subject MAST-CELL
dc.subject GENETIC-VARIATION
dc.subject C/EBP-ALPHA
dc.subject PARTITIONING HERITABILITY
dc.subject 3111 Biomedicine
dc.title Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms en
dc.type Article
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Genomics of Neurological and Neuropsychiatric Disorders
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1073/pnas.1619052114
dc.relation.issn 0027-8424
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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