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Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

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Item Type:Article
Title:Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis
Creators Name:Nandakumar, S.K. and McFarland, S.K. and Mateyka, L.M. and Lareau, C.A. and Ulirsch, J.C. and Ludwig, L.S. and Agarwal, G. and Engreitz, J.M. and Przychodzen, B. and McConkey, M. and Cowley, G.S. and Doench, J.G. and Maciejewski, J.P. and Ebert, B.L. and Root, D.E. and Sankaran, V.G.
Abstract:Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.
Keywords:Erythrocytes, Genetic Predisposition to Disease, Genome-Wide Association Study, Hematopoiesis, Inborn Genetic Diseases, Single Nucleotide Polymorphism, Quantitative Trait Loci
Publisher:eLife Sciences Publications
Page Range:e44080
Date:9 May 2019
Official Publication:https://doi.org/10.7554/eLife.44080
PubMed:View item in PubMed

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