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

By Satish K Nandakumar, Sean K McFarland, Laura Mateyka, Caleb A. Lareau, Jacob Ulirsch, Leif S Ludwig, Gaurav Agarwal, Jesse M. Engreitz, Bartlomiej Przychodzen, Marie McConkey, Glenn Cowley, John G. Doench, Jaroslaw P. Maciejewski, Benjamin L Ebert, David E Root, Vijay G. Sankaran

Posted 20 Dec 2018
bioRxiv DOI: 10.1101/500579 (published DOI: 10.7554/eLife.44080)

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 genomic regions 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 relevant biological pathways, allowing regulators of human erythropoiesis and blood disease modifiers 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.

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