The Polygenic and Monogenic Basis of Blood Traits and Diseases
Authors: Vuckovic Dragana , Bao Erik L. , Akbari Parsa , Lareau Caleb A. , Mousas Abdou , Jiang Tao , Chen Ming-Huei , Raffield Laura M. , Tardaguila Manuel , Huffman Jennifer E. , Ritchie Scott C. , Megy Karyn , Ponstingl Hannes , Penkett Christopher J. , Albers Patrick K. , Wigdor Emilie M. , Sakaue Saori , Moscati Arden , Manansala Regina , Lo Ken Sin , Qian Huijun , Akiyama Masato , Bartz Traci M. , Ben-Shlomo Yoav , Beswick Andrew , Bork-Jensen Jette , Bottinger Erwin P. , Brody Jennifer A. , van Rooij Frank J.A. , Chitrala Kumaraswamy N. , Cho Kelly , Choquet Hélène , Correa Adolfo , Danesh John , Di Angelantonio Emanuele , Dimou Niki , Ding Jingzhong , Elliott Paul , Esko Tõnu , Evans Michele K. , Felix Stephan B. , Floyd James S. , Broer Linda , Grarup Niels , Guo Michael H. , Greinacher Andreas , Haessler Jeff , Hansen Torben , Howson Joanna M. M. , Huang Wei , Jorgenson Eric , Kacprowski Tim , Kähönen Mika , Kamatani Yoichiro , Kanai Masahiro , Karthikeyan Savita , Koskeridis Fotis , Lange Leslie A. , Lehtimäki Terho , Linneberg Allan , Liu Yongmei , Lyytikäinen Leo-Pekka , Manichaikul Ani , Matsuda Koichi , Mohlke Karen L. , Mononen Nina , Murakami Yoshinori , Nadkarni Girish N. , Nikus Kjell , Pankratz Nathan , Pedersen Oluf , Preuss Michael , Psaty Bruce M. , Raitakari Olli T. , Rich Stephen S. , Rodriguez Benjamin A.T. , Rosen Jonathan D. , Rotter Jerome I. , Schubert Petra , Spracklen Cassandra N. , Surendran Praveen , Tang Hua , Tardif Jean-Claude , Ghanbari Mohsen , Völker Uwe , Völzke Henry , Watkins Nicholas A. , Weiss Stefan ,   VA Million Veteran Program, Cai Na , Kundu Kousik , Watt Stephen B. , Walter Klaudia , Zonderman Alan B. , Wilson Peter W.F. , Li Yun , Loos Ruth J.F. , Knight Julian , Georges Michel , Stegle Oliver , Evangelou Evangelos , Okada Yukinori , Roberts David J. , Inouye Michael , Johnson Andrew D. , Auer Paul L. , Astle William J. , Reiner Alexander P. , Butterworth Adam S. , Ouwehand Willem H. , Lettre Guillaume , Sankaran Vijay G. , Soranzo Nicole 
Published: February 2020

SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.