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The Polygenic and Monogenic Basis of Blood Traits and Diseases

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

Posted 03 Feb 2020
medRxiv DOI: 10.1101/2020.02.02.20020065

Blood 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.

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