Rare coding variants pinpoint genes that control human hematological traits.

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Title: Rare coding variants pinpoint genes that control human hematological traits.
Authors: Mousas, A
Ntritsos, G
Chen, M-H
Huffman, JE
Tzoulaki, I
Elliott, P
Psaty, BM
Auer, PL
Johnson, AD
Evangelou, E
Lettre, G
Reiner, AP
Item Type: Journal Article
Abstract: The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45–0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39–0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
Issue Date: 7-Aug-2017
Date of Acceptance: 14-Jul-2017
ISSN: 1553-7404
Publisher: Public Library of Science
Journal / Book Title: Plos Genetics
Volume: 13
Issue: 8
Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Sponsor/Funder: Home Office
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
National Institute for Health Research
Funder's Grant Number: PG0484
RDC01 79560
Keywords: Blood-Cell Consortium
0604 Genetics
Developmental Biology
Publication Status: Published
Article Number: e1006925
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care

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