Journal article
Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
G Band, QS Le, GM Clarke, K Kivinen, C Hubbart, AE Jeffreys, K Rowlands, EM Leffler, M Jallow, DJ Conway, F Sisay-Joof, G Sirugo, U d’Alessandro, OB Toure, MA Thera, S Konate, S Sissoko, VD Mangano, EC Bougouma, SB Sirima Show all
Nature Communications | Published : 2019
Abstract
The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start ..
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Awarded by Istituto Pasteur-Fondazione Cenci Bolognetti
Funding Acknowledgements
This manuscript is dedicated to the memory of Professor Ogobara Doumbo (1956-2018). We thank all the study participants and the members of the MalariaGEN Consortial Projects 1 and 3 (https://www.malariagen.net/projects). These MalariaGEN Consortial Projects were supported by Wellcome (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundations of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by Wellcome (090770/Z/09/Z; 204911/Z/16/Z). This research was supported by the Medical Research Council (G0600718; G0600230; MR/M006212/1). Wellcome also provides core awards to The Wellcome Centre for Human Genetics (203141/Z/16/Z) and the Wellcome Sanger Institute (206194). C.C.A.S. was supported by a Wellcome Trust Career Development Fellowship grant (097364/Z/11/Z). O.K.A. was supported by the European Community under grant agreement LSHPCT-2004-503578 and Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242095. This paper is submitted with the permission of the Director of KEMRI. A.J.M. was supported by an Oxford University Clinical Academic School Transitional Fellowship and a Wellcome Trust Clinical Research Training Fellowship reference 106289/Z/14/Z. We thank Will Rayner at the Wellcome Centre for Human genetics, Oxford, for supplying genotyping platform strand files. E.A. received partial funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242095-EVIMalaR and the Central African Network for Tuberculosis, HIV/AIDS and Malaria (CANTAM) funded by the European and Developing Countries Clinical Trials Partnership (EDCTP). T.N.W. was funded by Senior Fellowships from the Wellcome Trust (076934/Z/05/Z and 091758/Z/10/Z) and through the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242095-EVIMalaR. The KEMRI-Wellcome Trust Programme is funded through core support from the Wellcome Trust. C.N. is supported through a strategic award to the KEMRI-Wellcome Trust Programme by the Wellcome Trust (084538). Tanzania/KCMC/JMP received funding from MRC grant number (G9901439). The Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) is a Major Overseas Programme of Wellcome. M.M. was funded by a Wellcome Trust Research Leave Fellowship. V.D.M. was funded by Istituto Pasteur-Fondazione Cenci Bolognetti, BioMalPar and Evimalar (European Community FP6,FP7). HLA typing was supported by G.M. under Wellcome Trust grant 100956/Z/13/Z. We thank Sarah Peacock and Sarah Maxwell at the Tissue Typing Laboratory, Addenbrooke's Hospital, Cambridge, for their assistance with HLA typing.