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Title: Genome-wide and fine-resolution association analysis of malaria in West Africa
Authors: Muminatou Jallow
Yik Ying Teo
Kerrin S. Small
Kirk A. Rockett
Panos Deloukas
Taane G. Clark
Katja Kivinen
Kalifa A. Bojang
David J. Conway
Margaret Pinder
Giorgio Sirugo
Fatou Sisay-Joof
Stanley Usen
Sarah Auburn
Suzannah J. Bumpstead
Susana Campino
Alison Coffey
Andrew Dunham
Andrew E. Fry
Angela Green
Rhian Gwilliam
Sarah E. Hunt
Michael Inouye
Anna E. Jeffreys
Alieu Mendy
Aarno Palotie
Simon Potter
Jiannis Ragoussis
Jane Rogers
Kate Rowlands
Elilan Somaskantharajah
Pamela Whittaker
Claire Widden
Peter Donnelly
Bryan Howie
Jonathan Marchini
Andrew Morris
Miguel Sanjoaquin
Eric Akum Achidi
Tsiri Agbenyega
Angela Allen
Olukemi Amodu
Patrick Corran
Abdoulaye Djimde
Amagana Dolo
Ogobara K. Doumbo
Chris Drakeley
Sarah Dunstan
Jennifer Evans
Jeremy Farrar
Deepika Fernando
Tran Tinh Hien
Rolf D. Horstmann
Muntaser Ibrahim
Nadira Karunaweera
Gilbert Kokwaro
Kwadwo A. Koram
Martha Lemnge
Julie Makani
Kevin Marsh
Pascal Michon
David Modiano
Malcolm E. Molyneux
Ivo Mueller
Michael Parker
Norbert Peshu
Christopher V. Plowe
Odile Puijalon
John Reeder
Hugh Reyburn
Eleanor M. Riley
Anavaj Sakuntabhai
Pratap Singhasivanon
Sodiomon Sirima
Adama Tall
Terrie E. Taylor
Mahamadou Thera
Marita Troye-Blomberg
Thomas N. Williams
Michael Wilson
Dominic P. Kwiatkowski
Medical Research Council Laboratories Gambia
Wellcome Trust Centre for Human Genetics
Wellcome Trust Sanger Institute
University of Oxford
University of Malawi College of Medicine
University of Buea
Kwame Nkrumah University of Science and Technology
Papua New Guinea Institute of Medical Research
Weatherall Institute of Molecular Medicine
University of Ibadan
National Institute for Biological Standards and Control
University of Bamako
London School of Hygiene & Tropical Medicine
Kilimanjaro Christian Medical Centre
Bernhard Nocht Institut fur Tropenmedizin Hamburg
University of Colombo Faculty of Medicine
Khartoum University
Wellcome Trust Research Laboratories Nairobi
University of Ghana
National Institute for Medical Research Tanga
Muhimbili University of Health and Allied Sciences
Universita degli Studi di Roma La Sapienza
Blantyre Malaria Project
University of Maryland, Baltimore
Institut Pasteur, Paris
Mahidol University
Centre National de Recherche et de Formation sur le Paludisme
Lnstitut Pasteur de Dakar
Michigan State University
Department of Molecular Biosciences, The Wenner-Gren Institute
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Jun-2009
Citation: Nature Genetics. Vol.41, No.6 (2009), 657-665
Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10 7 to P = 4 × 10 14, with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
ISSN: 15461718
Appears in Collections:Scopus 2006-2010

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