Article abstract
Nature Genetics 41, 657 - 665 (2009)
Published online: 24 May 2009 | doi:10.1038/ng.388
Genome-wide and fine-resolution association analysis of malaria in West Africa
Muminatou Jallow1,34, Yik Ying Teo2,3,34, Kerrin S Small2,3,34, Kirk A Rockett2,3, Panos Deloukas3, Taane G Clark2,3, Katja Kivinen3, Kalifa A Bojang1, David J Conway1, Margaret Pinder1, Giorgio Sirugo1, Fatou Sisay-Joof1, Stanley Usen1, Sarah Auburn2,3, Suzannah J Bumpstead3, Susana Campino2,3, Alison Coffey3, Andrew Dunham3, Andrew E Fry2, Angela Green2, Rhian Gwilliam3, Sarah E Hunt3, Michael Inouye3, Anna E Jeffreys2, Alieu Mendy2, Aarno Palotie3, Simon Potter3, Jiannis Ragoussis2, Jane Rogers3, Kate Rowlands2, Elilan Somaskantharajah3, Pamela Whittaker3, Claire Widden3, Peter Donnelly2,4, Bryan Howie4, Jonathan Marchini2,4, Andrew Morris2, Miguel SanJoaquin2,5, Eric Akum Achidi6, Tsiri Agbenyega7, Angela Allen8,9, Olukemi Amodu10, Patrick Corran11, Abdoulaye Djimde12, Amagana Dolo12, Ogobara K Doumbo12, Chris Drakeley13,14, Sarah Dunstan15, Jennifer Evans7,16, Jeremy Farrar15, Deepika Fernando17, Tran Tinh Hien15, Rolf D Horstmann16, Muntaser Ibrahim18, Nadira Karunaweera17, Gilbert Kokwaro19, Kwadwo A Koram20, Martha Lemnge21, Julie Makani22, Kevin Marsh19, Pascal Michon8, David Modiano23, Malcolm E Molyneux5, Ivo Mueller8, Michael Parker24, Norbert Peshu19, Christopher V Plowe25,26, Odile Puijalon27, John Reeder8, Hugh Reyburn13,14, Eleanor M Riley13,14, Anavaj Sakuntabhai27, Pratap Singhasivanon28, Sodiomon Sirima29, Adama Tall30, Terrie E Taylor25,31, Mahamadou Thera12, Marita Troye-Blomberg32, Thomas N Williams19, Michael Wilson20, Dominic P Kwiatkowski2,3, Wellcome Trust Case Control Consortium33 & Malaria Genomic Epidemiology Network33
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.
- MRC Laboratories, Fajara, Banjul, Gambia.
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
- The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
- Department of Statistics, Oxford University, Oxford, UK.
- Malawi–Liverpool–Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Chichiri, Blantyre, Malawi.
- The University of Buea, Buea, South West Province, Cameroon.
- Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
- Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
- National Institute for Biological Standards and Control, Hertfordshire, UK.
- The Malaria Research & Training Centre, University of Bamako, Bamako, Mali.
- London School of Hygiene & Tropical Medicine, London, UK.
- Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
- Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
- Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
- Institute for Endemic Diseases, University of Khartoum, Medical Service Science Campus, Khartoum, Sudan.
- Kenyan Medical Research Institute (KEMRI)–Wellcome Trust Programme, Kilifi, Kenya.
- Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
- National Institute for Medical Research, Dar es Salaam, Tanzania.
- Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
- University of Rome 'La Sapienza', Rome, Italy.
- The Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Headington, Oxford, UK.
- Blantyre Malaria Project, Chichiri, Blantyre 3, Malawi.
- Howard Hughes Medical Institute/University of Maryland School of Medicine, Baltimore, Maryland, USA.
- Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France.
- Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand.
- Centre National de Recherche et Formation sur le Paludisme, Ouagadougou, Burkina Faso.
- lnstitut Pasteur de Dakar, Dakar, Senegal.
- Michigan State University, Department of Internal Medicine, College of Osteopathic Medicine, East Lansing, Michigan, USA.
- The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
- A full list of members is provided in the Supplementary Note online.
- These authors contributed equally to this work.
Correspondence to: Dominic P Kwiatkowski2,3 e-mail: dominic@sanger.ac.uk
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