Genome-wide and fine-resolution association analysis of malaria in West Africa

Jallow, Muminatou, Teo, Yik Ying, Small, Kerrin S, Rockett, Kirk A, Deloukas, Panos, Clark, Taane G, Kivinen, Katja, Bojang, Kalifa A, Conway, David J, Pinder, Margaret, Sirugo, Giorgio, Sisay-Joof, Fatou, Usen, Stanley, Auburn, Sarah, Bumpstead, Suzannah J, Campino, Susana, Coffey, Alison, Dunham, Andrew, Fry, Andrew E, Green, Angela, Gwilliam, Rhian, Hunt, Sarah E, Inouye, Michael, Jeffreys, Anna E, Mendy, Alieu, Palotie, Aarno, Potter, Simon, Ragoussis, Jiannis, Rogers, Jane, Rowlands, Kate, Somaskantharajah, Elilan, Whittaker, Pamela, Widden, Claire, Donnelly, Peter, Howie, Bryan, Marchini, Jonathan, Morris, Andrew, SanJoaquin, Miguel, Achidi, Eric Akum, Agbenyega, Tsiri, Allen, Angela, Amodu, Olukemi, Corran, Patrick, Djimde, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara K, Drakeley, Chris, Dunstan, Sarah, Evans, Jennifer, Farrar, Jeremy, Fernando, Deepika, Hien, Tran Tinh, Horstmann, Rolf D, Ibrahim, Muntaser, Karunaweera, Nadira, Kokwaro, Gilbert, Koram, Kwadwo A, Lemnge, Martha, Makani, Julie, Marsh, Kevin, Michon, Pascal, Modiano, David, Molyneux, Malcolm E, Mueller, Ivo, Parker, Michael, Peshu, Norbert, Plowe, Christopher V, Puijalon, Odile, Reeder, John, Reyburn, Hugh, Riley, Eleanor M, Sakuntabhai, Anavaj, Singhasivanon, Pratap, Sirima, Sodiomon, Tall, Adama, Taylor, Terrie E, Thera, Mahamadou, Troye-Blomberg, Marita, Williams, Thomas N, Wilson, Michael, Kwiatkowski, Dominic P, Wellcome Trust Case Control Consortium & Malaria Genomic Epidemi, and Newport, Melanie (2009) Genome-wide and fine-resolution association analysis of malaria in West Africa. Nature Genetics, 41 (6). pp. 657-665. ISSN 1061-4036

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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.

Item Type: Article
Additional Information: Melanie Newport is part of the Wellcome Trust Case Control Consortium (Gambian Controls) and is not listed as a main author
Schools and Departments: Brighton and Sussex Medical School > Primary Care and Public Health
Subjects: R Medicine > RC Internal medicine > RC0251 Constitutional diseases (General)
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Depositing User: pam Thompson
Date Deposited: 13 May 2014 13:52
Last Modified: 13 May 2014 13:52
URI: http://sro.sussex.ac.uk/id/eprint/48369
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