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1. Malaria protection due to sickle haemoglobin depends on parasite genotype

Author

Band, Gavin, Leffler, Ellen M., Jallow, Muminatou, Sisay-Joof, Fatoumatta, Ndila, Carolyne M., Macharia, Alexander W., Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Nguyen, Thuy, Gonçalves, Sónia, Ariani, Cristina V., Stalker, Jim, Pearson, Richard D., Amato, Roberto, Drury, Eleanor, Sirugo, Giorgio, d’Alessandro, Umberto, Bojang, Kalifa A., Marsh, Kevin, Peshu, Norbert, Saelens, Joseph W., Diakité, Mahamadou, Taylor, Steve M., Conway, David J., Williams, Thomas N., Rockett, Kirk A., and Kwiatkowski, Dominic P.

Published
2022
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2. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Author

Abathina, Amadou, Abubakar, Ismaela, Achidi, Eric, Agbenyega, Tsiri, Aiyegbo, Mohammed, Akoto, Alex, Allen, Angela, Allen, Stephen, Amenga-Etego, Lucas, Amodu, Folakemi, Amodu, Olukemi, Anchang-Kimbi, Judith, Ansah, Nana, Ansah, Patrick, Ansong, Daniel, Antwi, Sampson, Anyorigiya, Thomas, Apinjoh, Tobias, Asafo-Agyei, Emmanuel, Asoala, Victor, Atuguba, Frank, Auburn, Sarah, Bah, Abdou, Bamba, Kariatou, Bancone, Germana, Band, Gavin, Barnwell, David, Barry, Abdoulaye, Bauni, Evasius, Besingi, Richard, Bojang, Kalifa, Bougouma, Edith, Bull, Susan, Busby, George, Camara, Abdoulie, Camara, Landing, Campino, Susana, Carter, Richard, Carucci, Dan, Casals-Pascual, Climent, Ceesay, Ndey, Ceesay, Pa, Chau, Tran, Chuong, Ly, Clark, Taane, Clarke, Geraldine, Cole-Ceesay, Ramou, Conway, David, Cook, Katharine, Cook, Olivia, Cornelius, Victoria, Corran, Patrick, Correa, Simon, Cox, Sharon, Craik, Rachel, Danso, Bakary, Davis, Timothy, Day, Nicholas, Deloukas, Panos, Dembele, Awa, deVries, Jantina, Dewasurendra, Rajika, Diakite, Mahamadou, Diarra, Elizabeth, Dibba, Yaya, Diss, Andrea, Djimdé, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Doyle, Alan, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Dunstan, Sarah, Ebonyi, Augustine, Elhassan, Ahmed, Elhassan, Ibrahim, Elzein, Abier, Enimil, Anthony, Esangbedo, Pamela, Evans, Jennifer, Evans, Julie, Farrar, Jeremy, Fernando, Deepika, Fitzpatrick, Kathryn, Fullah, Janet, Garcia, Jacob, Ghansah, Anita, Gottleib, Michael, Green, Angie, Hart, Lee, Hennsman, Meike, Hien, Tran, Hieu, Nguyen, Hilton, Eliza, Hodgson, Abraham, Horstmann, Rolf, Hubbart, Christina, Hughes, Catherine, Hussein, Ayman, Hutton, Robert, Ibrahim, Muntaser, Ishengoma, Deus, Jaiteh, Jula, Jallow, Mariatou, Jallow, Muminatou, Jammeh, Kebba, Jasseh, Momodou, Jeffreys, Anna, Jobarteh, Amie, Johnson, Kimberly, Joseph, Sarah, Jyothi, Dushyanth, Kachala, David, Kamuya, Dorcas, Kanyi, Haddy, Karunajeewa, Harin, Karunaweera, Nadira, Keita, Momodou, Kerasidou, Angeliki, Khan, Aja, Kivinen, Katja, Kokwaro, Gilbert, Konate, Amadou, Konate, Salimata, Koram, Kwadwo, Kwiatkowski, Dominic, Laman, Moses, Le, Si, Leffler, Ellen, Lemnge, Martha, Lin, Enmoore, Ly, Alioune, Macharia, Alexander, MacInnis, Bronwyn, Mai, Nguyen, Makani, Julie, Malangone, Cinzia, Mangano, Valentina, Manjurano, Alphaxard, Manneh, Lamin, Manning, Laurens, Manske, Magnus, Marsh, Kevin, Marsh, Vicki, Maslen, Gareth, Maxwell, Caroline, Mbunwe, Eric, McCreight, Marilyn, Mead, Daniel, Mendy, Alieu, Mendy, Anthony, Mensah, Nathan, Michon, Pascal, Miles, Alistair, Miotto, Olivo, Modiano, David, Mohamed, Hiba, Molloy, Sile, Molyneux, Malcolm, Molyneux, Sassy, Moore, Mike, Moyes, Catherine, Mtei, Frank, Mtove, George, Mueller, Ivo, Mugri, Regina, Munthali, Annie, Mutabingwa, Theonest, Nadjm, Behzad, Ndi, Andre, Ndila, Carolyne, Newton, Charles, Niangaly, Amadou, Njie, Haddy, Njie, Jalimory, Njie, Madi, Njie, Malick, Njie, Sophie, Njiragoma, Labes, Nkrumah, Francis, Ntunthama, Neema, Nyika, Aceme, Nyirongo, Vysaul, O'Brien, John, Obu, Herbert, Oduro, Abraham, Ofori, Alex, Olaniyan, Subulade, Olaosebikan, Rasaq, Oluoch, Tom, Omotade, Olayemi, Oni, Olajumoke, Onykwelu, Emmanuel, Opi, Daniel, Orimadegun, Adebola, O'Riordan, Sean, Ouedraogo, Issa, Oyola, Samuel, Parker, Michael, Pearson, Richard, Pensulo, Paul, Peshu, Norbert, Phiri, Ajib, Phu, Nguyen, Pinder, Margaret, Pirinen, Matti, Plowe, Chris, Potter, Claire, Poudiougou, Belco, Puijalon, Odile, Quyen, Nguyen, Ragoussis, Ioannis, Ragoussis, Jiannis, Rasheed, Oba, Reeder, John, Reyburn, Hugh, Riley, Eleanor, Risley, Paul, Rockett, Kirk, Rodford, Joanne, Rogers, Jane, Rogers, William, Rowlands, Kate, Ruano-Rubio, Valentín, Sabally-Ceesay, Kumba, Sadiq, Abubacar, Saidy-Khan, Momodou, Saine, Horeja, Sakuntabhai, Anavaj, Sall, Abdourahmane, Sambian, David, Sambou, Idrissa, SanJoaquin, Miguel, Sepúlveda, Nuno, Shah, Shivang, Shelton, Jennifer, Siba, Peter, Silva, Nilupa, Simmons, Cameron, Simpore, Jaques, Singhasivanon, Pratap, Sinh, Dinh, Sirima, Sodiomon, Sirugo, Giorgio, Sisay-Joof, Fatoumatta, Sissoko, Sibiry, Small, Kerrin, Somaskantharajah, Elilan, Spencer, Chris, Stalker, Jim, Stevens, Marryat, Suriyaphol, Prapat, Sylverken, Justice, Taal, Bintou, Tall, Adama, Taylor, Terrie, Teo, Yik, Thai, Cao, Thera, Mahamadou, Titanji, Vincent, Toure, Ousmane, Troye-Blomberg, Marita, Usen, Stanley, Uyoga, Sophie, Vanderwal, Aaron, Wangai, Hannah, Watson, Renee, Williams, Thomas, Wilson, Michael, Wrigley, Rebecca, Yafi, Clarisse, Yamoah, Lawrence, Ndila, Carolyne M, Macharia, Alexander W, Nyutu, Gideon, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O, Mturi, Neema, Tsofa, Benjamin, Clark, Taane G, Kariuki, Silvia, Mackinnon, Margaret, Maitland, Kathryn, Kwiatkowski, Dominic P, Rockett, Kirk A, and Williams, Thomas N

Published
2018
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3. Resistance to malaria through structural variation of red blood cell invasion receptors

Author

Malaria Genomic Epidemiology Network, Leffler, Ellen M., Band, Gavin, Busby, George B. J., Kivinen, Katja, Le, Quang Si, Clarke, Geraldine M., Bojang, Kalifa A., Conway, David J., Jallow, Muminatou, Sisay-Joof, Fatoumatta, Bougouma, Edith C., Mangano, Valentina D., Modiano, David, Sirima, Sodiomon B., Achidi, Eric, Apinjoh, Tobias O., Marsh, Kevin, Ndila, Carolyne M., Peshu, Norbert, Williams, Thomas N., Drakeley, Chris, Manjurano, Alphaxard, Reyburn, Hugh, Riley, Eleanor, Kachala, David, Molyneux, Malcolm, Nyirongo, Vysaul, Taylor, Terrie, Thornton, Nicole, Tilley, Louise, Grimsley, Shane, Drury, Eleanor, Stalker, Jim, Cornelius, Victoria, Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Rockett, Kirk A., Spencer, Chris C. A., and Kwiatkowski, Dominic P.

Published
2017

5. The African Genome Variation Project shapes medical genetics in Africa

Author

Gurdasani, Deepti, Carstensen, Tommy, Tekola-Ayele, Fasil, Pagani, Luca, Tachmazidou, Ioanna, Hatzikotoulas, Konstantinos, Karthikeyan, Savita, Iles, Louise, Pollard, Martin O., Choudhury, Ananyo, Ritchie, Graham R. S., Xue, Yali, Asimit, Jennifer, Nsubuga, Rebecca N., Young, Elizabeth H., Pomilla, Cristina, Kivinen, Katja, Rockett, Kirk, Kamali, Anatoli, Doumatey, Ayo P., Asiki, Gershim, Seeley, Janet, Sisay-Joof, Fatoumatta, Jallow, Muminatou, Tollman, Stephen, Mekonnen, Ephrem, Ekong, Rosemary, Oljira, Tamiru, Bradman, Neil, Bojang, Kalifa, Ramsay, Michele, Adeyemo, Adebowale, Bekele, Endashaw, Motala, Ayesha, Norris, Shane A., Pirie, Fraser, Kaleebu, Pontiano, Kwiatkowski, Dominic, Tyler-Smith, Chris, Rotimi, Charles, Zeggini, Eleftheria, and Sandhu, Manjinder S.

Published
2015
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6. Malaria protection due to sickle haemoglobin depends on parasite genotype

Author

Band, Gavin, primary, Leffler, Ellen M., additional, Jallow, Muminatou, additional, Sisay-Joof, Fatoumatta, additional, Ndila, Carolyne M., additional, Macharia, Alexander W., additional, Hubbart, Christina, additional, Jeffreys, Anna E., additional, Rowlands, Kate, additional, Nguyen, Thuy, additional, Gonçalves, Sónia, additional, Ariani, Cristina V., additional, Stalker, Jim, additional, Pearson, Richard D., additional, Amato, Roberto, additional, Drury, Eleanor, additional, Sirugo, Giorgio, additional, d’Alessandro, Umberto, additional, Bojang, Kalifa A., additional, Marsh, Kevin, additional, Peshu, Norbert, additional, Saelens, Joseph W., additional, Diakité, Mahamadou, additional, Taylor, Steve M., additional, Conway, David J., additional, Williams, Thomas N., additional, Rockett, Kirk A., additional, and Kwiatkowski, Dominic P., additional

Published
2021
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9. The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Author

Band, Gavin, primary, Leffler, Ellen M., additional, Jallow, Muminatou, additional, Sisay-Joof, Fatoumatta, additional, Ndila, Carolyne M., additional, Macharia, Alexander W., additional, Hubbart, Christina, additional, Jeffreys, Anna E., additional, Rowlands, Kate, additional, Nguyen, Thuy, additional, Goncalves, Sonia M., additional, Ariani, Cristina V., additional, Stalker, Jim, additional, Pearson, Richard D., additional, Amato, Roberto, additional, Drury, Eleanor, additional, Sirugo, Giorgio, additional, D’Alessandro, Umberto, additional, Bojang, Kalifa A., additional, Marsh, Kevin, additional, Peshu, Norbert, additional, Conway, David J., additional, Williams, Thomas N., additional, Rockett, Kirk A., additional, and Kwiatkowski, Dominic P., additional

Published
2021
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11. Insights into malaria susceptibility using genome - wide data on 17,000 individuals from Africa, Asia and Oceania

Author

Band, Gavin, Le, Quang Si, Clarke, Geraldine M., Kivinen, Katja, Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Leffler, Ellen M., Jallow, Muminatou, Conway, David J., Sisay-Joof, Fatoumatta, Sirugo, Giorgio, d’Alessandro, Umberto, Toure, Ousmane B., Thera, Mahamadou A., Konate, Salimata, Sissoko, Sibiri, Mangano, Valentina D., Bougouma, Edith C., Sirima, Sodiomon B., Amenga-Etego, Lucas N., Ghansah, Anita K., Hodgson, Abraham V. O., Wilson, Michael D., Enimil, Anthony, Ansong, Daniel, Evans, Jennifer, Ademola, Subulade A., Apinjoh, Tobias O., Ndila, Carolyne M., Manjurano, Alphaxard, Drakeley, Chris, Reyburn, Hugh, Phu, Nguyen Hoan, Ngoc Quyen, Nguyen Thi, Thai, Cao Quang, Hien, Tran Tinh, Teo, Yik Ying, Manning, Laurens, Laman, Moses, Michon, Pascal, Karunajeewa, Harin, Siba, Peter, Allen, Steve, Allen, Angela, Bahlo, Melanie, Davis, Timothy M. E., Cornelius, Victoria, Shelton, Jennifer, Spencer, Chris C.A., Busby, George B.J., Kerasidou, Angeliki, Drury, Eleanor, Stalker, Jim, Dilthey, Alexander, Mentzer, Alexander J., McVean, Gil, Bojang, Kalifa A., Doumbo, Ogobara, Modiano, David, Koram, Kwadwo A., Agbenyega, Tsiri, Amodu, Olukemi K., Achidi, Eric, Williams, Thomas N., Marsh, Kevin, Riley, Eleanor M., Molyneux, Malcolm, Taylor, Terrie, Dunstan, Sarah J., Farrar, Jeremy, Mueller, Ivo, Rockett, Kirk A., Kwiatkowski, Dominic P., HUS Gynecology and Obstetrics, and Wellcome Trust

Subjects
0301 basic medicine, Male, RESISTANCE LOCI, General Physics and Astronomy, Datasets as Topic, Genome-wide association study, Disease, Genome-wide association studies, DISEASE, 0302 clinical medicine, HLA Antigens, BLOOD-GROUP, Prevalence, qu_460, Malaria, Falciparum, Child, lcsh:Science, GENE-EXPRESSION, 11832 Microbiology and virology, Genetics, Multidisciplinary, PLASMODIUM-FALCIPARUM, biology, GENOTYPE, 3. Good health, ALLELE, Cerebral Malaria, Chromosomes, Human, Pair 6, Female, Malaria Genomic Epidemiology Network, Medical genomics, Adult, Asia, Science, Oceania, wa_395, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, malaria genomic epidemiology, plasmodium-falciparum, genotype, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, parasitic diseases, medicine, Immunogenetics, Humans, Genetic Predisposition to Disease, Genetic association, TRANSCRIPTOME ANALYSES, IDENTIFICATION, Case-control study, Plasmodium falciparum, wc_755, General Chemistry, biology.organism_classification, medicine.disease, wc_750, Malaria, ASSOCIATION ANALYSIS, 030104 developmental biology, Infectious disease (medical specialty), Genetic Loci, Case-Control Studies, Africa, lcsh:Q, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
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 site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on the genetic determinants of malaria resistance in diverse populations., Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.

Published
2019

12. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Author

Ndila, Carolyne M, Uyoga, Sophie, Macharia, Alexander W, Nyutu, Gideon, Peshu, Norbert, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O, Mturi, Neema, Tsofa, Benjamin, Sepúlveda, Nuno, Clark, Taane G, Band, Gavin, Clarke, Geraldine, Rowlands, Kate, Hubbart, Christina, Jeffreys, Anna, Kariuki, Silvia, Marsh, Kevin, Mackinnon, Margaret, Maitland, Kathryn, Kwiatkowski, Dominic P, Rockett, Kirk A, Williams, Thomas N, Abathina, Amadou, Abubakar, Ismaela, Achidi, Eric, Agbenyega, Tsiri, Aiyegbo, Mohammed, Akoto, Alex, Allen, Angela, Allen, Stephen, Amenga-Etego, Lucas, Amodu, Folakemi, Amodu, Olukemi, Anchang-Kimbi, Judith, Ansah, Nana, Ansah, Patrick, Ansong, Daniel, Antwi, Sampson, Anyorigiya, Thomas, Apinjoh, Tobias, Asafo-Agyei, Emmanuel, Asoala, Victor, Atuguba, Frank, Auburn, Sarah, Bah, Abdou, Bamba, Kariatou, Bancone, Germana, Barnwell, David, Barry, Abdoulaye, Bauni, Evasius, Besingi, Richard, Bojang, Kalifa, Bougouma, Edith, Bull, Susan, Busby, George, Camara, Abdoulie, Camara, Landing, Campino, Susana, Carter, Richard, Carucci, Dan, Casals-Pascual, Climent, Ceesay, Ndey, Ceesay, Pa, Chau, Tran, Chuong, Ly, Clark, Taane, Cole-Ceesay, Ramou, Conway, David, Cook, Katharine, Cook, Olivia, Cornelius, Victoria, Corran, Patrick, Correa, Simon, Cox, Sharon, Craik, Rachel, Danso, Bakary, Davis, Timothy, Day, Nicholas, Deloukas, Panos, Dembele, Awa, Devries, Jantina, Dewasurendra, Rajika, Diakite, Mahamadou, Diarra, Elizabeth, Dibba, Yaya, Diss, Andrea, Djimdé, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Doyle, Alan, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Dunstan, Sarah, Ebonyi, Augustine, Elhassan, Ahmed, Elhassan, Ibrahim, Elzein, Abier, Enimil, Anthony, Esangbedo, Pamela, Evans, Jennifer, Evans, Julie, Farrar, Jeremy, Fernando, Deepika, Fitzpatrick, Kathryn, Fullah, Janet, Garcia, Jacob, Ghansah, Anita, Gottleib, Michael, Green, Angie, Hart, Lee, Hennsman, Meike, Hien, Tran, Hieu, Nguyen, Hilton, Eliza, Hodgson, Abraham, Horstmann, Rolf, Hughes, Catherine, Hussein, Ayman, Hutton, Robert, Ibrahim, Muntaser, Ishengoma, Deus, Jaiteh, Jula, Jallow, Mariatou, Jallow, Muminatou, Jammeh, Kebba, Jasseh, Momodou, Jobarteh, Amie, Johnson, Kimberly, Joseph, Sarah, Jyothi, Dushyanth, Kachala, David, Kamuya, Dorcas, Kanyi, Haddy, Karunajeewa, Harin, Karunaweera, Nadira, Keita, Momodou, Kerasidou, Angeliki, Khan, Aja, Kivinen, Katja, Kokwaro, Gilbert, Konate, Amadou, Konate, Salimata, Koram, Kwadwo, Kwiatkowski, Dominic, Laman, Moses, Si, Le, Leffler, Ellen, Lemnge, Martha, Lin, Enmoore, Alioune, Ly, Macharia, Alexander, Macinnis, Bronwyn, Mai, Nguyen, Makani, Julie, Malangone, Cinzia, Mangano, Valentina, Manjurano, Alphaxard, Manneh, Lamin, Manning, Laurens, Manske, Magnus, Marsh, Vicki, Maslen, Gareth, Maxwell, Caroline, Mbunwe, Eric, Mccreight, Marilyn, Mead, Daniel, Mendy, Alieu, Mendy, Anthony, Mensah, Nathan, Michon, Pascal, Miles, Alistair, Miotto, Olivo, Modiano, David, Mohamed, Hiba, Molloy, Sile, Molyneux, Malcolm, Molyneux, Sassy, Moore, Mike, Moyes, Catherine, Mtei, Frank, Mtove, George, Mueller, Ivo, Mugri, Regina, Munthali, Annie, Mutabingwa, Theonest, Nadjm, Behzad, Ndi, Andre, Ndila, Carolyne, Newton, Charles, Niangaly, Amadou, Njie, Haddy, Njie, Jalimory, Njie, Madi, Njie, Malick, Njie, Sophie, Njiragoma, Labes, Nkrumah, Francis, Ntunthama, Neema, Nyika, Aceme, Nyirongo, Vysaul, O'Brien, John, Obu, Herbert, Oduro, Abraham, Ofori, Alex, Olaniyan, Subulade, Olaosebikan, Rasaq, Oluoch, Tom, Omotade, Olayemi, Oni, Olajumoke, Onykwelu, Emmanuel, Opi, Daniel, Orimadegun, Adebola, O'Riordan, Sean, Ouedraogo, Issa, Oyola, Samuel, Parker, Michael, Pearson, Richard, Pensulo, Paul, Phiri, Ajib, Phu, Nguyen, Pinder, Margaret, Pirinen, Matti, Plowe, Chris, Potter, Claire, Poudiougou, Belco, Puijalon, Odile, Quyen, Nguyen, Ragoussis, Ioannis, Ragoussis, Jiannis, Rasheed, Oba, Reeder, John, Reyburn, Hugh, Riley, Eleanor, Risley, Paul, Rockett, Kirk, Rodford, Joanne, Rogers, Jane, Rogers, William, Ruano-Rubio, Valentín, Sabally-Ceesay, Kumba, Sadiq, Abubacar, Saidy-Khan, Momodou, Saine, Horeja, Sakuntabhai, Anavaj, Sall, Abdourahmane, Sambian, David, Sambou, Idrissa, Sanjoaquin, Miguel, Shah, Shivang, Shelton, Jennifer, Siba, Peter, Silva, Nilupa, Simmons, Cameron, Simpore, Jaques, Singhasivanon, Pratap, Sinh, Dinh, Sirima, Sodiomon, Sirugo, Giorgio, Sisay-Joof, Fatoumatta, Sissoko, Sibiry, Small, Kerrin, Somaskantharajah, Elilan, Spencer, Chris, Stalker, Jim, Stevens, Marryat, Suriyaphol, Prapat, Sylverken, Justice, Taal, Bintou, Tall, Adama, Taylor, Terrie, Teo, Yik, Thai, Cao, Thera, Mahamadou, Titanji, Vincent, Toure, Ousmane, Troye-Blomberg, Marita, Usen, Stanley, Vanderwal, Aaron, Wangai, Hannah, Watson, Renee, Williams, Thomas, Wilson, Michael, Wrigley, Rebecca, Yafi, Clarisse, Yamoah, Lawrence, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, London School of Hygiene and Tropical Medicine (LSHTM), The Wellcome Trust Sanger Institute [Cambridge], St Mary's Hospital, Imperial College, TNW and MM are funded through awards from the Wellcome Trust (grants 091758 and 202800 [to TNW] and grant 088634 [to MM]) and DPK and TGC receive support from the Medical Research Council (grant G19/9 [to DPK] and grants MR/K000551/1, MR/M01360X/1, MR/N010469/1, and MC_PC_15103 [to TGC]). The research leading to these results received funding from the European Community's Seventh Framework Programme (FP7/2007-2013, under grant agreement 242095) and from the Medical Research Council (grant G0600718). MalariaGEN is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (grant 566) as part of the Bill & Melinda Gates' Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (grant 090770/Z/09/Z). Support was also provided by the Medical Research Council (grant G0600718). The Wellcome Trust also provides core awards to the Wellcome Trust Centre for Human Genetics (grant 090532/Z/09/Z) and to the Wellcome Trust Sanger Institute (grant 098051). This work forms part of a larger collaboration with the MalariaGEN Consortium, whose members are listed at http://www.malariagen.net/projects/host/consortium-members. This paper is published with permission from the Director of the Kenya Medical Research Institute (KEMRI)., MalariaGEN Consortium (Anavaj Sakuntabhai), and European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009)

Subjects
Case-Control Studies, Child, Child, Preschool, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Kenya, Malaria, Male, Polymorphism, Genetic, Hematology, macromolecular substances, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Article, Genetic, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parasitic diseases, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Polymorphism, Preschool
Abstract

Summary Background Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.

Published
2018

14. Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania.

Author

Malaria Genomic Epidemiology Network, Band, Gavin, Le, Quang Si, Clarke, Geraldine M., Kivinen, Katja, Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Leffler, Ellen M., Jallow, Muminatou, Conway, David J., Sisay-Joof, Fatoumatta, Sirugo, Giorgio, d'Alessandro, Umberto, Toure, Ousmane B., Thera, Mahamadou A., Konate, Salimata, Sissoko, Sibiri, Mangano, Valentina D., and Bougouma, Edith C.

Subjects
MALARIA, DISEASE susceptibility, COMMUNICABLE diseases, BIRTH control, CHROMOSOMES
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 site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on thegenetic determinants of malaria resistance in diverse populations. Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6. [ABSTRACT FROM AUTHOR]

Published
2019
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16. Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations

Author

Band, Gavin, Le, Quang Si, Jostins, Luke, Pirinen, Matti, Kivinen, Katja, Jallow, Muminatou, Sisay-Joof, Fatoumatta, Bojang, Kalifa, Pinder, Margaret, Sirugo, Giorgio, Conway, David J, Nyirongo, Vysaul, Kachala, David, Molyneux, Malcolm, Taylor, Terrie, Ndila, Carolyne, Peshu, Norbert, Marsh, Kevin, Williams, Thomas N, Alcock, Daniel, Andrews, Robert, Edkins, Sarah, Gray, Emma, Hubbart, Christina, Jeffreys, Anna, Rowlands, Kate, Schuldt, Kathrin, Clark, Taane G, Small, Kerrin S, Teo, Yik Ying, Kwiatkowski, Dominic P, Rockett, Kirk A, Barrett, Jeffrey C, Spencer, Chris CA, and Malaria Genomic Epidemiology Network

Subjects
wa_950, qu_500, qu_550, wc_750
Abstract

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.

Published
2013

17. The African Genome Variation Project shapes medical genetics in Africa

Author

Gurdasani, Deepti, primary, Carstensen, Tommy, additional, Tekola-Ayele, Fasil, additional, Pagani, Luca, additional, Tachmazidou, Ioanna, additional, Hatzikotoulas, Konstantinos, additional, Karthikeyan, Savita, additional, Iles, Louise, additional, Pollard, Martin O., additional, Choudhury, Ananyo, additional, Ritchie, Graham R. S., additional, Xue, Yali, additional, Asimit, Jennifer, additional, Nsubuga, Rebecca N., additional, Young, Elizabeth H., additional, Pomilla, Cristina, additional, Kivinen, Katja, additional, Rockett, Kirk, additional, Kamali, Anatoli, additional, Doumatey, Ayo P., additional, Asiki, Gershim, additional, Seeley, Janet, additional, Sisay-Joof, Fatoumatta, additional, Jallow, Muminatou, additional, Tollman, Stephen, additional, Mekonnen, Ephrem, additional, Ekong, Rosemary, additional, Oljira, Tamiru, additional, Bradman, Neil, additional, Bojang, Kalifa, additional, Ramsay, Michele, additional, Adeyemo, Adebowale, additional, Bekele, Endashaw, additional, Motala, Ayesha, additional, Norris, Shane A., additional, Pirie, Fraser, additional, Kaleebu, Pontiano, additional, Kwiatkowski, Dominic, additional, Tyler-Smith, Chris, additional, Rotimi, Charles, additional, Zeggini, Eleftheria, additional, and Sandhu, Manjinder S., additional

Published
2014
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18. Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Author

Clarke, Geraldine M., Rockett, Kirk, Kivinen, Katja, Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Jallow, Muminatou, Conway, David J., Bojang, Kalifa A., Pinder, Margaret, Usen, Stanley, Sisay-Joof, Fatoumatta, Sirugo, Giorgio, Toure, Ousmane, Thera, Mahamadou A., Konate, Salimata, Sissoko, Sibiry, Niangaly, Amadou, Poudiougou, Belco, and Mangano, Valentina D.

Published
2017
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20. Effects of Genetic Variation at the CYP2C19 / CYP2C9 Locus on Pharmacokinetics of Chlorcycloguanil in Adult Gambians

Author

Janha, Ramatoulie E, primary, Sisay-Joof, Fatoumatta, additional, Hamid-Adiamoh, Majidah, additional, Worwui, Archibald, additional, Chapman, Hannah L, additional, Opara, Hyginus, additional, Dunyo, Sam, additional, Milligan, Paul, additional, Rockett, Kirk, additional, Winstanley, Peter, additional, Pirmohamed, Munir, additional, Miller, Ann K, additional, Conway, David J, additional, and Walton, Robert T, additional

Published
2009
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22. Immunoglobulin G Antibodies to Merozoite Surface Antigens Are Associated with Recovery from Chloroquine-Resistant Plasmodium falciparum in Gambian Children

Author

Pinder, Margaret, Sutherland, Colin J., Sisay-Joof, Fatoumatta, Ismaili, Jamila, McCall, Matthew B. B., Ord, Rosalyn, Hallett, Rachel, Holder, Anthony A., and Milligan, Paul

Abstract

We examined the hypothesis that recovery from uncomplicated malaria in patients carrying drug-resistant Plasmodium falciparum is a measure of acquired functional immunity and may therefore be associated with humoral responses to candidate vaccine antigens. Gambian children with malaria were treated with chloroquine in 28-day trials, and recovery was defined primarily as the absence of severe clinical malaria at any time and absence of parasitemia with fever after 3 days. Plasma samples from these children were assayed by enzyme-linked immunosorbent assay for immunoglobulin G (IgG) to recombinant merozoite antigens: apical membrane antigen 1 (AMA-1) and the 19-kDa C-terminal region of merozoite surface protein 1 (MSP-119), including antigenic variants of MSP-119 with double and triple substitutions. Antigen-specific IgG was more frequent in children who recovered, particularly that for MSP-119 (age-adjusted odds ratios: 0.32 [95% confidence interval, 0.05, 1.87; P = 0.168] for AMA-1, 0.19 [0.03, 1.11; P = 0.019] for recombinant MSP-119, 0.24 [0.04, 1.31; P = 0.032] for the recombinant MSP-119 double variant, and 0.18 [0.03, 0.97; P = 0.013] for the triple variant). IgG titers to MSP-119 and to the triple variant were higher in plasma samples taken 7 days after chloroquine treatment from children who carried resistant parasites but recovered and remained parasite free. Moreover, in children who were parasitemic on day 14 or day 28, there was an age-independent relationship between parasite density and IgG to both MSP-119 and the triple variant (coefficients of –0.550 and –0.590 and P values of 0.002 and 0.001, respectively). The results validate the use of this approach to identify antigens that are associated with protection from malaria.

Published
2006

23. Immunoglobulin G Antibodies to Merozoite Surface Antigens Are Associated with Recovery from Chloroquine-Resistant Plasmodium falciparumin Gambian Children

Author

Pinder, Margaret, Sutherland, Colin J., Sisay-Joof, Fatoumatta, Ismaili, Jamila, McCall, Matthew B. B., Ord, Rosalyn, Hallett, Rachel, Holder, Anthony A., and Milligan, Paul

Abstract

ABSTRACTWe examined the hypothesis that recovery from uncomplicated malaria in patients carrying drug-resistant Plasmodium falciparumis a measure of acquired functional immunity and may therefore be associated with humoral responses to candidate vaccine antigens. Gambian children with malaria were treated with chloroquine in 28-day trials, and recovery was defined primarily as the absence of severe clinical malaria at any time and absence of parasitemia with fever after 3 days. Plasma samples from these children were assayed by enzyme-linked immunosorbent assay for immunoglobulin G (IgG) to recombinant merozoite antigens: apical membrane antigen 1 (AMA-1) and the 19-kDa C-terminal region of merozoite surface protein 1 (MSP-119), including antigenic variants of MSP-119with double and triple substitutions. Antigen-specific IgG was more frequent in children who recovered, particularly that for MSP-119(age-adjusted odds ratios: 0.32 [95% confidence interval, 0.05, 1.87; P= 0.168] for AMA-1, 0.19 [0.03, 1.11; P= 0.019] for recombinant MSP-119, 0.24 [0.04, 1.31; P= 0.032] for the recombinant MSP-119double variant, and 0.18 [0.03, 0.97; P= 0.013] for the triple variant). IgG titers to MSP-119and to the triple variant were higher in plasma samples taken 7 days after chloroquine treatment from children who carried resistant parasites but recovered and remained parasite free. Moreover, in children who were parasitemic on day 14 or day 28, there was an age-independent relationship between parasite density and IgG to both MSP-119and the triple variant (coefficients of −0.550 and −0.590 and Pvalues of 0.002 and 0.001, respectively). The results validate the use of this approach to identify antigens that are associated with protection from malaria.

Published
2006
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24. The African Genome Variation Project shapes medical genetics in Africa

Author

Gurdasani, Deepti, Carstensen, Tommy, Tekola-Ayele, Fasil, Pagani, Luca, Tachmazidou, Ioanna, Hatzikotoulas, Konstantinos, Karthikeyan, Savita, Iles, Louise, Pollard, Martin O, Choudhury, Ananyo, Ritchie, Graham RS, Xue, Yali, Asimit, Jennifer, Nsubuga, Rebecca N, Young, Elizabeth H, Pomilla, Cristina, Kivinen, Katja, Rockett, Kirk, Kamali, Anatoli, Doumatey, Ayo P, Asiki, Gershim, Seeley, Janet, Sisay-Joof, Fatoumatta, Jallow, Muminatou, Tollman, Stephen, Mekonnen, Ephrem, Ekong, Rosemary, Oljira, Tamiru, Bradman, Neil, Bojang, Kalifa, Ramsay, Michele, Adeyemo, Adebowale, Bekele, Endashaw, Motala, Ayesha, Norris, Shane A, Pirie, Fraser, Kaleebu, Pontiano, Kwiatkowski, Dominic, Tyler-Smith, Chris, Rotimi, Charles, Zeggini, Eleftheria, and Sandhu, Manjinder S

Subjects
Europe, Asia, Genome, Human, Risk Factors, Genetics, Medical, parasitic diseases, Africa, Genetic Variation, Humans, Genomics, Selection, Genetic, Africa South of the Sahara, 3. Good health
Abstract

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

25. Resistance to malaria through structural variation of red blood cell invasion receptors.

Author

Leffler, Ellen M., Band, Gavin, Busby, George B. J., Kivinen, Katja, Si Le, Quang, Clarke, Geraldine M., Bojang, Kalifa A., Conway, David J., Jallow, Muminatou, Sisay-Joof, Fatoumatta, Bougouma, Edith C., Mangano, Valentina D., Modiano, David, Sirima, Sodiomon B., Achidi, Eric, Apinjoh, Tobias O., Marsh, Kevin, Ndila, Carolyne M., Peshu, Norbert, and Williams, Thomas N.

Published
2017
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26. Haplotypic analysis of the TNFlocus by association efficiency and entropy

Author

Ackerman, Hans, Usen, Stanley, Mott, Richard, Richardson, Anna, Sisay-Joof, Fatoumatta, Katundu, Pauline, Taylor, Terrie, Ward, Ryk, Molyneux, Malcolm, Pinder, Margaret, and Kwiatkowski, Dominic P

Abstract

Background: To understand the causal basis of TNFassociations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and population-based reconstruction methods. Results: We found 32 different haplotypes, of which 13 were shared between the two populations. Both populations were haplotypically diverse (gene diversity = 0.80, Gambia; 0.85, Malawi) and significantly differentiated (p< 10-5by exact test). More than a quarter of marker pairs showed evidence of intragenic recombination (29% Gambia; 27% Malawi). We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure. AEA revealed that many SNPs in TNFare poor markers of each other. The EMM showed that 8 of 12 SNPs (Gambia) and 7 of 12 SNPs (Malawi) are required to describe 95% of the haplotypic diversity. Conclusions: The TNFlocus in the Gambian and Malawi sample is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNFSNPs must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.

Published
2003
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27. Imputation-based meta-analysis of severe malaria in three African populations.

Author

Band G, Le QS, Jostins L, Pirinen M, Kivinen K, Jallow M, Sisay-Joof F, Bojang K, Pinder M, Sirugo G, Conway DJ, Nyirongo V, Kachala D, Molyneux M, Taylor T, Ndila C, Peshu N, Marsh K, Williams TN, Alcock D, Andrews R, Edkins S, Gray E, Hubbart C, Jeffreys A, Rowlands K, Schuldt K, Clark TG, Small KS, Teo YY, Kwiatkowski DP, Rockett KA, Barrett JC, and Spencer CC

Subjects
Africa, Bayes Theorem, Chromosome Mapping, Genetic Heterogeneity, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome, Human, Haplotypes, Humans, Linkage Disequilibrium, Malaria epidemiology, Malaria pathology, Polymorphism, Single Nucleotide, Black People genetics, Genome-Wide Association Study, Hemoglobin, Sickle genetics, Malaria genetics
Abstract

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles., Competing Interests: The authors have declared that no competing interests exist.

Published
2013
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