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1. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples.

Author

MalariaGEN, Ahouidi, A, Ali, M, Almagro-Garcia, J, Amambua-Ngwa, A, Amaratunga, C, Amato, R, Amenga-Etego, L, Andagalu, B, Anderson, TJC, Andrianaranjaka, V, Apinjoh, T, Ariani, C, Ashley, EA, Auburn, S, Awandare, GA, Ba, H, Baraka, V, Barry, Alyssa, Bejon, P, Bertin, GI, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Busby, GBJ, Chookajorn, T, Chotivanich, K, Claessens, A, Conway, D, Craig, A, D'Alessandro, U, Dama, S, Day, NP, Denis, B, Diakite, M, Djimdé, A, Dolecek, C, Dondorp, AM, Drakeley, C, Drury, E, Duffy, P, Echeverry, DF, Egwang, TG, Erko, B, Fairhurst, RM, Faiz, A, Fanello, CA, Fukuda, MM, Gamboa, D, Ghansah, A, Golassa, L, Goncalves, S, Hamilton, WL, Harrison, GLA, Hart, L, Henrichs, C, Hien, TT, Hill, CA, Hodgson, A, Hubbart, C, Imwong, M, Ishengoma, DS, Jackson, SA, Jacob, CG, Jeffery, B, Jeffreys, AE, Johnson, KJ, Jyothi, D, Kamaliddin, C, Kamau, E, Kekre, M, Kluczynski, K, Kochakarn, T, Konaté, A, Kwiatkowski, DP, Kyaw, MP, Lim, P, Lon, C, Loua, KM, Maïga-Ascofaré, O, Malangone, C, Manske, M, Marfurt, J, Marsh, K, Mayxay, M, Miles, A, Miotto, O, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Newton, PN, Nguyen, T, Nguyen, T-N, Noedl, H, Nosten, F, Noviyanti, R, Nzila, A, Ochola-Oyier, LI, Ocholla, H, Oduro, A, Omedo, I, Onyamboko, MA, Ouedraogo, J-B, Oyebola, K, Pearson, RD, Peshu, N, Phyo, AP, Plowe, CV, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Rayner, JC, Ringwald, P, Rockett, KA, Rowlands, K, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Simpson, VJ, Stalker, J, Su, X-Z, Sutherland, C, Takala-Harrison, S, Tavul, L, Thathy, V, Tshefu, A, Verra, F, Vinetz, J, Wellems, TE, Wendler, J, White, NJ, Wright, I, Yavo, W, Ye, H, MalariaGEN, Ahouidi, A, Ali, M, Almagro-Garcia, J, Amambua-Ngwa, A, Amaratunga, C, Amato, R, Amenga-Etego, L, Andagalu, B, Anderson, TJC, Andrianaranjaka, V, Apinjoh, T, Ariani, C, Ashley, EA, Auburn, S, Awandare, GA, Ba, H, Baraka, V, Barry, Alyssa, Bejon, P, Bertin, GI, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Busby, GBJ, Chookajorn, T, Chotivanich, K, Claessens, A, Conway, D, Craig, A, D'Alessandro, U, Dama, S, Day, NP, Denis, B, Diakite, M, Djimdé, A, Dolecek, C, Dondorp, AM, Drakeley, C, Drury, E, Duffy, P, Echeverry, DF, Egwang, TG, Erko, B, Fairhurst, RM, Faiz, A, Fanello, CA, Fukuda, MM, Gamboa, D, Ghansah, A, Golassa, L, Goncalves, S, Hamilton, WL, Harrison, GLA, Hart, L, Henrichs, C, Hien, TT, Hill, CA, Hodgson, A, Hubbart, C, Imwong, M, Ishengoma, DS, Jackson, SA, Jacob, CG, Jeffery, B, Jeffreys, AE, Johnson, KJ, Jyothi, D, Kamaliddin, C, Kamau, E, Kekre, M, Kluczynski, K, Kochakarn, T, Konaté, A, Kwiatkowski, DP, Kyaw, MP, Lim, P, Lon, C, Loua, KM, Maïga-Ascofaré, O, Malangone, C, Manske, M, Marfurt, J, Marsh, K, Mayxay, M, Miles, A, Miotto, O, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Newton, PN, Nguyen, T, Nguyen, T-N, Noedl, H, Nosten, F, Noviyanti, R, Nzila, A, Ochola-Oyier, LI, Ocholla, H, Oduro, A, Omedo, I, Onyamboko, MA, Ouedraogo, J-B, Oyebola, K, Pearson, RD, Peshu, N, Phyo, AP, Plowe, CV, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Rayner, JC, Ringwald, P, Rockett, KA, Rowlands, K, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Simpson, VJ, Stalker, J, Su, X-Z, Sutherland, C, Takala-Harrison, S, Tavul, L, Thathy, V, Tshefu, A, Verra, F, Vinetz, J, Wellems, TE, Wendler, J, White, NJ, Wright, I, Yavo, W, and Ye, H

Abstract

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

Published
2021

2. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples.

Author

MalariaGEN, Ahouidi, A, Ali, M, Almagro-Garcia, J, Amambua-Ngwa, A, Amaratunga, C, Amato, R, Amenga-Etego, L, Andagalu, B, Anderson, TJC, Andrianaranjaka, V, Apinjoh, T, Ariani, C, Ashley, EA, Auburn, S, Awandare, GA, Ba, H, Baraka, V, Barry, AE, Bejon, P, Bertin, GI, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Busby, GBJ, Chookajorn, T, Chotivanich, K, Claessens, A, Conway, D, Craig, A, D'Alessandro, U, Dama, S, Day, NP, Denis, B, Diakite, M, Djimdé, A, Dolecek, C, Dondorp, AM, Drakeley, C, Drury, E, Duffy, P, Echeverry, DF, Egwang, TG, Erko, B, Fairhurst, RM, Faiz, A, Fanello, CA, Fukuda, MM, Gamboa, D, Ghansah, A, Golassa, L, Goncalves, S, Hamilton, WL, Harrison, GLA, Hart, L, Henrichs, C, Hien, TT, Hill, CA, Hodgson, A, Hubbart, C, Imwong, M, Ishengoma, DS, Jackson, SA, Jacob, CG, Jeffery, B, Jeffreys, AE, Johnson, KJ, Jyothi, D, Kamaliddin, C, Kamau, E, Kekre, M, Kluczynski, K, Kochakarn, T, Konaté, A, Kwiatkowski, DP, Kyaw, MP, Lim, P, Lon, C, Loua, KM, Maïga-Ascofaré, O, Malangone, C, Manske, M, Marfurt, J, Marsh, K, Mayxay, M, Miles, A, Miotto, O, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Newton, PN, Nguyen, T, Nguyen, T-N, Noedl, H, Nosten, F, Noviyanti, R, Nzila, A, Ochola-Oyier, LI, Ocholla, H, Oduro, A, Omedo, I, Onyamboko, MA, Ouedraogo, J-B, Oyebola, K, Pearson, RD, Peshu, N, Phyo, AP, Plowe, CV, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Rayner, JC, Ringwald, P, Rockett, KA, Rowlands, K, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Simpson, VJ, Stalker, J, Su, X-Z, Sutherland, C, Takala-Harrison, S, Tavul, L, Thathy, V, Tshefu, A, Verra, F, Vinetz, J, Wellems, TE, Wendler, J, White, NJ, Wright, I, Yavo, W, Ye, H, MalariaGEN, Ahouidi, A, Ali, M, Almagro-Garcia, J, Amambua-Ngwa, A, Amaratunga, C, Amato, R, Amenga-Etego, L, Andagalu, B, Anderson, TJC, Andrianaranjaka, V, Apinjoh, T, Ariani, C, Ashley, EA, Auburn, S, Awandare, GA, Ba, H, Baraka, V, Barry, AE, Bejon, P, Bertin, GI, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Busby, GBJ, Chookajorn, T, Chotivanich, K, Claessens, A, Conway, D, Craig, A, D'Alessandro, U, Dama, S, Day, NP, Denis, B, Diakite, M, Djimdé, A, Dolecek, C, Dondorp, AM, Drakeley, C, Drury, E, Duffy, P, Echeverry, DF, Egwang, TG, Erko, B, Fairhurst, RM, Faiz, A, Fanello, CA, Fukuda, MM, Gamboa, D, Ghansah, A, Golassa, L, Goncalves, S, Hamilton, WL, Harrison, GLA, Hart, L, Henrichs, C, Hien, TT, Hill, CA, Hodgson, A, Hubbart, C, Imwong, M, Ishengoma, DS, Jackson, SA, Jacob, CG, Jeffery, B, Jeffreys, AE, Johnson, KJ, Jyothi, D, Kamaliddin, C, Kamau, E, Kekre, M, Kluczynski, K, Kochakarn, T, Konaté, A, Kwiatkowski, DP, Kyaw, MP, Lim, P, Lon, C, Loua, KM, Maïga-Ascofaré, O, Malangone, C, Manske, M, Marfurt, J, Marsh, K, Mayxay, M, Miles, A, Miotto, O, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Newton, PN, Nguyen, T, Nguyen, T-N, Noedl, H, Nosten, F, Noviyanti, R, Nzila, A, Ochola-Oyier, LI, Ocholla, H, Oduro, A, Omedo, I, Onyamboko, MA, Ouedraogo, J-B, Oyebola, K, Pearson, RD, Peshu, N, Phyo, AP, Plowe, CV, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Rayner, JC, Ringwald, P, Rockett, KA, Rowlands, K, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Simpson, VJ, Stalker, J, Su, X-Z, Sutherland, C, Takala-Harrison, S, Tavul, L, Thathy, V, Tshefu, A, Verra, F, Vinetz, J, Wellems, TE, Wendler, J, White, NJ, Wright, I, Yavo, W, and Ye, H

Abstract

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

Published
2021

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

Author

Band, G, Le, QS, Clarke, GM, Kivinen, K, Hubbart, C, Jeffreys, AE, Rowlands, K, Leffler, EM, Jallow, M, Conway, DJ, Sisay-Joof, F, Sirugo, G, d'Alessandro, U, Toure, OB, Thera, MA, Konate, S, Sissoko, S, Mangano, VD, Bougouma, EC, Sirima, SB, Amenga-Etego, LN, Ghansah, AK, Hodgson, AVO, Wilson, MD, Enimil, A, Ansong, D, Evans, J, Ademola, SA, Apinjoh, TO, Ndila, CM, Manjurano, A, Drakeley, C, Reyburn, H, Nguyen, HP, Nguyen, TNQ, Cao, QT, Tran, TH, Teo, YY, Manning, L, Laman, M, Michon, P, Karunajeewa, H, Siba, P, Allen, S, Allen, A, Bahlo, M, Davis, TME, Simpson, V, Shelton, J, Spencer, CCA, Busby, GBJ, Kerasidou, A, Drury, E, Stalker, J, Dilthey, A, Mentzer, AJ, McVean, G, Bojang, KA, Doumbo, O, Modiano, D, Koram, KA, Agbenyega, T, Amodu, OK, Achidi, E, Williams, TN, Marsh, K, Riley, EM, Molyneux, M, Taylor, T, Dunstan, SJ, Farrar, J, Mueller, I, Rockett, KA, Kwiatkowski, DP, Band, G, Le, QS, Clarke, GM, Kivinen, K, Hubbart, C, Jeffreys, AE, Rowlands, K, Leffler, EM, Jallow, M, Conway, DJ, Sisay-Joof, F, Sirugo, G, d'Alessandro, U, Toure, OB, Thera, MA, Konate, S, Sissoko, S, Mangano, VD, Bougouma, EC, Sirima, SB, Amenga-Etego, LN, Ghansah, AK, Hodgson, AVO, Wilson, MD, Enimil, A, Ansong, D, Evans, J, Ademola, SA, Apinjoh, TO, Ndila, CM, Manjurano, A, Drakeley, C, Reyburn, H, Nguyen, HP, Nguyen, TNQ, Cao, QT, Tran, TH, Teo, YY, Manning, L, Laman, M, Michon, P, Karunajeewa, H, Siba, P, Allen, S, Allen, A, Bahlo, M, Davis, TME, Simpson, V, Shelton, J, Spencer, CCA, Busby, GBJ, Kerasidou, A, Drury, E, Stalker, J, Dilthey, A, Mentzer, AJ, McVean, G, Bojang, KA, Doumbo, O, Modiano, D, Koram, KA, Agbenyega, T, Amodu, OK, Achidi, E, Williams, TN, Marsh, K, Riley, EM, Molyneux, M, Taylor, T, Dunstan, SJ, Farrar, J, Mueller, I, Rockett, KA, and Kwiatkowski, DP

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.

Published
2019

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

Author

Ndila, CM, Uyoga, S, Macharia, AW, Nyutu, G, Peshu, N, Ojal, J, Shebe, M, Awuondo, KO, Mturi, N, Tsofa, B, Sepulveda, N, Clark, TG, Band, G, Clarke, G, Rowlands, K, Hubbart, C, Jeffreys, A, Kariuki, S, Marsh, K, Mackinnon, M, Maitland, K, Kwiatkowski, DP, Rockett, KA, Williams, TN, Ndila, CM, Uyoga, S, Macharia, AW, Nyutu, G, Peshu, N, Ojal, J, Shebe, M, Awuondo, KO, Mturi, N, Tsofa, B, Sepulveda, N, Clark, TG, Band, G, Clarke, G, Rowlands, K, Hubbart, C, Jeffreys, A, Kariuki, S, Marsh, K, Mackinnon, M, Maitland, K, Kwiatkowski, DP, Rockett, KA, and Williams, TN

Abstract

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

Published
2018

5. Genomic epidemiology of artemisinin resistant malaria

Author

Amato, R, Miotto, O, Woodrow, CJ, Almagro-Garcia, J, Sinha, I, Campino, S, Mead, D, Drury, E, Kekre, M, Sanders, M, Amambua-Ngwa, A, Amaratunga, C, Amenga-Etego, L, Andrianaranjaka, V, Apinjoh, T, Ashley, E, Auburn, S, Awandare, GA, Baraka, V, Barry, A, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Chotivanich, K, Conway, DJ, Craig, A, Day, NP, Djimde, A, Dolecek, C, Dondorp, AM, Drakeley, C, Duffy, P, Echeverry, DF, Egwang, TG, Fairhurst, RM, Faiz, MA, Fanello, CI, Tran, TH, Hodgson, A, Imwong, M, Ishengoma, D, Lim, P, Lon, C, Marfurt, J, Marsh, K, Mayxay, M, Michon, P, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Kyaw, MP, Newton, PN, Nosten, F, Noviyanti, R, Nzila, A, Ocholla, H, Oduro, A, Onyamboko, M, Ouedraogo, J-B, Phyo, APP, Plowe, C, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Ringwald, P, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Takala-Harrison, S, Thanh, T-NN, Thathy, V, Verra, F, Wendler, J, White, NJ, Ye, H, Cornelius, VJ, Giacomantonio, R, Muddyman, D, Henrichs, C, Malangone, C, Jyothi, D, Pearson, RD, Rayner, JC, McVean, G, Rockett, KA, Miles, A, Vauterin, P, Jeffery, B, Manske, M, Stalker, J, Maclnnis, B, Kwiatkowski, DP, Amato, R, Miotto, O, Woodrow, CJ, Almagro-Garcia, J, Sinha, I, Campino, S, Mead, D, Drury, E, Kekre, M, Sanders, M, Amambua-Ngwa, A, Amaratunga, C, Amenga-Etego, L, Andrianaranjaka, V, Apinjoh, T, Ashley, E, Auburn, S, Awandare, GA, Baraka, V, Barry, A, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Chotivanich, K, Conway, DJ, Craig, A, Day, NP, Djimde, A, Dolecek, C, Dondorp, AM, Drakeley, C, Duffy, P, Echeverry, DF, Egwang, TG, Fairhurst, RM, Faiz, MA, Fanello, CI, Tran, TH, Hodgson, A, Imwong, M, Ishengoma, D, Lim, P, Lon, C, Marfurt, J, Marsh, K, Mayxay, M, Michon, P, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Kyaw, MP, Newton, PN, Nosten, F, Noviyanti, R, Nzila, A, Ocholla, H, Oduro, A, Onyamboko, M, Ouedraogo, J-B, Phyo, APP, Plowe, C, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Ringwald, P, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Takala-Harrison, S, Thanh, T-NN, Thathy, V, Verra, F, Wendler, J, White, NJ, Ye, H, Cornelius, VJ, Giacomantonio, R, Muddyman, D, Henrichs, C, Malangone, C, Jyothi, D, Pearson, RD, Rayner, JC, McVean, G, Rockett, KA, Miles, A, Vauterin, P, Jeffery, B, Manske, M, Stalker, J, Maclnnis, B, and Kwiatkowski, DP

Abstract

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.

Published
2016

6. Genomic analysis of local variation and recent evolution in Plasmodium vivax

Author

Pearson, RD, Amato, R, Auburn, S, Miotto, O, Almagro-Garcia, J, Amaratunga, C, Suon, S, Mao, S, Noviyanti, R, Trimarsanto, H, Marfurt, J, Anstey, NM, William, T, Boni, MF, Dolecek, C, Hien, TT, White, NJ, Michon, P, Siba, P, Tavul, L, Harrison, G, Barry, A, Mueller, I, Ferreira, MU, Karunaweera, N, Randrianarivelojosia, M, Gao, Q, Hubbart, C, Hart, L, Jeffery, B, Drury, E, Mead, D, Kekre, M, Campino, S, Manske, M, Cornelius, VJ, MacInnis, B, Rockett, KA, Miles, A, Rayner, JC, Fairhurst, RM, Nosten, F, Price, RN, Kwiatkowski, DP, Pearson, RD, Amato, R, Auburn, S, Miotto, O, Almagro-Garcia, J, Amaratunga, C, Suon, S, Mao, S, Noviyanti, R, Trimarsanto, H, Marfurt, J, Anstey, NM, William, T, Boni, MF, Dolecek, C, Hien, TT, White, NJ, Michon, P, Siba, P, Tavul, L, Harrison, G, Barry, A, Mueller, I, Ferreira, MU, Karunaweera, N, Randrianarivelojosia, M, Gao, Q, Hubbart, C, Hart, L, Jeffery, B, Drury, E, Mead, D, Kekre, M, Campino, S, Manske, M, Cornelius, VJ, MacInnis, B, Rockett, KA, Miles, A, Rayner, JC, Fairhurst, RM, Nosten, F, Price, RN, and Kwiatkowski, DP

Abstract

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for the elimination of malaria. To characterize the genetic diversity of this parasite in individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region and analyzed data on >300,000 SNPs and nine regions of the genome with large copy number variations. Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding. At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at new loci, and these varied markedly between geographical locations. These findings demonstrate a dynamic landscape of local evolutionary adaptation in the parasite population and provide a foundation for genomic surveillance to guide effective strategies for control and elimination of P. vivax.

Published
2016

7. Admixture into and within sub-Saharan Africa

Author

Busby, GBJ, Band, G, Le, QS, Jallow, M, Bougama, E, Mangano, VD, Amenga-Etego, LN, Enimil, A, Apinjoh, T, Ndila, CM, Manjurano, A, Nyirongo, V, Doumbo, O, Rockett, KA, Kwiatkowski, DP, Spencer, CCA, Busby, GBJ, Band, G, Le, QS, Jallow, M, Bougama, E, Mangano, VD, Amenga-Etego, LN, Enimil, A, Apinjoh, T, Ndila, CM, Manjurano, A, Nyirongo, V, Doumbo, O, Rockett, KA, Kwiatkowski, DP, and Spencer, CCA

Abstract

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.

Published
2016

8. Reappraisal of known malaria resistance loci in a large multicenter study

Author

Rockett, KA, Clarke, GM, Fitzpatrick, K, Hubbart, C, Jeffreys, AE, Rowlands, K, Craik, R, Jallow, M, Conway, DJ, Bojang, KA, Pinder, M, Usen, S, Sisay-Joof, F, Sirugo, G, Toure, O, Thera, MA, Konate, S, Sissoko, S, Niangaly, A, Poudiougou, B, Mangano, VD, Bougouma, EC, Sirima, SB, Modiano, D, Amenga-Etego, LN, Ghansah, A, Koram, KA, Wilson, MD, Enimil, A, Evans, J, Amodu, O, Olaniyan, S, Apinjoh, T, Mugri, R, Ndi, A, Ndila, CM, Uyoga, S, Macharia, A, Peshu, N, Williams, TN, Manjurano, A, Riley, E, Drakeley, C, Reyburn, H, Nyirongo, V, Kachala, D, Molyneux, M, Dunstan, SJ, Nguyen, HP, Nguyen, TNQ, Cao, QT, Tran, TH, Manning, L, Laman, M, Siba, P, Karunajeewa, H, Allen, S, Allen, A, Davis, TME, Michon, P, Mueller, I, Green, A, Molloy, S, Johnson, KJ, Kerasidou, A, Cornelius, V, Hart, L, Vanderwal, A, SanJoaquin, M, Band, G, Le, SQ, Pirinen, M, Sepulveda, N, Spencer, CCA, Clark, TG, Agbenyega, T, Achidi, E, Doumbo, O, Farrar, J, Marsh, K, Taylor, T, Kwiatkowski, DP, Rockett, KA, Clarke, GM, Fitzpatrick, K, Hubbart, C, Jeffreys, AE, Rowlands, K, Craik, R, Jallow, M, Conway, DJ, Bojang, KA, Pinder, M, Usen, S, Sisay-Joof, F, Sirugo, G, Toure, O, Thera, MA, Konate, S, Sissoko, S, Niangaly, A, Poudiougou, B, Mangano, VD, Bougouma, EC, Sirima, SB, Modiano, D, Amenga-Etego, LN, Ghansah, A, Koram, KA, Wilson, MD, Enimil, A, Evans, J, Amodu, O, Olaniyan, S, Apinjoh, T, Mugri, R, Ndi, A, Ndila, CM, Uyoga, S, Macharia, A, Peshu, N, Williams, TN, Manjurano, A, Riley, E, Drakeley, C, Reyburn, H, Nyirongo, V, Kachala, D, Molyneux, M, Dunstan, SJ, Nguyen, HP, Nguyen, TNQ, Cao, QT, Tran, TH, Manning, L, Laman, M, Siba, P, Karunajeewa, H, Allen, S, Allen, A, Davis, TME, Michon, P, Mueller, I, Green, A, Molloy, S, Johnson, KJ, Kerasidou, A, Cornelius, V, Hart, L, Vanderwal, A, SanJoaquin, M, Band, G, Le, SQ, Pirinen, M, Sepulveda, N, Spencer, CCA, Clark, TG, Agbenyega, T, Achidi, E, Doumbo, O, Farrar, J, Marsh, K, Taylor, T, and Kwiatkowski, DP

Abstract

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Published
2014

9. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Author

Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, J-B, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, X-Z, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, Kwiatkowski, DP, Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, J-B, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, X-Z, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, and Kwiatkowski, DP

Abstract

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

Published
2012

10. Genome-wide association study identifies eight loci associated with blood pressure

Author

Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K, Nilsson, P, Van Der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliot, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, De Jong, PE, Snieder, H, Van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Altshuler, D, Jarvelin, M, Elliott, P, Lakatta, EG, Forouhi, N, Wareham, NJ, Loos, RJF, Deloukas, P, Lathrop, GM, Zelenika, D, Strachan, DP, Soranzo, N, Williams, FM, Zhai, G, Spector, TD, Peden, JF, Watkins, H, Ferrucci, L, Caulfield, M, Munroe, PB, Berglund, G, Melander, O, Matullo, G, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Ernst, F, Homuth, G, Völker, U, Elosua, R, Laakso, M, Connell, JM, Mooser, V, Salomaa, V, Tuomilehto, J, Laan, M, Navis, G, Seedorf, U, Syvänen, A, Tognoni, G, Sanna, S, Uda, M, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Felix, SB, Reffelmann, T, Lorbeer, R, Völzke, H, Rettig, R, Galan, P, Hercberg, S, Bingham, SA, Kooner, JS, Bandinelli, S, Meneton, P, Abecasis, G, Thompson, JR, Braga Marcano, CA, Barke, B, Dobson, R, Gungadoo, J, Lee, KL, Onipinla, A, Wallace, I, Xue, M, Clayton, DG, Leung, H, Nutland, S, Walker, NM, Todd, JA, Stevens, HE, Dunger, DB, Widmer, B, Downes, K, Cardon, LR, Kwiatkowski, DP, Barrett, JC, Evans, D, Morris, AP, Lindgren, CM, Rayner, NW, Timpson, NJ, Lyons, E, Vannberg, F, Hill, AVS, Teo, YY, Rockett, KA, Craddock, N, Attwood, AP, Bryan, C, Bumpstead, SJ, Chaney, A, Ghori, J, William, RG, Hunt, SE, Inouye, M, Keniry, E, King, E, McGinnis, R, Potter, S, Ravindrarajan, R, Whittaker, P, Withers, D, Bentley, D, Groves, CJ, Duncanson, A, Ouwehand, WH, Boorman, JP, Cant, B, Jolley, JD, Knight, AS, Koch, K, Taylor, NC, Watkins, NA, Winzer, T, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Donnely, P, Davidson, D, Marchini, JL, Spencer, ICA, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, IB, Howie, BN, Su, Z, Vukcevic, D, Easton, D, Everson, U, Hussey, JM, Meech, E, Prowse, CV, Walters, GR, Jones, RW, Ring, SM, Prembey, M, Breen, G, St Clair, D, Ceasar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskovina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGruffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Lewis, CM, Onnie, CM, Prescott, NJ, Mathew, CG, Forbes, A, Sanderson, J, Mathew, C, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Weedon, MN, Hattersley, AT, Shields, BM, Hitman, GA, Walker, M, Newport, M, Sirugo, G, Conway, D, Jallow, M, Bradbury, LA, Pointon, JL, Brown, MA, Farrar, C, Wordsworth, P, Franklyn, JA, Heward, JM, Simmonds, MJ, Cough, SCL, Seal, S, Stratton, MR, Ban, M, Goris, A, Sawcer, SJ, Compston, A, Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K, Nilsson, P, Van Der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliot, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, De Jong, PE, Snieder, H, Van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Altshuler, D, Jarvelin, M, Elliott, P, Lakatta, EG, Forouhi, N, Wareham, NJ, Loos, RJF, Deloukas, P, Lathrop, GM, Zelenika, D, Strachan, DP, Soranzo, N, Williams, FM, Zhai, G, Spector, TD, Peden, JF, Watkins, H, Ferrucci, L, Caulfield, M, Munroe, PB, Berglund, G, Melander, O, Matullo, G, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Ernst, F, Homuth, G, Völker, U, Elosua, R, Laakso, M, Connell, JM, Mooser, V, Salomaa, V, Tuomilehto, J, Laan, M, Navis, G, Seedorf, U, Syvänen, A, Tognoni, G, Sanna, S, Uda, M, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Felix, SB, Reffelmann, T, Lorbeer, R, Völzke, H, Rettig, R, Galan, P, Hercberg, S, Bingham, SA, Kooner, JS, Bandinelli, S, Meneton, P, Abecasis, G, Thompson, JR, Braga Marcano, CA, Barke, B, Dobson, R, Gungadoo, J, Lee, KL, Onipinla, A, Wallace, I, Xue, M, Clayton, DG, Leung, H, Nutland, S, Walker, NM, Todd, JA, Stevens, HE, Dunger, DB, Widmer, B, Downes, K, Cardon, LR, Kwiatkowski, DP, Barrett, JC, Evans, D, Morris, AP, Lindgren, CM, Rayner, NW, Timpson, NJ, Lyons, E, Vannberg, F, Hill, AVS, Teo, YY, Rockett, KA, Craddock, N, Attwood, AP, Bryan, C, Bumpstead, SJ, Chaney, A, Ghori, J, William, RG, Hunt, SE, Inouye, M, Keniry, E, King, E, McGinnis, R, Potter, S, Ravindrarajan, R, Whittaker, P, Withers, D, Bentley, D, Groves, CJ, Duncanson, A, Ouwehand, WH, Boorman, JP, Cant, B, Jolley, JD, Knight, AS, Koch, K, Taylor, NC, Watkins, NA, Winzer, T, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Donnely, P, Davidson, D, Marchini, JL, Spencer, ICA, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, IB, Howie, BN, Su, Z, Vukcevic, D, Easton, D, Everson, U, Hussey, JM, Meech, E, Prowse, CV, Walters, GR, Jones, RW, Ring, SM, Prembey, M, Breen, G, St Clair, D, Ceasar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskovina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGruffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Lewis, CM, Onnie, CM, Prescott, NJ, Mathew, CG, Forbes, A, Sanderson, J, Mathew, C, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Weedon, MN, Hattersley, AT, Shields, BM, Hitman, GA, Walker, M, Newport, M, Sirugo, G, Conway, D, Jallow, M, Bradbury, LA, Pointon, JL, Brown, MA, Farrar, C, Wordsworth, P, Franklyn, JA, Heward, JM, Simmonds, MJ, Cough, SCL, Seal, S, Stratton, MR, Ban, M, Goris, A, Sawcer, SJ, and Compston, A

Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10−24), CYP1A2 (P = 1 × 10−23), FGF5 (P = 1 × 10−21), SH2B3 (P = 3 × 10−18), MTHFR (P = 2 × 10−13), c10orf107 (P = 1 × 10−9), ZNF652 (P = 5 × 10−9) and PLCD3 (P = 1 × 10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

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