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13 results on '"Pearson RD"'

1. An open dataset of Plasmodium vivax genome variation in 1,895 worldwide samples.

Author

MalariaGEN, Adam, I, Alam, MS, Alemu, S, Amaratunga, C, Amato, R, Andrianaranjaka, V, Anstey, NM, Aseffa, A, Ashley, E, Assefa, A, Auburn, S, Barber, BE, Barry, A, Batista Pereira, D, Cao, J, Chau, NH, Chotivanich, K, Chu, C, Dondorp, AM, Drury, E, Echeverry, DF, Erko, B, Espino, F, Fairhurst, R, Faiz, A, Fernanda Villegas, M, Gao, Q, Golassa, L, Goncalves, S, Grigg, MJ, Hamedi, Y, Hien, TT, Htut, Y, Johnson, KJ, Karunaweera, N, Khan, W, Krudsood, S, Kwiatkowski, DP, Lacerda, M, Ley, B, Lim, P, Liu, Y, Llanos-Cuentas, A, Lon, C, Lopera-Mesa, T, Marfurt, J, Michon, P, Miotto, O, Mohammed, R, Mueller, I, Namaik-Larp, C, Newton, PN, Nguyen, T-N, Nosten, F, Noviyanti, R, Pava, Z, Pearson, RD, Petros, B, Phyo, AP, Price, RN, Pukrittayakamee, S, Rahim, AG, Randrianarivelojosia, M, Rayner, JC, Rumaseb, A, Siegel, SV, Simpson, VJ, Thriemer, K, Tobon-Castano, A, Trimarsanto, H, Urbano Ferreira, M, Vélez, ID, Wangchuk, S, Wellems, TE, White, NJ, William, T, Yasnot, MF, Yilma, D, MalariaGEN, Adam, I, Alam, MS, Alemu, S, Amaratunga, C, Amato, R, Andrianaranjaka, V, Anstey, NM, Aseffa, A, Ashley, E, Assefa, A, Auburn, S, Barber, BE, Barry, A, Batista Pereira, D, Cao, J, Chau, NH, Chotivanich, K, Chu, C, Dondorp, AM, Drury, E, Echeverry, DF, Erko, B, Espino, F, Fairhurst, R, Faiz, A, Fernanda Villegas, M, Gao, Q, Golassa, L, Goncalves, S, Grigg, MJ, Hamedi, Y, Hien, TT, Htut, Y, Johnson, KJ, Karunaweera, N, Khan, W, Krudsood, S, Kwiatkowski, DP, Lacerda, M, Ley, B, Lim, P, Liu, Y, Llanos-Cuentas, A, Lon, C, Lopera-Mesa, T, Marfurt, J, Michon, P, Miotto, O, Mohammed, R, Mueller, I, Namaik-Larp, C, Newton, PN, Nguyen, T-N, Nosten, F, Noviyanti, R, Pava, Z, Pearson, RD, Petros, B, Phyo, AP, Price, RN, Pukrittayakamee, S, Rahim, AG, Randrianarivelojosia, M, Rayner, JC, Rumaseb, A, Siegel, SV, Simpson, VJ, Thriemer, K, Tobon-Castano, A, Trimarsanto, H, Urbano Ferreira, M, Vélez, ID, Wangchuk, S, Wellems, TE, White, NJ, William, T, Yasnot, MF, and Yilma, D

Abstract

This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 samples of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new samples contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published samples from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each sample has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr, dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.

Published
2022

2. A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria

Author

Trimarsanto, H, Amato, R, Pearson, RD, Sutanto, E, Noviyanti, R, Trianty, L, Marfurt, J, Pava, Z, Echeverry, DF, Lopera-Mesa, TM, Montenegro, LM, Tobon-Castano, A, Grigg, MJ, Barber, B, William, T, Anstey, NM, Getachew, S, Petros, B, Aseffa, A, Assefa, A, Rahim, AG, Chau, NH, Hien, TT, Alam, MS, Khan, WA, Ley, B, Thriemer, K, Wangchuck, S, Hamedi, Y, Adam, I, Liu, Y, Gao, Q, Sriprawat, K, Ferreira, MU, Laman, M, Barry, A, Mueller, I, Lacerda, MVG, Llanos-Cuentas, A, Krudsood, S, Lon, C, Mohammed, R, Yilma, D, Pereira, DB, Espino, FEJ, Chu, CS, Velez, ID, Namaik-larp, C, Villegas, MF, Green, JA, Koh, G, Rayner, JC, Drury, E, Goncalves, S, Simpson, V, Miotto, O, Miles, A, White, NJ, Nosten, F, Kwiatkowski, DP, Price, RN, Auburn, S, Trimarsanto, H, Amato, R, Pearson, RD, Sutanto, E, Noviyanti, R, Trianty, L, Marfurt, J, Pava, Z, Echeverry, DF, Lopera-Mesa, TM, Montenegro, LM, Tobon-Castano, A, Grigg, MJ, Barber, B, William, T, Anstey, NM, Getachew, S, Petros, B, Aseffa, A, Assefa, A, Rahim, AG, Chau, NH, Hien, TT, Alam, MS, Khan, WA, Ley, B, Thriemer, K, Wangchuck, S, Hamedi, Y, Adam, I, Liu, Y, Gao, Q, Sriprawat, K, Ferreira, MU, Laman, M, Barry, A, Mueller, I, Lacerda, MVG, Llanos-Cuentas, A, Krudsood, S, Lon, C, Mohammed, R, Yilma, D, Pereira, DB, Espino, FEJ, Chu, CS, Velez, ID, Namaik-larp, C, Villegas, MF, Green, JA, Koh, G, Rayner, JC, Drury, E, Goncalves, S, Simpson, V, Miotto, O, Miles, A, White, NJ, Nosten, F, Kwiatkowski, DP, Price, RN, and Auburn, S

Abstract

Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection's country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs > 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.

Published
2022

3. 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

4. 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

5. Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea

Author

Miotto, O, Sekihara, M, Tachibana, SI, Yamauchi, M, Pearson, RD, Amato, R, Gonçalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, A, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, Mita, T, Miotto, O, Sekihara, M, Tachibana, SI, Yamauchi, M, Pearson, RD, Amato, R, Gonçalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, A, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, and Mita, T

Abstract

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.

Published
2020

6. Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea

Author

Billker, O, Miotto, O, Sekihara, M, Tachibana, S-I, Yamauchi, M, Pearson, RD, Amato, R, Goncalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, AE, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, Mita, T, Billker, O, Miotto, O, Sekihara, M, Tachibana, S-I, Yamauchi, M, Pearson, RD, Amato, R, Goncalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, AE, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, and Mita, T

Abstract

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.

Published
2020

7. Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

Author

Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, van de Bunt, M, Pearson, RD, Kumar, A, Mueller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, de Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RCW, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, McCarthy, MI, Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, van de Bunt, M, Pearson, RD, Kumar, A, Mueller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, de Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RCW, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, and McCarthy, MI

Abstract

This corrects the article DOI: 10.1038/sdata.2017.179.

Published
2018

8. Data Descriptor: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

Author

Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, De Bunt, MV, Pearson, RD, Kumar, A, Muller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, De Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RC, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, McCarthy, MI, Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, De Bunt, MV, Pearson, RD, Kumar, A, Muller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, De Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RC, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, and McCarthy, MI

Abstract

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Published
2017

9. 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

10. 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

11. An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Author

Morris, DW, Pearson, RD, Cormican, P, Kenny, EM, O'Dushlaine, CT, Perreault, L-PL, Giannoulatou, E, Tropea, D, Maher, BS, Wormley, B, Kelleher, E, Fahey, C, Molinos, I, Bellini, S, Pirinen, M, Strange, A, Freeman, C, Thiselton, DL, Elves, RL, Regan, R, Ennis, S, Dinan, TG, McDonald, C, Murphy, KC, O'Callaghan, E, Waddington, JL, Walsh, D, O'Donovan, M, Grozeva, D, Craddock, N, Stone, J, Scolnick, E, Purcell, S, Sklar, P, Coe, B, Eichler, EE, Ophoff, R, Buizer, J, Szatkiewicz, J, Hultman, C, Sullivan, P, Gurling, H, Mcquillin, A, St Clair, D, Rees, E, Kirov, G, Walters, J, Blackwood, D, Johnstone, M, Donohoe, G, International Schizophrenia Consortium, SGENE+ Consortium, O'Neill, FA, Wellcome Trust Case Control Consortium 2, Kendler, KS, Gill, M, Riley, BP, Spencer, CCA, Corvin, A, Morris, DW, Pearson, RD, Cormican, P, Kenny, EM, O'Dushlaine, CT, Perreault, L-PL, Giannoulatou, E, Tropea, D, Maher, BS, Wormley, B, Kelleher, E, Fahey, C, Molinos, I, Bellini, S, Pirinen, M, Strange, A, Freeman, C, Thiselton, DL, Elves, RL, Regan, R, Ennis, S, Dinan, TG, McDonald, C, Murphy, KC, O'Callaghan, E, Waddington, JL, Walsh, D, O'Donovan, M, Grozeva, D, Craddock, N, Stone, J, Scolnick, E, Purcell, S, Sklar, P, Coe, B, Eichler, EE, Ophoff, R, Buizer, J, Szatkiewicz, J, Hultman, C, Sullivan, P, Gurling, H, Mcquillin, A, St Clair, D, Rees, E, Kirov, G, Walters, J, Blackwood, D, Johnstone, M, Donohoe, G, International Schizophrenia Consortium, SGENE+ Consortium, O'Neill, FA, Wellcome Trust Case Control Consortium 2, Kendler, KS, Gill, M, Riley, BP, Spencer, CCA, and Corvin, A

Abstract

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Published
2014

12. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Author

Ripke, S, O'Dushlaine, C, Chambert, K, Moran, JL, Kähler, AK, Akterin, S, Bergen, SE, Collins, AL, Crowley, JJ, Fromer, M, Kim, Y, Lee, SH, Magnusson, PKE, Sanchez, N, Stahl, EA, Williams, S, Wray, NR, Xia, K, Bettella, F, Borglum, AD, Bulik-Sullivan, BK, Cormican, P, Craddock, N, de Leeuw, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, ML, Holmans, P, Hougaard, DM, Kendler, KS, Lin, K, Morris, DW, Mors, O, Mortensen, PB, Neale, BM, O'Neill, FA, Owen, MJ, Milovancevic, MP, Posthuma, D, Powell, J, Richards, AL, Riley, BP, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, AB, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, S, Verhage, M, Walters, JT, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, DF, Gejman, PV, Laurent, C, Mowry, BJ, O'Donovan, MC, Pulver, AE, Schwab, SG, Wildenauer, DB, Dudbridge, F, Shi, J, Albus, M, Alexander, M, Campion, D, Cohen, D, Dikeos, D, Duan, J, Eichhammer, P, Godard, S, Hansen, M, Lerer, FB, Liang, K-Y, Maier, W, Mallet, J, Nertney, DA, Nestadt, G, Norton, N, Papadimitriou, GN, Ribble, R, Sanders, AR, Silverman, JM, Walsh, D, Williams, NM, Wormley, B, Psychosis Endophenotypes International Consortium, Arranz, MJ, Bakker, S, Bender, S, Bramon, E, Collier, D, Crespo-Facorro, B, Hall, J, Iyegbe, C, Jablensky, A, Kahn, RS, Kalaydjieva, L, Lawrie, S, Lewis, CM, Linszen, DH, Mata, I, McIntosh, A, Murray, RM, Ophoff, RA, Van Os, J, Walshe, M, Weisbrod, M, Wiersma, D, Wellcome Trust Case Control Consortium 2, Donnelly, P, Barroso, I, Blackwell, JM, Brown, MA, Casas, JP, Corvin, AP, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, RD, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Tashakkori-Ghanbaria, A, Waller, MJ, Weston, P, Widaa, S, Whittaker, P, McCarthy, MI, Stefansson, K, Scolnick, E, Purcell, S, McCarroll, SA, Sklar, P, Hultman, CM, Sullivan, PF, Ripke, S, O'Dushlaine, C, Chambert, K, Moran, JL, Kähler, AK, Akterin, S, Bergen, SE, Collins, AL, Crowley, JJ, Fromer, M, Kim, Y, Lee, SH, Magnusson, PKE, Sanchez, N, Stahl, EA, Williams, S, Wray, NR, Xia, K, Bettella, F, Borglum, AD, Bulik-Sullivan, BK, Cormican, P, Craddock, N, de Leeuw, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, ML, Holmans, P, Hougaard, DM, Kendler, KS, Lin, K, Morris, DW, Mors, O, Mortensen, PB, Neale, BM, O'Neill, FA, Owen, MJ, Milovancevic, MP, Posthuma, D, Powell, J, Richards, AL, Riley, BP, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, AB, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, S, Verhage, M, Walters, JT, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, DF, Gejman, PV, Laurent, C, Mowry, BJ, O'Donovan, MC, Pulver, AE, Schwab, SG, Wildenauer, DB, Dudbridge, F, Shi, J, Albus, M, Alexander, M, Campion, D, Cohen, D, Dikeos, D, Duan, J, Eichhammer, P, Godard, S, Hansen, M, Lerer, FB, Liang, K-Y, Maier, W, Mallet, J, Nertney, DA, Nestadt, G, Norton, N, Papadimitriou, GN, Ribble, R, Sanders, AR, Silverman, JM, Walsh, D, Williams, NM, Wormley, B, Psychosis Endophenotypes International Consortium, Arranz, MJ, Bakker, S, Bender, S, Bramon, E, Collier, D, Crespo-Facorro, B, Hall, J, Iyegbe, C, Jablensky, A, Kahn, RS, Kalaydjieva, L, Lawrie, S, Lewis, CM, Linszen, DH, Mata, I, McIntosh, A, Murray, RM, Ophoff, RA, Van Os, J, Walshe, M, Weisbrod, M, Wiersma, D, Wellcome Trust Case Control Consortium 2, Donnelly, P, Barroso, I, Blackwell, JM, Brown, MA, Casas, JP, Corvin, AP, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, RD, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Tashakkori-Ghanbaria, A, Waller, MJ, Weston, P, Widaa, S, Whittaker, P, McCarthy, MI, Stefansson, K, Scolnick, E, Purcell, S, McCarroll, SA, Sklar, P, Hultman, CM, and Sullivan, PF

Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Published
2013

13. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Donnelly, P, Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, and Donnelly, P

Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Published
2010

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