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

Author

Band, G, Leffler, EM, Jallow, M, Sisay-Joof, F, Ndila, CM, Macharia, AW, Hubbart, C, Jeffreys, AE, Rowlands, K, Nguyen, T, Gonçalves, S, Ariani, CV, Stalker, J, Pearson, RD, Amato, R, Drury, E, Sirugo, G, d'Alessandro, U, Bojang, KA, Marsh, K, Peshu, N, Saelens, JW, Diakité, M, Taylor, SM, Conway, DJ, Rockett, KA, Kwiatkowski, DP, Williams, TN, and Wellcome Trust

Subjects
EXPRESSION, Male, RESISTANCE LOCI, Genotype, PROTEINS, General Science & Technology, Genes, Protozoan, Hemoglobin, Sickle, Plasmodium falciparum, DIVERSITY, Host Adaptation, Linkage Disequilibrium, MOLECULAR-BASIS, parasitic diseases, Animals, Humans, Parasites, GENOME-WIDE ASSOCIATION, Malaria, Falciparum, Child, Alleles, Science & Technology, Polymorphism, Genetic, Multidisciplinary, PLASMODIUM-FALCIPARUM, Kenya, EXPORT, Multidisciplinary Sciences, Science & Technology - Other Topics, VIRULENCE, Female, Gambia, PLASMEPSIN V
Abstract

Host genetic factors can confer resistance against malaria1, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member2–4PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

Published
2021
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2. BIRC6 modifies risk of invasive bacterial infection in Kenyan children

Author

Gilchrist, JJ, Kariuki, SN, Watson, JA, Band, G, Uyoga, S, Ndila, CM, Mturi, N, Mwarumba, S, Mohammed, S, Mosobo, M, Alasoo, K, Rockett, KA, Mentzer, AJ, Kwiatkowski, DP, Hill, AVS, Maitland, K, Scott, JAG, Williams, TN, and Wellcome Trust

Subjects
bacteraemia, General Immunology and Microbiology, General Neuroscience, infectious disease, microbiology, malaria, Bacteremia, General Medicine, Bacterial Infections, 0601 Biochemistry and Cell Biology, Kenya, General Biochemistry, Genetics and Molecular Biology, Inhibitor of Apoptosis Proteins, genomics, GWAS, Humans, genetics, human, Malaria, Falciparum, Child, Genome-Wide Association Study
Abstract

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with Plasmodium falciparum parasitaemia. We construct a joint dataset including 1445 bacteraemia cases and 1143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data, we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so, we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.

Published
2022

3. The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

Author

Uyoga, S, Watson, JA, Wanjiku, P, Rop, JC, Makale, J, Macharia, AW, Kariuki, SN, Nyutu, GM, Shebe, M, Mosobo, M, Mturi, N, Rockett, KA, Woodrow, CJ, Dondorp, AM, Maitland, K, White, NJ, Williams, TN, Intensive Care Medicine, AII - Infectious diseases, and Wellcome Trust

Subjects
Multidisciplinary, Erythrocytes, Plasmodium falciparum, Protozoan Proteins, General Physics and Astronomy, Antigens, Protozoan, General Chemistry, Kenya, General Biochemistry, Genetics and Molecular Biology, Malaria, Plasma Membrane Calcium-Transporting ATPases, parasitic diseases, Blood Group Antigens, Animals, Humans, Parasites, Biomass, Malaria, Falciparum, Child
Abstract

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. The sequestration of parasitized erythrocytes in the microvasculature of vital organs is a central pathophysiological feature. The plasma concentration of the parasite protein P. falciparum Histidine-Rich Protein 2 (PfHRP2) has diagnostic and prognostic value in severe malaria. In the current study we investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of plasma PfHRP2 to circulating parasites) as quantitative traits in the conduct of case-only genetic association studies of severe malaria. We demonstrate the utility of this approach using data from over 2,000 Kenyan children with severe malaria, genotyped for 14 major candidate genes that were found to be associated with protection against severe malaria in previous studies. We show that PfHRP2 is a more informative quantitative trait than peripheral parasite density, and that polymorphisms in four major red cell genes (the βS sickle mutation in HBB, the blood group mutation O in ABO, the α-thalassaemia mutation in HBA, and the Dantu blood group mutation in GYP) are associated with substantially lower concentrations of plasma PfHRP2 at admission. Further, the effect sizes we observed were considerably larger than those relating to peripheral parasite density. An unexpected outlier was the rs1541255 A>G polymorphism in ATP2B4 for which we saw higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for how this might be explained in the context of this specific protective allele.

Published
2022

4. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data [version 2; peer review: 2 approved]

Author

Ndila, CM, Nyirongo, V, Macharia, AW, Jeffreys, AE, Rowlands, K, Hubbart, C, Busby, GBJ, Band, G, Harding, RM, Rockett, KA, Williams, TN, and MalariaGEN Consortium

Subjects
hemic and lymphatic diseases, Science, Medicine
Abstract

Background: The -α 3.7I-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study, we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha ( HBA) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.

Published
2021

5. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data [version 1; peer review: 1 approved, 1 approved with reservations]

Author

Ndila, CM, Nyirongo, V, Macharia, AW, Jeffreys, AE, Rowlands, K, Hubbart, C, Busby, GBJ, Band, G, Harding, RM, Rockett, KA, and Williams, TN

Abstract

Background: The -α3.7I-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (HBA) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.

Published
2020

6. 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

7. Tumour necrosis factor alpha promoter polymorphism, TNF-238 is associated with severe clinical outcome of falciparum malaria in Ibadan southwest Nigeria

Author

Olaniyan, SA, Amodu, OK, Bakare, AA, Troye-Blomberg, M, Omotade, OO, Rockett, KA, and Consortium, Malariagen

Subjects
Male, 0301 basic medicine, Necrosis, Adolescent, Genotype, Veterinary (miscellaneous), Malaria, Cerebral, Promoter polymorphism, Nigeria, Biology, Severity of Illness Index, Asymptomatic, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, medicine, Humans, Genetic Predisposition to Disease, Malaria, Falciparum, Child, Promoter Regions, Genetic, Polymorphism, Genetic, Tumor Necrosis Factor-alpha, Infant, medicine.disease, 030104 developmental biology, Infectious Diseases, Cerebral Malaria, Child, Preschool, Insect Science, Immunology, Female, Parasitology, Tumor necrosis factor alpha, medicine.symptom, Malaria, 030215 immunology
Abstract

Tumour necrosis factor (TNF) – α has been shown to play an important role in the pathogenesis of falciparum malaria. Two TNF promoter polymorphisms, TNF-308 and TNF-238 have been associated with differential activity and production of TNF. In order to investigate the association between TNF-308 and TNF-238 and the clinical outcome of malaria in a Nigerian population, the two TNF polymorphisms were analysed using Sequenom iPLEX Platform. A total of 782 children; 283 children with uncomplicated malaria, 255 children with severe malaria and 244 children with asymptomatic infection (controls) were studied. The distribution of TNF-308 and TNF-238 genotypes were consistent with the Hardy-Weinberg equilibrium. Distribution of both TNF polymorphisms differed significantly across all clinical groups (TNF-308: p = 0.007; TNF-238: p = 0.001). Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI = 1.43–6.02, OR = 2.94, p = 0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI = 1.99–18.17, OR = 6.02, p < 0.001 and 95% CI = 1.78–8.23, OR = 3.84, p < 0.001 respectively). No significant association was found between TNF-308 and malaria outcome. These results show thegenetic association of TNF-238 in the clinical outcome of malaria in Ibadan, southwest Nigeria. These findings add support to the role of TNF in the outcome of malaria infection. Further large scale studies across multiple malaria endemic populations will be required to determine the specific roles of TNF-308 and TNF-238 in the outcome of falciparum malaria infection.

Published
2016
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8. Two complement receptor one alleles have opposing associations with cerebral malaria and interact with ethalassaemia

Author

Opi, DH, Swann, O, Macharia, A, Uyoga, S, Band, G, Ndila, CM, Harrison, EM, Thera, MA, Kone, AK, Diallo, DA, Doumbo, OK, Lyke, KE, Plowe, CV, Moulds, JM, Shebbe, M, Mturi, N, Peshu, N, Maitland, K, Raza, A, Kwiatkowski, DP, Rockett, KA, Williams, TN, Rowe, JA, Commission of the European Communities, and Wellcome Trust

Subjects
Life Sciences & Biomedicine - Other Topics, AFRICAN CHILDREN, Knops blood group, Science & Technology, p. falciparum, Alpha thalassaemia, infectious disease, ERYTHROCYTE-MEMBRANE, microbiology, SICKLE-CELL TRAIT, global health, PLASMODIUM-FALCIPARUM MALARIA, KNOPS BLOOD-GROUP, SUSCEPTIBILITY, POLYMORPHISM, Complement receptor 1, parasitic diseases, epidemiology, KENYAN CHILDREN, PROTECTION, human, Life Sciences & Biomedicine, Biology, Cerebral malaria, RESISTANCE
Abstract

Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.

Published
2018

9. 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

10. 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

12. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Author

Burton, PR, Clayton, DG, Cardon, LR, Craddock, N, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Samani, NJ, Todd, JA, Donnelly, P, Barrett, JC, Davison, D, Easton, D, Evans, DM, Leung, HT, Marchini, JL, Morris, AP, Spencer, CC, Tobin, MD, Attwood, AP, Boorman, JP, Cant, B, Everson, U, Hussey, JM, Jolley, JD, Knight, AS, Koch, K, Meech, E, Nutland, S, Prowse, CV, Stevens, HE, Taylor, NC, Walters, GR, Walker, NM, Watkins, NA, Winzer, T, Jones, RW, McArdle, WL, Ring, SM, Strachan, DP, Pembrey, M, Breen, G, St Clair, D, Caesar, S, Gordon-Smith, K, Jones, L, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskivina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGuffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, TD, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Thompson, JR, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Forbes, A, Lewis, CM, Onnie, CM, Prescott, NJ, Sanderson, J, Matthew, CG, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Webster, J, Brown, MJ, Lathrop, MG, Connell, J, Dominiczak, A, Marcano, CA, Burke, B, Dobson, R, Gungadoo, J, Lee, KL, Munroe, PB, Newhouse, SJ, Onipinla, A, Wallace, C, Xue, M, Caulfield, M, Farrall, M, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hilder, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DP, Thomson, W, Worthington, J, Dunger, DB, Widmer, B, Frayling, TM, Freathy, RM, Lango, H, Perry, JR, Shields, BM, Weedon, MN, Hattersley, AT, Hitman, GA, Walker, M, Elliott, KS, Groves, CJ, Lindgren, CM, Rayner, NW, Timpson, NJ, Zeggini, E, Newport, M, Sirugo, G, Lyons, E, Vannberg, F, Hill, AV, Bradbury, LA, Farrar, C, Pointon, JJ, Wordsworth, P, Brown, MA, Franklyn, JA, Heward, JM, Simmonds, MJ, Gough, SC, Seal, S, Stratton, MR, Rahman, N, Ban, M, Goris, A, Sawcer, SJ, Compston, A, Conway, D, Jallow, M, Rockett, KA, Bumpstead, SJ, Chaney, A, Downes, K, Ghori, MJ, Gwilliam, R, Hunt, SE, Inouye, M, Keniry, A, King, E, McGinnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Withers, D, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdo'ttir, IB, Howie, BN, Su, Z, Teo, YY, Vukcevic, D, Bentley, D, Mitchell, SL, Newby, PR, Brand, OJ, Carr-Smith, J, Pearce, SH, Reveille, JD, Zhou, X, Sims, AM, Dowling, A, Taylor, J, Doan, T, Davis, JC, Savage, L, Ward, MM, Learch, TL, Weisman, MH, and Brown, M

Subjects
Linkage disequilibrium, Multiple Sclerosis, Genotype, Population, Single-nucleotide polymorphism, Genome-wide association study, Autoimmunity, Breast Neoplasms, Biology, medicine.disease_cause, Aminopeptidases, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Minor Histocompatibility Antigens, Genetics, medicine, Humans, Spondylitis, Ankylosing, Receptors, Immunologic, education, Genetic association, education.field_of_study, Ankylosing spondylitis, Thyroiditis, Autoimmune, Chromosome Mapping, Receptors, Interleukin, medicine.disease, Endoplasmic reticulum aminopeptidase 2, Genetics, Population, Haplotypes, Case-Control Studies, Immunology, North America
Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Published
2016
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13. 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, JB, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, XZ, 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

Subjects
Genotype, 030231 tropical medicine, Population, Plasmodium falciparum, Genomics, Biology, Polymorphism, Single Nucleotide, Deep sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Humans, Genetic variability, Malaria, Falciparum, education, Genotyping, Alleles, Phylogeny, 030304 developmental biology, Genetics, Whole genome sequencing, 0303 health sciences, Genetic diversity, education.field_of_study, Principal Component Analysis, Multidisciplinary, High-Throughput Nucleotide Sequencing, Biodiversity, biology.organism_classification, 3. Good health, Genome, Protozoan
Abstract

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 genomewide 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. The genetic diversity and evolutionary plasticity of P. falciparum are major obstacles for malaria elimination. New forms of resistance against antimalarial drugs are continually emerging 1,2 , and new forms of antigenic variation are a critical point of vulnerability for future malaria vaccines. Effective tools are needed to detect evolutionary changes in the parasite population and to monitor the spread of genetic variants that affect malaria control. Here we describe the use of deep sequencing to analyse P. falciparum diversity, using blood samples from patients with malaria. The P. falciparum genome has several unusual features that greatly complicate sequence analysis, such as extreme AT bias, large tracts of nonunique sequence and several large families of intensely polymorphic genes 3 . Our aim was therefore not to determine the entire genome sequence of individual field samples—which would be prohibitively expensive with current technologies—but to define an initial set of single nucleotide polymorphisms (SNPs) distributed across the P. falciparum genome, whose genotype can be ascertained with confidence in parasitized blood samples by deep sequencing. An additional complication in the analysis of P. falciparum genome variation is that the billions of haploid parasites that infect a single individual can be a complex mixture of genetic types. Previous studies 4–8 have largely focused on laboratory-adapted parasite clones, but the within-host diversity of natural infections is of fundamental biological interest. Parasites in the blood replicate asexually, but when they are taken up in the blood meal of an Anopheles mosquito they undergo sexual mating. If the parasites in the blood are of diverse genetic types, this process of sexual mating can generate novel recombinant forms. Deep sequencing provides new ways of investigating within-host diversity and the role of sexual recombination in parasite evolution.

Published
2016

14. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

Author

Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN, Burnett MS, Devaney JM, Knouff CW, Thompson JR, Horne BD, Stewart AF, Assimes TL, Wild PS, Allayee H, Nitschke PL, Patel RS, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Martinelli N, Girelli D, Quyyumi AA, Anderson JL, Erdmann J, Hall AS, Schunkert H, Quertermous T, Blankenberg S, Hazen SL, Roberts R, Kathiresan S, Samani NJ, Epstein SE, Rader DJ, Qasim AN, DerOhannessian SL, Qu L, Cappola TP, Chen Z, Matthai W, Hakonarson HH, Wilensky R, Kent KM, Lindsay JM, Pichard AD, Satler L, Waksman R, Knoupf CW, Walker MC, Waterworth DM, Mosser V, Braund PS, Wright B, Balmforth AJ, Ball SG, Chen L, Wells GA, McPherson R, Lackner K, Munzel TF, Schillert A, Schnabel R, Zeller T, Ziegler A, Absher D, Hlatky MA, Iribaren C, Knowles JW, Linsel Nitschke P, König IR, Hengstenberg C, Nahrstaedt J, Peters A, Schreiber S, Wichmann E, Willenborg C, Su S, Bouzyk M, Vaccarino V, Zafari AM, Carlquist JF, Muhlestein JB, Olivieri O, Barnard J, Hartiala J, Tang WH, Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Barrett JH, Bishop DT, Iles MM, Maqbool A, Yuldasheva N, Dixon RJ, Mangino M, Stevens S, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Mathew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop M, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hider SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Ferreira T, Pereira Gale J, Hallgrimsdóttir IB, Bowie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, CASARI , GIORGIO NEVIO, Reilly, Mp, Li, M, He, J, Ferguson, Jf, Stylianou, Im, Mehta, Nn, Burnett, M, Devaney, Jm, Knouff, Cw, Thompson, Jr, Horne, Bd, Stewart, Af, Assimes, Tl, Wild, P, Allayee, H, Nitschke, Pl, Patel, R, Myocardial Infarction Genetics, Consortium, Wellcome Trust Case Control, Consortium, Martinelli, N, Girelli, D, Quyyumi, Aa, Anderson, Jl, Erdmann, J, Hall, A, Schunkert, H, Quertermous, T, Blankenberg, S, Hazen, Sl, Roberts, R, Kathiresan, S, Samani, Nj, Epstein, Se, Rader, Dj, Qasim, An, Derohannessian, Sl, Qu, L, Cappola, Tp, Chen, Z, Matthai, W, Hakonarson, Hh, Wilensky, R, Kent, Km, Lindsay, Jm, Pichard, Ad, Satler, L, Waksman, R, Knoupf, Cw, Walker, Mc, Waterworth, Dm, Mosser, V, Braund, P, Wright, B, Balmforth, Aj, Ball, Sg, Chen, L, Wells, Ga, Mcpherson, R, Lackner, K, Munzel, Tf, Schillert, A, Schnabel, R, Zeller, T, Ziegler, A, Absher, D, Hlatky, Ma, Iribaren, C, Knowles, Jw, Linsel Nitschke, P, König, Ir, Hengstenberg, C, Nahrstaedt, J, Peters, A, Schreiber, S, Wichmann, E, Willenborg, C, Su, S, Bouzyk, M, Vaccarino, V, Zafari, Am, Carlquist, Jf, Muhlestein, Jb, Olivieri, O, Barnard, J, Hartiala, J, Tang, Wh, Burton, Pr, Clayton, Dg, Cardon, Lr, Craddock, N, Deloukas, P, Duncanson, A, Kwiatkowski, Dp, Mccarthy, Mi, Ouwehand, Wh, Todd, Ja, Donnelly, P, Barrett, Jc, Davison, D, Easton, D, Evans, Dm, Leung, Ht, Marchini, Jl, Morris, Ap, Spencer, Cc, Tobin, Md, Attwood, Ap, Boorman, Jp, Cant, B, Everson, U, Hussey, Jm, Jolley, Jd, Knight, A, Koch, K, Meech, E, Nutland, S, Prowse, Cv, Stevens, He, Taylor, Nc, Walters, Gr, Walker, Nm, Watkins, Na, Winzer, T, Jones, Rw, Mcardle, Wl, Ring, Sm, Strachan, Dp, Pembrey, M, Breen, G, St Clair, D, Caesar, S, Gordon Smith, K, Jones, L, Fraser, C, Green, Ek, Grozeva, D, Hamshere, Ml, Holmans, Pa, Jones, Ir, Kirov, G, Moskvina, V, Nikolov, I, O'Donovan, Mc, Owen, Mj, Collier, Da, Elkin, A, Farmer, A, Williamson, R, Mcguffin, P, Young, Ah, Ferrier, In, Barrett, Jh, Bishop, Dt, Iles, Mm, Maqbool, A, Yuldasheva, N, Dixon, Rj, Mangino, M, Stevens, S, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, Cw, Nimmo, Er, Satsangi, J, Fisher, Sa, Forbes, A, Lewis, Cm, Onnie, Cm, Prescott, Nj, Sanderson, J, Mathew, Cg, Barbour, J, Mohiuddin, Mk, Todhunter, Ce, Mansfield, Jc, Ahmad, T, Cummings, Fr, Jewell, Dp, Webster, J, Brown, Mj, Lathrop, M, Connell, J, Dominiczak, A, Marcano, Ca, Burke, B, Dobson, R, Gungadoo, J, Lee, Kl, Munroe, Pb, Newhouse, Sj, Onipinla, A, Wallace, C, Xue, M, Caulfield, M, Farrall, M, Barton, A, Bruce, In, Donovan, H, Eyre, S, Gilbert, Pd, Hider, Sl, Hinks, Am, John, Sl, Potter, C, Silman, Aj, Symmons, Dp, Thomson, W, Worthington, J, Dunger, Db, Widmer, B, Frayling, Tm, Freathy, Rm, Lango, H, Perry, Jr, Shields, Bm, Weedon, Mn, Hattersley, At, Hitman, Ga, Walker, M, Elliott, K, Groves, Cj, Lindgren, Cm, Rayner, Nw, Timpson, Nj, Zeggini, E, Newport, M, Sirugo, G, Lyons, E, Vannberg, F, Hill, Av, Bradbury, La, Farrar, C, Pointon, Jj, Wordsworth, P, Brown, Ma, Franklyn, Ja, Heward, Jm, Simmonds, Mj, Gough, Sc, Seal, S, Stratton, Mr, Rahman, N, Ban, M, Goris, A, Sawcer, Sj, Compston, A, Conway, D, Jallow, M, Rockett, Ka, Bumpstead, Sj, Chaney, A, Downes, K, Ghori, Mj, Gwilliam, R, Hunt, Se, Inouye, M, Keniry, A, King, E, Mcginnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Withers, D, Cardin, Nj, Ferreira, T, Pereira Gale, J, Hallgrimsdóttir, Ib, Bowie, Bn, Su, Z, Teo, Yy, Vukcevic, D, Bentley, D, Meigs, Jb, Williams, G, Nathan, Dm, Macrae, Ca, O'Donnell, Cj, Ardissino, D, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, GIORGIO NEVIO, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Mannucci, Pm, Schwartz, Sm, Siscovick, D, Yee, J, Friedlander, Y, Elosua, R, Marrugat, J, Lucas, G, Subirana, I, Sala, J, Ramos, R, Salomaa, V, Havulinna, A, Peltonen, L, Melander, O, Berglund, G, Voight, Bf, Hirschhorn, Jn, Asselta, R, Duga, S, Spreafico, M, Musunuru, K, Daly, Mj, Purcell, S, Surti, A, Guiducci, C, Gianniny, L, Mirel, D, Parkin, M, Burtt, N, and Gabriel, Sb

Subjects
Adult, Male, medicine.medical_specialty, Linkage disequilibrium, ABO, ADAMTS7 Protein, ADAMTS7, Genome-wide association study, Coronary Angiography, Polymorphism, Single Nucleotide, Linkage Disequilibrium, ABO Blood-Group System, Coronary artery disease, Gene Frequency, ABO blood group system, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, Genetic risk factor, genetic locus, Coronary atherosclerosis, Aged, business.industry, coronary atherosclerosis, General Medicine, Middle Aged, medicine.disease, ADAM Proteins, myocardial infarction, Genetic Loci, Cardiology, Myocardial infarction complications, Female, business, coronary artery disease, Genome-Wide Association Study
Abstract

BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

Published
2011

15. 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

16. 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

17. 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

18. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya

Author

Wendler, JP, Okombo, J, Amato, R, Miotto, O, Kiara, SM, Mwai, L, Pole, L, O'Brien, J, Manske, M, Alcock, D, Drury, E, Sanders, M, Oyola, SO, Malangone, C, Jyothi, D, Miles, A, Rockett, KA, Macinnis, BL, Marsh, K, Bejon, P, Nzila, A, and Kwiatkowski, DP

Subjects
Evolutionary Processes, Plasmodium falciparum, Drug Resistance, lcsh:Medicine, Protozoology, Polymorphism, Single Nucleotide, Microbiology, Antimalarials, parasitic diseases, Genome-Wide Association Studies, Natural Selection, Genetics, Medicine and Health Sciences, Parasitic Diseases, Humans, Genome Sequencing, Malaria, Falciparum, Child, Molecular Biology Techniques, Sequencing Techniques, lcsh:Science, Molecular Biology, Protozoans, Evolutionary Biology, Population Biology, lcsh:R, Organisms, Malarial Parasites, Biology and Life Sciences, Computational Biology, Genomics, DNA, Protozoan, Genome Analysis, Tropical Diseases, Kenya, Parasitic Protozoans, Malaria, Infectious Diseases, Mutation, lcsh:Q, Population Genetics, Genome-Wide Association Study, Research Article
Abstract

BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

Published
2014

22. Astrocytic hypertrophy: An important pathological feature of chronic experimental autoimmune encephalitis in aged rats

Author

David O. Willenborg, Hugh A, Ludowyk Pa, Christopher R. Parish, Hughes W, and Rockett Ka

Subjects
Male, Encephalomyelitis, Autoimmune, Experimental, Encephalomyelitis, Immunology, Central nervous system, Biology, Muscle hypertrophy, Pathogenesis, Immunopathology, medicine, Animals, Immunology and Allergy, Autoimmune disease, Autoimmune encephalitis, Experimental autoimmune encephalomyelitis, Age Factors, Myelin Basic Protein, Hypertrophy, medicine.disease, Rats, medicine.anatomical_structure, Spinal Cord, Neurology, Rats, Inbred Lew, Astrocytes, Female, Neurology (clinical)
Abstract

Experimental autoimmune encephalomyelitis (EAE) was induced in young (2–3 month old), middle-aged (12–13 month old) and geriatric (24–26 month old) Lewis (JC) rats by active immunisation with myelin basic protein (MBP) in complete Freund's adjuvant (CFA). It was found that aged Lewis (JC) rats developed a more chronic form of EAE than younger rats of the same strain, a phenomenon observed in both male and female rats despite males developing more severe disease than females at all ages. Middle-aged recipients also developed more severe disease than young recipients when EAE was induced by the adoptive transfer of lymphocytes from actively immunised young donors, suggesting that disease chronicity in middle-aged animals is a property of the central nervous system (CNS) milieu. Histological studies demonstrated that disease chronicity did not correlate with the number of inflammatory lesions in the CNS, young animals containing substantial numbers of CNS lesions following recovery and lesions being largely absent from middle-aged animals which still exhibited signs of disease. No significant differences were found in the degree of fibrin deposition or demyelination between young and middle-aged or symptomatic and asymptomatic animals. However, astrocytic hypertrophy was found to correlate with manifestation of disease in both young and middle-aged animals and in particular with disease chronicity in middle-aged animals. In parallel studies, no significant differences were found in the levels of the inflammatory mediators tumor necrosis factor (TNF)-α, prostaglandin E (PGE)2, reactive nitrogen intermediates (RNI) and corticosterone in young and middle-aged animals. However, markedly elevated corticosterone levels were found in both young and middle-aged animals with the development of clinical signs which returned to baseline levels with the resolution of clinical signs. Elevated levels of RNI were evident in animals immediately prior to and during the early stages of symptomatic EAE. Although these results suggest that nitric oxide may play a role in the pathogenesis of disease, whereas corticosterone may play a role in the immunoregulation of the disease, these factors cannot explain differences in disease chronicity evident in middle-aged animals. Based on the results presented in this paper, it is proposed that the neurological deficit of chronic EAE in middle-aged animals may be caused by astrocytic hypertrophy with the resolution of this CNS response being a major factor contributing to recovery from the disease in animals of all ages.

Published
1993
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26. A global network for genomic epidemiology of malaria

Author

Malaria Genomic Epidemiology Network, Achidi, Ea, Agbenyega, T, Allen, S, Amodu, O, Bojang, K, Conway, D, Corran, P, Deloukas, P, Djimde, A, Dolo, A, Doumbo, O, Drakeley, C, Duffy, P, Dunstan, S, Evans, J, Farrar, J, Fernando, D, Tran, Th, Horstmann, R, Ibrahim, M, Karunaweera, N, Kokwaro, G, Koram, K, Kwiatkowski, D, Lemnge, M, Makani, J, Marsh, K, Michon, P, Modiano, D, Molyneux, Me, Mueller, I, Mutabingwa, T, Parker, M, Peshu, N, Plowe, C, Puijalon, O, Ragoussis, J, Reeder, J, Reyburn, H, Riley, E, Rogers, J, Sakuntabhai, A, Singhasivanon, P, Sirima, S, Sirugo, G, Tall, A, Taylor, T, Thera, M, Troye Blomberg, M, Williams, T, Wilson, M, Amenga Etego, L, Apinjoh, To, Bougouma, E, Dewasurendra, R, Diakite, M, Enimil, A, Hussein, A, Ishengoma, D, Jallow, M, Lin, E, Ly, A, Mangano, Valentina, Manjurano, A, Manning, L, Ndila, Cm, Nyirongo, V, Oluoch, T, Nguyen, Tn, Suriyaphol, P, Toure, O, Rockett, Ka, Vanderwal, A, Clark, T, Wrigley, R, Alcock, D, Auburn, S, Barnwell, D, Bull, S, Campino, S, Devries, J, Elzein, A, Fitzpatrick, K, Ghansah, A, Green, A, Hart, L, Hilton, E, Hubbart, C, Hughes, C, Jeffreys, Ae, Kivinen, K, Macinnis, B, Manske, M, Maslen, G, Mccreight, M, Mendy, A, Moyes, C, Nyika, A, Potter, C, Risley, P, Rowlands, K, Sanjoaquin, M, Small, K, Somaskantharajah, E, Stevens, M, Teo, Y, Watson, R, Carucci, D, Cook, K, Doyle, A, Duombo, O, Gottlieb, M, and Kwiatkowski, D.

Published
2008

27. Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection

Author

Mangano, VD, Luoni, G, Rockett, KA, Sirima, BS, Konaté, A, Forton, J, Clark, TG, Bancone, G, Sadighi Akha, E, Akha, ES, Kwiatkowski, DP, and Modiano, D

Subjects
Adult, Mossi, Adolescent, Fulani, Plasmodium falciparum, Immunology, Locus (genetics), Single-nucleotide polymorphism, Biology, association study, Article, Polymorphism (computer science), Burkina Faso, parasitic diseases, Genetic variation, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Malaria, Falciparum, Child, Genetics (clinical), IRF-1, Polymorphism, Genetic, Haplotype, Case-control study, 5q31, medicine.disease, biology.organism_classification, Cross-Sectional Studies, Haplotypes, Case-Control Studies, malaria susceptibility, Malaria, Interferon Regulatory Factor-1
Abstract

We describe the haplotypic structure of the interferon regulatory factor-1 (IRF-1) locus in two West African ethnic groups, Fulani and Mossi, that differ in their susceptibility and immune response to Plasmodium falciparum malaria. Both populations showed significant associations between IRF-1 polymorphisms and carriage of P. falciparum infection, with different patterns of association that may reflect their different haplotypic architecture. Genetic variation at this locus does not therefore account for the Fulani-specific resistance to malaria while it could contribute to parasite clearance's ability in populations living in endemic areas. We then conducted a case-control study of three haplotype-tagging single nucleotide polymorphisms (htSNPs) in 370 hospitalised malaria patients (160 severe and 210 uncomplicated) and 410 healthy population controls, all from the Mossi ethnic group. All three htSNPs showed correlation with blood infection levels in malaria patients, and the rs10065633 polymorphism was associated with severe disease (P=0.02). These findings provide the first evidence of the involvement in malaria susceptibility of a specific locus within the 5q31 region, previously shown to be linked with P. falciparum infection levels.

Published
2008

29. 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

30. 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

32. Editorial

Author

Rockett Katharine

Subjects
Social Sciences, Economics as a science, HB71-74
Published
2021
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33. Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

Author

Clark TG, Diakite M, Auburn S, Campino S, Fry AE, Green A, Richardson A, Small K, Teo YY, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, and Rockett KA

Abstract

The tumor necrosis factor gene (TNF) and lymphotoxin-alpha gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving >10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF -238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms. [ABSTRACT FROM AUTHOR]

Published
2009
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34. 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.

36. Admixture into and within sub-Saharan Africa

Author

Angeliki Kerasidou, J O'Brien, Aaron Vanderwal, Christina Hubbart, Alistair Miles, Catherine L. Moyes, A Nyika, Abier Elzein, J Shelton, Spencer Cca., Anthony Enimil, A Diss, C Hughes, Lucas Amenga-Etego, E Somaskantharajah, Ogobara K. Doumbo, Jacob Almagro Garcia, Valentina D. Mangano, E Drury, Edith Bougama, Angie Green, Busby Gbj., Geraldine M. Clarke, Dominic P. Kwiatkowski, Jiannis Ragoussis, Alphaxard Manjurano, Bronwyn MacInnis, Tobias O. Apinjoh, D Mead, Gareth Maslen, George B.J. Busby, Kirk A. Rockett, Dushyanth Jyothi, C Potter, C Malangone, Muminatou Jallow, I Ragoussis, Ellen M. Leffler, J Rogers, J Stalker, Quang Si Le, J Rodford, D Barnwell, Alieu Mendy, J deVries, Anna E. Jeffreys, Carolyne M. Ndila, E Hilton, Vysaul Nyirongo, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Medical Research Council Unit The Gambia (MRC), Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), Komfo Anokye Teaching Hospital, University of Buéa, KEMRI-Wellcome Trust Research Programme (KWTRP), London School of Hygiene and Tropical Medicine (LSHTM), University of Malawi, University of Bamako [Mali], Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Wellcome Trust, Medical Research Council, Foundation for the National Institutes of Health, Malaria Genomics Epidemiology Network : Vanderwal A, Elzein A, Nyika A, Mendy A, Miles A, Diss A, Kerasidou A, Green A, Jeffreys AE, MacInnis B, Hughes C, Moyes C, Spencer CC, Hubbart C, Malangone C, Potter C, Mead D, Barnwell D, Kwiatkowski DP, Jyothi D, Drury E, Somaskantharajah E, Hilton E, Leffler E, Maslen G, Band G, Busby G, Clarke GM, Ragoussis I, Garcia JA, Rogers J, deVries J, Shelton J, Ragoussis J, Stalker J, Rodford J, O'Brien J, Evans J, Rowlands K, Cook K, Fitzpatrick K, Kivinen K, Small K, Johnson KJ, Rockett KA, Hart L, Manske M, McCreight M, Stevens M, Pirinen M, Hennsman M, Parker M, SanJoaquin M, Seplúveda N, Cook O, Miotto O, Deloukas P, Craik R, Wrigley R, Watson R, Pearson R, Hutton R, Oyola S, Auburn S, Shah S, Le SQ, Molloy S, Bull S, Campino S, Clark TG, Ruano-Rubio V, Cornelius V, Teo YY, Corran P, Silva ND, Risley P, Doyle A, Evans J, Horstmann R, Plowe C, Duffy P, Carucci D, Gottleib M, Tall A, Ly AB, Dolo A, Sakuntabhai A, Puijalon O, Bah A, Camara A, Sadiq A, Khan AA, Jobarteh A, Mendy A, Ebonyi A, Danso B, Taal B, Casals-Pascual C, Conway DJ, Onykwelu E, Sisay-Joof F, Sirugo G, Kanyi H, Njie H, Obu H, Saine H, Sambou I, Abubakar I, Njie J, Fullah J, Jaiteh J, Bojang KA, Jammeh K, Sabally-Ceesay K, Manneh L, Camara L, Yamoah L, Njie M, Njie M, Pinder M, Jallow M, Aiyegbo M, Jasseh M, Keita ML, Saidy-Khan M, Jallow M, Ceesay N, Rasheed O, Ceesay PL, Esangbedo P, Cole-Ceesay R, Olaosebikan R, Correa S, Njie S, Usen S, Dibba Y, Barry A, Djimdé A, Sall AH, Abathina A, Niangaly A, Dembele A, Poudiougou B, Diarra E, Bamba K, Thera MA, Doumbo O, Toure O, Konate S, Sissoko S, Diakite M, Konate AT, Modiano D, Bougouma EC, Bancone G, Ouedraogo IN, Simpore J, Sirima SB, Mangano VD, Troye-Blomberg M, Oduro AR, Hodgson AV, Ghansah A, Nkrumah F, Atuguba F, Koram KA, Amenga-Etego LN, Wilson MD, Ansah NA, Mensah N, Ansah PA, Anyorigiya T, Asoala V, Rogers WO, Akoto AO, Ofori AO, Enimil A, Ansong D, Sambian D, Asafo-Agyei E, Sylverken J, Antwi S, Agbenyega T, Orimadegun AE, Amodu FA, Oni O, Omotade OO, Amodu O, Olaniyan S, Ndi A, Yafi C, Achidi EA, Mbunwe E, Anchang-Kimbi J, Mugri R, Besingi R, Apinjoh TO, Titanji V, Elhassan A, Hussein A, Mohamed H, Elhassan I, Ibrahim M, Kokwaro G, Oluoch T, Macharia A, Ndila CM, Newton C, Opi DH, Kamuya D, Bauni E, Marsh K, Peshu N, Molyneux S, Uyoga S, Williams TN, Marsh V, Manjurano A, Nadjm B, Maxwell C, Drakeley C, Riley E, Mtei F, Mtove G, Wangai H, Reyburn H, Joseph S, Ishengoma D, Lemnge M, Mutabingwa T, Makani J, Cox S, Phiri A, Munthali A, Kachala D, Njiragoma L, Molyneux ME, Moore M, Ntunthama N, Pensulo P, Taylor T, Nyirongo V, Carter R, Fernando D, Karunaweera N, Dewasurendra R, Suriyaphol P, Singhasivanon P, Simmons CP, Thai CQ, Sinh DX, Farrar J, Chuong LV, Phu NH, Hieu NT, Hoang Mai NT, Ngoc Quyen NT, Day N, Dunstan SJ, O'Riordan SE, Hong Chau TT, Hien TT, Allen A, Lin E, Karunajeewa H, Mueller I, Reeder J, Manning L, Laman M, Michon P, Siba P, Allen S, Davis TM., Commission of the European Communities, and Wellcome Trust

Subjects
0301 basic medicine, Population genetics, Gene flow, 0302 clinical medicine, MESH: Genetic Variation, Biology (General), African Continental Ancestry Group, media_common, Genetics, 0303 health sciences, education.field_of_study, Human migration, General Neuroscience, 030305 genetics & heredity, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Geography, Genomics and Evolutionary Biology, MESH: Human Migration, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, admixture, gene-flow, Research Article, Gene Flow, QH301-705.5, Science, media_common.quotation_subject, Human Migration, Population, Black People, Genomics, Biology, africa, chromosome painting, evolutionary biology, genomics, human, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Genetic variation, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, MESH: Africa South of the Sahara, Allele, education, Africa South of the Sahara, MESH: Gene Flow, MESH: Genome, Human, 030304 developmental biology, Genetic diversity, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], General Immunology and Microbiology, business.industry, Genome, Human, Haplotype, Genetic Variation, MESH: Haplotypes, 030104 developmental biology, Genetic epidemiology, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Agriculture, Evolutionary biology, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: African Continental Ancestry Group, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Demography, Diversity (politics)
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. DOI: http://dx.doi.org/10.7554/eLife.15266.001, eLife digest Our genomes contain a record of historical events. This is because when groups of people are separated for generations, the DNA sequence in the two groups’ genomes will change in different ways. Looking at the differences in the genomes of people from the same population can help researchers to understand and reconstruct the historical interactions that brought their ancestors together. The mixing of two populations that were previously separate is known as admixture. Africa as a continent has few written records of its history. This means that it is somewhat unknown which important movements of people in the past generated the populations found in modern-day Africa. Busby et al. have now attempted to use DNA to look into this and reconstruct the last 4000 years of genetic history in African populations. As has been shown in other regions of the world, the new analysis showed that all African populations are the result of historical admixture events. However, Busby et al. could characterize these events to unprecedented level of detail. For example, multiple ethnic groups from The Gambia and Mali all show signs of sharing the same set of ancestors from West Africa, Europe and Asia who mixed around 2000 years ago. Evidence of a migration of people from Central West Africa, known as the Bantu expansion, could also be detected, and was shown to carry genes to the south and east. An important next step will be to now look at the consequences of the observed gene-flow, and ask if it has contributed to spreading beneficial, or detrimental, mutations around Africa. DOI: http://dx.doi.org/10.7554/eLife.15266.002

Published
2016
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37. Genome-wide association study identifies eight loci associated with blood pressure

Author

Peter Holmans, Udo Seedorf, Beverley M. Shields, Peter McGruffin, Arne Pfeufer, Steve Eyre, Nathalie J. Prescott, Michael Boehnke, Valentina Moskovina, Abiodun Onipinla, Leena Peltonen, Nadira Yuldasheva, Peter M. Nilsson, Valeria Romanazzi, Vincent Mooser, Göran Berglund, Alistair S. Hall, Dominic P. Kwiatkowski, Barry Widmer, Benjamin F. Voight, Stefania Bandinelli, Mark M. Iles, Sven Bergmann, Thomas Meitinger, James P. Boorman, Simonetta Guarrera, Nazneen Rahman, Murielle Bochud, Graham A. Hitman, Emma Keniry, Nelson B. Freimer, Richard Dobson, Francis S. Collins, Gerjan Navis, Jennifer L. Pointon, Richard N. Bergman, Ruth J. F. Loos, Roberto Lorbeer, Carolina A. Braga Marcano, Christian Gieger, Florian Ernst, Xin Yuan, Catherine Potter, Hazel E. Drummond, Allan H. Young, George Kirov, John F. Peden, Helen Stevens, David Clayton, Mattijs E. Numans, Katherine Gordon-Smith, Anne Farmer, Alastair Forbes, M. Khalid Mohiuddin, John A. Todd, Christopher G. Mathew, David A. Collier, Mark I. McCarthy, Francesca Bredin, Clive M. Onnie, Dan Davidson, Markus Perola, Pamela Whittaker, Yvonne T. van der Schouw, Rathi Ravindrarajan, I. C.A. Spencer, Teresa Ferreira, Nilesh J. Samani, Serge Hercberg, Gonçalo R. Abecasis, Christopher J. Groves, Nicholas John Craddock, Angela Döring, Edward G. Lakatta, Muminatou Jallow, Wendy L. McArdle, David Bentley, Susana Eyheramendy, Uwe Völker, Christopher Newton-Cheh, Jaspal S. Kooner, Hugh Watkins, Gavin Lucas, H. T. Leung, Marjo Ritta Jarvelin, Johanna Kuusisto, Wiek H. van Gilst, Wendy Thomson, Lou R. Cardon, Harold Snieder, Marju Orho-Melander, Patricia B. Munroe, Toshiko Tanaka, Jeffrey C. Barrett, Azhar Maqbool, Henry Völzke, John M. C. Connell, Elaine R. Nimmo, John R. B. Perry, Michael R. Stratton, Ralph McGinnis, Pekka Jousilahti, Michiel L. Bots, Ian Jones, Elizabeth Meech, Matthew A. Brown, Johannie Gungadoo, Jian'an Luan, Jilur Ghori, Richard J. Dixon, N. Charlotte Onland-Moret, Fulvio Ricceri, Anthony J. Balmforth, Catherine E. Todhunter, Inês Barroso, Sheila Bingham, Timo T. Valle, Fredrik O. Vannberg, Diana Zelenika, Stephen Sawcer, Anneli Pouta, David M. Evans, Cuno S. P. M. Uiterwaal, Pilar Galan, Georg Homuth, Hannah Donovan, David J. Conway, Paul Elliott, Alessandra Allione, Paul E. de Jong, Miles Parkes, Amy Chaney, John C. Chambers, Toby Johnson, Isaac Subirana, Vesela Gateva, Cathryn M. Lewis, Christopher J. O'Donnell, Hana Lango, David Schlessinger, Mark J. Caulfield, Thorsten Reffelmann, Jamie Barbour, Karen L. Mohlke, Sarah E. Hunt, Thilo Winzer, Frances M K Williams, Christopher Mathew, I. Wallace, Anuj Goel, Jaakko Tuomilehto, Louise V. Wain, Gabriel Crawford, Samantha L. Hider, Detelinea Grozeva, Elaine K. Green, Paul D. Gilbert, Peter S. Braund, Jaume Marrugat, Rainer Rettig, Pim van der Harst, Yik Ying Teo, Andrew P. Morris, Guiseppe Matullo, Serena Sanna, Cristen J. Willer, Suzannah Bumpstead, Niall C. Taylor, Jacques S. Beckmann, Pierre Meneton, Elin Org, Luigi Ferrucci, Doug Easton, Sheila Seal, Joanne M. Heward, Anne U. Jackson, Eleftheria Zeggini, Rachel M. Freathy, Maris Laan, Paul Wordsworth, Sarah Nutland, Kerstin Koch, Sian Ceasar, Anders Hamsten, Judith M. Hussey, Tariq Ahmad, Derek P. Jewell, Paul Scheet, Charlie W. Lees, C Farrar, Christopher Prowse, Markku Laakso, David St Clair, Kate Downes, Diederick E. Grobbee, Paul Burton, Simon C. Potter, Ian N. Bruce, Tim D. Spector, Anne Barton, H.-Erich Wichmann, Matthew J. Simmonds, David Hadley, Cecilia M. Lindgren, Gérard Waeber, Nigel W. Rayner, Melanie J. Newport, Manjinder S. Sandhu, Audrey Duncanson, Guangju Zhai, Simon Heath, Susan M. Ring, Alessandra Di Gregorio, Richard Williamson, Nicholas J. Wareham, Zhan Su, Olle Melander, John R. Thompson, Alexander Teumer, Sheila A. Fisher, Lachlan J. M. Coin, Leif Groop, Giovanni Tognoni, Amanda Elkin, Alan J. Silman, Jack Satsangi, Jane Worthington, Martin Farrall, John Webster, Niall Cardin, Neil Walker, Anna F. Dominiczak, Jeremy D. Sanderson, Damjan Vukcevic, Bryan Howie, Silvia Polidoro, Stephen G. Ball, Mark Tremelling, Stephen Newhouse, Stephen M. Schwartz, Lori L. Bonnycastle, Chris Wallace, Kijoung Song, Mario A. Morken, I. Nicol Ferrier, Beverley Barke, Paolo Vineis, Manuela Uda, Deborah P M Symmons, Emily J. Lyons, Mingzhan Xue, Timothy M. Frayling, Stephen C.L. Cough, David Withers, Adrian V. S. Hill, Suzanne Stevens, Jennifer Jolley, Marcus Dörr, Kirk A. Rockett, David B. Dunger, Mark Walker, Jayne A. Franklyn, Lisa Jones, David S. Siscovick, Ann-Christine Syvänen, Laura J. Scott, Morris J. Brown, Barbera Cant, Michael Inouye, Feng Zhang, Carlotta Sacerdote, Katherine S. Elliott, Jonathan Marchini, Peter Donnely, Michael John Owen, An Goris, Marcus Prembey, Andrew T. Hattersley, Gerome Breen, Marian L. Hamshere, Thomas Illig, Samer S. Najjar, Nicole Soranzo, Kay-Tee Khaw, Graham R. Walters, Willem H. Ouwehand, David P. Strachan, Martin D. Tobin, Alastair Compston, John C. Mansfield, David Altshuler, Salvatore Panico, Sekar Kathiresan, Dawn M. Waterworth, Michael N. Weedon, D. Timothy Bishop, Claire Bryan, Alexandra S. Knight, Kate L. Lee, Paul F. O'Reilly, Massimo Mangino, Michael Conlon O'Donovan, Jing Hua Zhao, Konstantinos A. Papadakis, Jennifer H. Barrett, Joanne Pereira-Gale, N J Timpson, Stephan B. Felix, Panos Deloukas, Nicholas A. Watkins, Anna-Liisa Hartikainen, Peter Vollenweider, Richard Jones, Anne Hinks, Fraser Cummings, Noha Lim, Linda A. Bradbury, Rhian G. William, Nita G. Forouhi, Roberto Eluosa, Ingeleif B. Hallgrimsdottir, Giorgio Sirugo, Robert Luben, Veikko Salomaa, Robert Clarke, Sally John, Ursula Everson, Emma King, Ivan Nikolov, Heather M. Stringham, Antony P. Attwood, Angelo Scuteri, Wellcome Trust Case Control Consortium, Burton, PR., Clayton, DG., Cardon, LR., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, DP., McCarthy, MI., Ouwehand, WH., Samani, NJ., Todd, JA., Donnelly, P., Barrett, JC., Davison, D., Easton, D., Evans, D., Leung, HT., Marchini, JL., Morris, AP., Spencer, IC., Tobin, MD., Attwood, AP., Boorman, JP., Cant, B., Everson, U., Hussey, JM., Jolley, JD., Knight, AS., Koch, K., Meech, E., Nutland, S., Prowse, CV., Stevens, HE., Taylor, NC., Walters, GR., Walker, NM., Watkins, NA., Winzer, T., Jones, RW., McArdle, WL., Ring, SM., Strachan, DP., Pembrey, M., Breen, G., St Clair, D., Caesar, S., Gordon-Smith, K., Jones, L., Fraser, C., Green, EK., Grozeva, D., Hamshere, ML., Holmans, PA., Jones, IR., Kirov, G., Moskvina, V., Nikolov, I., O'Donovan, MC., Owen, MJ., Collier, DA., Elkin, A., Farmer, A., Williamson, R., McGuffin, P., Young, AH., Ferrier, IN., Ball, SG., Balmforth, AJ., Barrett, JH., Bishop, DT., Iles, MM., Maqbool, A., Yuldasheva, N., Hall, AS., Braund, PS., Dixon, RJ., Mangino, M., Stevens, S., Thompson, JR., Bredin, F., Tremelling, M., Parkes, M., Drummond, H., Lees, CW., Nimmo, ER., Satsangi, J., Fisher, SA., Forbes, A., Lewis, CM., Onnie, CM., Prescott, NJ., Sanderson, J., Mathew, CG., Barbour, J., Mohiuddin, MK., Todhunter, CE., Mansfield, JC., Ahmad, T., Cummings, FR., Jewell, DP., Webster, J., Brown, MJ., Lathrop, GM., Connell, J., Dominiczak, A., Braga Marcano, CA., Burke, B., Dobson, R., Gungadoo, J., Lee, KL., Munroe, PB., Newhouse, SJ., Onipinla, A., Wallace, I., Xue, M., Caulfield, M., Farrall, M., Barton, A., Bruce, IN., Donovan, H., Eyre, S., Gilbert, PD., Hider, SL., Hinks, AM., John, SL., Potter, C., Silman, AJ., Symmons, DP., Thomson, W., Worthington, J., Dunger, DB., Widmer, B., Frayling, TM., Freathy, RM., Lango, H., Perry, JR., Shields, BM., Weedon, MN., Hattersley, AT., Hitman, GA., Walker, M., Elliott, KS., Groves, CJ., Lindgren, CM., Rayner, NW., Timpson, NJ., Zeggini, E., Newport, M., Sirugo, G., Lyons, E., Vannberg, F., Hill, AV., Bradbury, LA., Farrar, C., Pointon, JJ., Wordsworth, P., Brown, MA., Franklyn, JA., Heward, JM., Simmonds, MJ., Gough, SC., Seal, S., Stratton, MR., Rahman, N., Ban, M., Goris, A., Sawcer, SJ., Compston, A., Conway, D., Jallow, M., Rockett, KA., Bryan, C., Bumpstead, SJ., Chaney, A., Downes, K., Ghori, J., Gwilliam, R., Hunt, SE., Inouye, M., Keniry, A., King, E., McGinnis, R., Potter, S., Ravindrarajah, R., Whittaker, P., Withers, D., Cardin, NJ., Ferreira, T., Pereira-Gale, J., Hallgrimsdóttir, IB., Howie, BN., Su, Z., Teo, YY., Vukcevic, D., Bentley, D., Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Medical Research Council (MRC)

Subjects
Hemodynamics, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, 0302 clinical medicine, Diastole, 11 Medical and Health Sciences, POPULATION, Genetics, Genetics & Heredity, RISK, 0303 health sciences, education.field_of_study, Econometric and Statistical Methods: General, CELL-DIFFERENTIATION, biology, Intracellular Signaling Peptides and Proteins, Chromosome Mapping, Steroid 17-alpha-Hydroxylase, COMMON VARIANTS, 3. Good health, DNA-Binding Proteins, Europe, Cardiovascular Diseases, PUBLIC-HEALTH, BARTTERS-SYNDROME, Blood Pressure/genetics, Cardiovascular Diseases/genetics, Cardiovascular Diseases/physiopathology, Cytochrome P-450 CYP1A2/genetics, DNA-Binding Proteins/genetics, Diastole/genetics, European Continental Ancestry Group/genetics, Fibroblast Growth Factor 5/genetics, Genetic Variation, Genome-Wide Association Study, Humans, India, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, Open Reading Frames/genetics, Phospholipase C delta/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Steroid 17-alpha-Hydroxylase/genetics, Systole/genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, hypertension, Fibroblast Growth Factor 5, Systole, Population, European Continental Ancestry Group, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Single-nucleotide polymorphism, LOW-RENIN HYPERTENSION, White People, Article, 03 medical and health sciences, Open Reading Frames, Fibroblast growth factor-5, Cytochrome P-450 CYP1A2, Geneeskunde(GENK), education, Methylenetetrahydrofolate Reductase (NADPH2), Adaptor Proteins, Signal Transducing, 030304 developmental biology, Genetic association, genome-wide association, Science & Technology, MUTATIONS, Proteins, 06 Biological Sciences, POLYMORPHISM, Blood pressure, Methylenetetrahydrofolate reductase, biology.protein, biology.gene, Phospholipase C delta, Developmental Biology
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.

Published
2009
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38. Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria.

Author

Opi DH, Ndila CM, Uyoga S, Macharia AW, Fennell C, Ochola LB, Nyutu G, Siddondo BR, Ojal J, Shebe M, Awuondo KO, Mturi N, Peshu N, Tsofa B, Band G, Maitland K, Kwiatkowski DP, Rockett KA, Williams TN, and Rowe JA

Subjects
Child, Humans, ABO Blood-Group System genetics, Plasmodium falciparum genetics, Case-Control Studies, Kenya, Genotype, Malaria, Malaria, Falciparum genetics
Abstract

Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that "double dose" non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than "single dose" heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO and BO genotypes rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Opi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2023
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39. Genome-wide association study of leprosy in Malawi and Mali.

Author

Gilchrist JJ, Auckland K, Parks T, Mentzer AJ, Goldblatt L, Naranbhai V, Band G, Rockett KA, Toure OB, Konate S, Sissoko S, Djimdé AA, Thera MA, Doumbo OK, Sow S, Floyd S, Pönnighaus JM, Warndorff DK, Crampin AC, Fine PEM, Fairfax BP, and Hill AVS

Subjects
Humans, Child, Genome-Wide Association Study, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Malawi, Mali, Nucleoside Transport Proteins genetics, Leprosy genetics, Inflammatory Bowel Diseases
Abstract

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations., Competing Interests: The authors have declared that no competing interests exist.

Published
2022
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40. BIRC6 modifies risk of invasive bacterial infection in Kenyan children.

Author

Gilchrist JJ, Kariuki SN, Watson JA, Band G, Uyoga S, Ndila CM, Mturi N, Mwarumba S, Mohammed S, Mosobo M, Alasoo K, Rockett KA, Mentzer AJ, Kwiatkowski DP, Hill AVS, Maitland K, Scott JAG, and Williams TN

Subjects
Child, Genome-Wide Association Study, Humans, Inhibitor of Apoptosis Proteins, Kenya epidemiology, Bacteremia microbiology, Bacterial Infections, Malaria complications, Malaria epidemiology
Abstract

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with Plasmodium falciparum parasitaemia. We construct a joint dataset including 1445 bacteraemia cases and 1143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data, we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so, we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children., Competing Interests: JG, SK, JW, GB, SU, CN, NM, SM, SM, MM, KA, KR, AM, DK, AH, KM, JS, TW No competing interests declared, (© 2022, Gilchrist et al.)

Published
2022
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41. Malaria protection due to sickle haemoglobin depends on parasite genotype.

Author

Band G, Leffler EM, Jallow M, Sisay-Joof F, Ndila CM, Macharia AW, Hubbart C, Jeffreys AE, Rowlands K, Nguyen T, Gonçalves S, Ariani CV, Stalker J, Pearson RD, Amato R, Drury E, Sirugo G, d'Alessandro U, Bojang KA, Marsh K, Peshu N, Saelens JW, Diakité M, Taylor SM, Conway DJ, Williams TN, Rockett KA, and Kwiatkowski DP

Subjects
Alleles, Animals, Child, Female, Gambia epidemiology, Genes, Protozoan genetics, Humans, Kenya epidemiology, Linkage Disequilibrium, Malaria, Falciparum epidemiology, Male, Polymorphism, Genetic, Genotype, Hemoglobin, Sickle genetics, Host Adaptation genetics, Malaria, Falciparum blood, Malaria, Falciparum parasitology, Parasites genetics, Plasmodium falciparum genetics
Abstract

Host genetic factors can confer resistance against malaria 1 , raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member 2-4 PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations., (© 2021. The Author(s).)

Published
2022
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42. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α 3.7I form of α-thalassaemia using genome-wide microarray data.

Author

Ndila CM, Nyirongo V, Macharia AW, Jeffreys AE, Rowlands K, Hubbart C, Busby GBJ, Band G, Harding RM, Rockett KA, and Williams TN

Abstract

Background: The -α 3.7I -thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study, we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha ( HBA ) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Ndila CM et al.)

Published
2021
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43. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples.

Author

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 TN, Noedl H, Nosten F, Noviyanti R, Nzila A, Ochola-Oyier LI, Ocholla H, Oduro A, Omedo I, Onyamboko MA, Ouedraogo JB, 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 XZ, 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., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 MalariaGEN et al.)

Published
2021
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44. Novel genotyping approaches to easily detect genomic admixture between the major Afrotropical malaria vector species, Anopheles coluzzii and An. gambiae.

Author

Caputo B, Pichler V, Bottà G, De Marco C, Hubbart C, Perugini E, Pinto J, Rockett KA, Miles A, and Della Torre A

Subjects
Animals, Gambia, Genomics, Genotype, Guinea-Bissau, Malaria transmission, Mosquito Vectors classification, Mosquito Vectors genetics, Senegal, Anopheles classification, Anopheles genetics, Genome, Insect
Abstract

The two most efficient and most recently radiated Afrotropical vectors of human malaria - Anopheles coluzzii and An. gambiae - are identified by single-locus diagnostic PCR assays based on species-specific markers in a 4 Mb region on chromosome-X centromere. Inherently, these diagnostic assays cannot detect interspecific autosomal admixture shown to be extensive at the westernmost and easternmost extremes of the species range. The main aim of this study was to develop novel, easy-to-implement tools for genotyping An. coluzzii and An. gambiae-specific ancestral informative markers (AIMs) identified from the Anopheles gambiae 1000 genomes (Ag1000G) project. First, we took advantage of this large set of data in order to develop a multilocus approach to genotype 26 AIMs on all chromosome arms valid across the species range. Second, we tested the multilocus assay on samples from Guinea Bissau, The Gambia and Senegal, three countries spanning the westernmost hybridization zone, where conventional species diagnostic is problematic due to the putative presence of a novel "hybrid form". The multilocus assay was able to capture patterns of admixture reflecting those revealed by the whole set of AIMs and provided new original data on interspecific admixture in the region. Third, we developed an easy-to-use, cost-effective PCR approach for genotyping two AIMs on chromosome-3 among those included in the multilocus approach, opening the possibility for advanced identification of species and of admixed specimens during routine large scale entomological surveys, particularly, but not exclusively, at the extremes of the range, where WGS data highlighted unexpected autosomal admixture., (© 2021 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.)

Published
2021
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45. High-throughput genotyping assays for identification of glycophorin B deletion variants in population studies.

Author

Amuzu DS, Rockett KA, Leffler EM, Ansah F, Amoako N, Morang'a CM, Hubbart C, Rowlands K, Jeffreys AE, Amenga-Etego LN, Kwiatkowski DP, and Awandare GA

Subjects
Adult, Child, Child, Preschool, Female, Ghana, Humans, Infant, Malaria genetics, Male, Base Sequence, Genotyping Techniques, Glycophorins genetics, Polymorphism, Restriction Fragment Length, Sequence Deletion
Abstract

Glycophorins are the most abundant sialoglycoproteins on the surface of human erythrocyte membranes. Genetic variation in glycophorin region of human chromosome 4 (containing GYPA , GYPB , and GYPE genes) is of interest because the gene products serve as receptors for pathogens of major public health interest, including Plasmodium sp. , Babesia sp. , Influenza virus, Vibrio cholerae El Tor Hemolysin, and Escherichia coli . A large structural rearrangement and hybrid glycophorin variant, known as Dantu , which was identified in East African populations, has been linked with a 40% reduction in risk for severe malaria. Apart from Dantu , other large structural variants exist, with the most common being deletion of the whole GYPB gene and its surrounding region, resulting in multiple different deletion forms. In West Africa particularly, these deletions are estimated to account for between 5 and 15% of the variation in different populations, mostly attributed to the forms known as DEL1 and DEL2. Due to the lack of specific variant assays, little is known of the distribution of these variants. Here, we report a modification of a previous GYPB DEL1 assay and the development of a novel GYPB DEL2 assay as high-throughput PCR-RFLP assays, as well as the identification of the crossover/breakpoint for GYPB DEL2. Using 393 samples from three study sites in Ghana as well as samples from HapMap and 1000 G projects for validation, we show that our assays are sensitive and reliable for genotyping GYPB DEL1 and DEL2. To the best of our knowledge, this is the first report of such high-throughput genotyping assays by PCR-RFLP for identifying specific GYPB deletion types in populations. These assays will enable better identification of GYPB deletions for large genetic association studies and functional experiments to understand the role of this gene cluster region in susceptibility to malaria and other diseases.

Published
2021
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46. Malaria is a cause of iron deficiency in African children.

Author

Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, Etyang AO, Kyobutungi C, Morovat A, Kimita W, Ndungu FM, Macharia AW, Ngetsa CJ, Makale J, Lule SA, Musani SK, Raffield LM, Cutland CL, Sirima SB, Diarra A, Tiono AB, Fried M, Gwamaka M, Adu-Afarwuah S, Wirth JP, Wegmüller R, Madhi SA, Snow RW, Hill AVS, Rockett KA, Sandhu MS, Kwiatkowski DP, Prentice AM, Byrd KA, Ndjebayi A, Stewart CP, Engle-Stone R, Green TJ, Karakochuk CD, Suchdev PS, Bejon P, Duffy PE, Davey Smith G, Elliott AM, Williams TN, and Atkinson SH

Subjects
Absorption, Physiological, Adolescent, Africa, Child, Child, Preschool, Female, Geography, Hepcidins metabolism, Humans, Infant, Male, Mendelian Randomization Analysis, Sickle Cell Trait complications, Iron Deficiencies, Malaria complications
Abstract

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID 1 . To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria 2 , as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Published
2021
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47. Temporal evolution of sulfadoxine-pyrimethamine resistance genotypes and genetic diversity in response to a decade of increased interventions against Plasmodium falciparum in northern Ghana.

Author

Amenga-Etego LN, Asoala V, Agongo G, Jacob C, Goncalves S, Awandare GA, Rockett KA, and Kwiatkowski D

Subjects
Adolescent, Child, Child, Preschool, Drug Combinations, Female, Ghana, Humans, Male, Plasmodium falciparum drug effects, Seasons, Young Adult, Antimalarials pharmacology, Drug Resistance genetics, Genetic Variation drug effects, Genotype, Malaria, Falciparum prevention & control, Plasmodium falciparum genetics, Pyrimethamine pharmacology, Sulfadoxine pharmacology
Abstract

Background: Anti-malarial drug resistance remains a key concern for the global fight against malaria. In Ghana sulfadoxine-pyrimethamine (SP) is used for intermittent preventive treatment of malaria in pregnancy and combined with amodiaquine for Seasonal Malaria Chemoprevention (SMC) during the high malaria season. Thus, surveillance of molecular markers of SP resistance is important to guide decision-making for these interventions in Ghana., Methods: A total of 4469 samples from uncomplicated malaria patients collected from 2009 to 2018 was submitted to the Wellcome Trust Sanger Institute, UK for DNA sequencing using MiSeq. Genotypes were successfully translated into haplotypes in 2694 and 846 mono infections respectively for pfdhfr and pfdhps genes and the combined pfhdfr/pfdhps genes across all years., Results: At the pfdhfr locus, a consistently high (> 60%) prevalence of parasites carrying triple mutants (IRNI) were detected from 2009 to 2018. Two double mutant haplotypes (NRNI and ICNI) were found, with haplotype NRNI having a much higher prevalence (average 13.8%) than ICNI (average 3.2%) across all years. Six pfdhps haplotypes were detected. Of these, prevalence of five fluctuated in a downward trend over time from 2009 to 2018, except a pfdhps double mutant (AGKAA), which increased consistently from 2.5% in 2009 to 78.2% in 2018. Across both genes, pfdhfr/pfdhps combined triple (NRNI + AAKAA) mutants were only detected in 2009, 2014, 2015 and 2018, prevalence of which fluctuated between 3.5 and 5.5%. The combined quadruple (IRNI + AAKAA) genotype increased in prevalence from 19.3% in 2009 to 87.5% in 2011 before fluctuating downwards to 19.6% in 2018 with an average prevalence of 37.4% within the nine years. Prevalence of parasites carrying the quintuple (IRNI + AGKAA or SGEAA) mutant haplotypes, which are highly refractory to SP increased over time from 14.0% in 2009 to 89.0% in 2016 before decreasing to 78.9 and 76.6% in 2017 and 2018 respectively. Though quintuple mutants are rising in prevalence in both malaria seasons, together these combined genotypes vary significantly within season but not between seasons., Conclusions: Despite high prevalence of pfdhfr triple mutants and combined pfdhfr/pfdhps quadruple and quintuple mutants in this setting SP may still be efficacious. These findings are significant as they highlight the need to continuously monitor SP resistance, particularly using deep targeted sequencing to ascertain changing resistance patterns.

Published
2021
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48. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α 3.7I form of α-thalassaemia using genome-wide microarray data.

Author

Ndila CM, Nyirongo V, Macharia AW, Jeffreys AE, Rowlands K, Hubbart C, Busby GBJ, Band G, Harding RM, Rockett KA, and Williams TN

Abstract

Background: The -α 3.7I -thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha ( HBA ) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Ndila CM et al.)

Published
2020
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49. Interferon-gamma polymorphisms and risk of iron deficiency and anaemia in Gambian children.

Author

Abuga KM, Rockett KA, Muriuki JM, Koch O, Nairz M, Sirugo G, Bejon P, Kwiatkowski DP, Prentice AM, and Atkinson SH

Abstract

Background : Anaemia is a major public health concern especially in African children living in malaria-endemic regions. Interferon-gamma (IFN-γ) is elevated during malaria infection and is thought to influence erythropoiesis and iron status. Genetic variants in the IFN-γ gene (IFNG ) are associated with increased IFN-γ production. We investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes of IFNG in relation to nutritional iron status and anaemia in Gambian children over a malaria season. Methods: We used previously available data from Gambian family trios to determine informative SNPs and then used the Agena Bioscience MassArray platform to type five SNPs from the IFNG gene in a cohort of 780 Gambian children aged 2-6 years. We also measured haemoglobin and biomarkers of iron status and inflammation at the start and end of a malaria season. Results: We identified five IFNG haplotype-tagging SNPs ( IFNG -1616 [rs2069705], IFNG +874 [rs2430561], IFNG +2200 [rs1861493], IFNG +3234 [rs2069718] and IFNG +5612 [rs2069728]). The IFNG +2200C [rs1861493] allele was associated with reduced haemoglobin concentrations (adjusted β -0.44 [95% CI -0.75, -0.12]; Bonferroni adjusted P = 0.03) and a trend towards iron deficiency compared to wild-type at the end of the malaria season in multivariable models adjusted for potential confounders. A haplotype uniquely identified by IFNG +2200C was similarly associated with reduced haemoglobin levels and trends towards iron deficiency, anaemia and iron deficiency anaemia at the end of the malaria season in models adjusted for age, sex, village, inflammation and malaria parasitaemia. Conclusion: We found limited statistical evidence linking IFNG polymorphisms with a risk of developing iron deficiency and anaemia in Gambian children. More definitive studies are needed to investigate the effects of genetically influenced IFN-γ levels on the risk of iron deficiency and anaemia in children living in malaria-endemic areas., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Abuga KM et al.)

Published
2020
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50. A high throughput multi-locus insecticide resistance marker panel for tracking resistance emergence and spread in Anopheles gambiae.

Author

Lucas ER, Rockett KA, Lynd A, Essandoh J, Grisales N, Kemei B, Njoroge H, Hubbart C, Rippon EJ, Morgan J, Van't Hof AE, Ochomo EO, Kwiatkowski DP, Weetman D, and Donnelly MJ

Subjects
Africa South of the Sahara, Animals, Anopheles parasitology, Genetic Markers genetics, Genotyping Techniques, Glutathione Transferase genetics, High-Throughput Nucleotide Sequencing, Insect Proteins genetics, Malaria prevention & control, Malaria transmission, Mosquito Vectors genetics, Mosquito Vectors parasitology, Polymerase Chain Reaction, Anopheles drug effects, Anopheles genetics, Insecticide Resistance genetics, Insecticides pharmacology
Abstract

The spread of resistance to insecticides in disease-carrying mosquitoes poses a threat to the effectiveness of control programmes, which rely largely on insecticide-based interventions. Monitoring mosquito populations is essential, but obtaining phenotypic measurements of resistance is laborious and error-prone. High-throughput genotyping offers the prospect of quick and repeatable estimates of resistance, while also allowing resistance markers to be tracked and studied. To demonstrate the potential of highly-mulitplexed genotypic screening for measuring resistance-association of mutations and tracking their spread, we developed a panel of 28 known or putative resistance markers in the major malaria vector Anopheles gambiae, which we used to screen mosquitoes from a wide swathe of Sub-Saharan Africa (Burkina Faso, Ghana, Democratic Republic of Congo (DRC) and Kenya). We found resistance association in four markers, including a novel mutation in the detoxification gene Gste2 (Gste2-119V). We also identified a duplication in Gste2 combining a resistance-associated mutation with its wild-type counterpart, potentially alleviating the costs of resistance. Finally, we describe the distribution of the multiple origins of kdr resistance, finding unprecedented diversity in the DRC. This panel represents the first step towards a quantitative genotypic model of insecticide resistance that can be used to predict resistance status in An. gambiae.

Published
2019
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