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

Wellcome Trust Case Control Consortium; Muminatou Jallow; Yik Ying Teo; Kerrin S Small; Kirk A Rockett; Panos Deloukas; Taane G Clark; Katja Kivinen; Kalifa A Bojang; David J Conway; Margaret Pinder; Giorgio Sirugo; Fatou Sisay-Joof; Stanley Usen; Sarah Auburn; Suzannah J Bumpstead; Susana Campino; Alison Coffey; Andrew Dunham; Andrew E Fry; Angela Green; Rhian Gwilliam; Sarah E Hunt; Michael Inouye; Anna E Jeffreys; Alieu Mendy; Aarno Palotie; Simon Potter; Jiannis Ragoussis; Jane Rogers; Kate Rowlands; Elilan Somaskantharajah; Pamela Whittaker; Claire Widden; Peter Donnelly; Bryan Howie; Jonathan Marchini; Andrew Morris; Miguel SanJoaquin; Eric Akum Achidi; Tsiri Agbenyega; Angela Allen; Olukemi Amodu; Patrick Corran; Abdoulaye Djimde; Amagana Dolo; Ogobara K Doumbo; Chris Drakeley; Sarah Dunstan; Jennifer Evans; Jeremy Farrar

doi:10.1038/ng.388

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

Wellcome Trust Case Control Consortium, Muminatou Jallow, Yik Ying Teo, Kerrin S Small, Kirk A Rockett, Panos Deloukas, Taane G Clark, Katja Kivinen, Kalifa A Bojang, David J Conway, Margaret Pinder, Giorgio Sirugo, Fatou Sisay-Joof, Stanley Usen, Sarah Auburn, Suzannah J Bumpstead, Susana Campino, Alison Coffey, Andrew Dunham, Andrew E FryAngela Green, Rhian Gwilliam, Sarah E Hunt, Michael Inouye, Anna E Jeffreys, Alieu Mendy, Aarno Palotie, Simon Potter, Jiannis Ragoussis, Jane Rogers, Kate Rowlands, Elilan Somaskantharajah, Pamela Whittaker, Claire Widden, Peter Donnelly, Bryan Howie, Jonathan Marchini, Andrew Morris, Miguel SanJoaquin, Eric Akum Achidi, Tsiri Agbenyega, Angela Allen, Olukemi Amodu, Patrick Corran, Abdoulaye Djimde, Amagana Dolo, Ogobara K Doumbo, Chris Drakeley, Sarah Dunstan, Jennifer Evans, Jeremy Farrar

College of Medicine and Veterinary Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Original language	English
Pages (from-to)	657-65
Number of pages	9
Journal	Nature Genetics
Volume	41
Issue number	6
DOIs	https://doi.org/10.1038/ng.388
Publication status	Published - 2009

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10.1038/ng.388

Genome-wide and fine-resolution association analysis of malaria in West Africa
Published in final edited form as: Nat Genet. 2009 June ; 41(6): 657–665. doi:10.1038/ng.388.
Accepted author manuscript, 1.27 MB

http://www.nature.com/ng/journal/v41/n6/full/ng.388.html

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Wellcome Trust Case Control Consortium, Jallow, M., Teo, Y. Y., Small, K. S., Rockett, K. A., Deloukas, P., Clark, T. G., Kivinen, K., Bojang, K. A., Conway, D. J., Pinder, M., Sirugo, G., Sisay-Joof, F., Usen, S., Auburn, S., Bumpstead, S. J., Campino, S., Coffey, A., Dunham, A., ... Farrar, J. (2009). Genome-wide and fine-resolution association analysis of malaria in West Africa. Nature Genetics, 41(6), 657-65. https://doi.org/10.1038/ng.388

@article{5978aca6dfa34277b598214dc5785a87,

title = "Genome-wide and fine-resolution association analysis of malaria in West Africa",

abstract = "We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.",

author = "{Wellcome Trust Case Control Consortium} and Muminatou Jallow and Teo, {Yik Ying} and Small, {Kerrin S} and Rockett, {Kirk A} and Panos Deloukas and Clark, {Taane G} and Katja Kivinen and Bojang, {Kalifa A} and Conway, {David J} and Margaret Pinder and Giorgio Sirugo and Fatou Sisay-Joof and Stanley Usen and Sarah Auburn and Bumpstead, {Suzannah J} and Susana Campino and Alison Coffey and Andrew Dunham and Fry, {Andrew E} and Angela Green and Rhian Gwilliam and Hunt, {Sarah E} and Michael Inouye and Jeffreys, {Anna E} and Alieu Mendy and Aarno Palotie and Simon Potter and Jiannis Ragoussis and Jane Rogers and Kate Rowlands and Elilan Somaskantharajah and Pamela Whittaker and Claire Widden and Peter Donnelly and Bryan Howie and Jonathan Marchini and Andrew Morris and Miguel SanJoaquin and Achidi, {Eric Akum} and Tsiri Agbenyega and Angela Allen and Olukemi Amodu and Patrick Corran and Abdoulaye Djimde and Amagana Dolo and Doumbo, {Ogobara K} and Chris Drakeley and Sarah Dunstan and Jennifer Evans and Jeremy Farrar",

year = "2009",

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pages = "657--65",

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Wellcome Trust Case Control Consortium, Jallow, M, Teo, YY, Small, KS, Rockett, KA, Deloukas, P, Clark, TG, Kivinen, K, Bojang, KA, Conway, DJ, Pinder, M, Sirugo, G, Sisay-Joof, F, Usen, S, Auburn, S, Bumpstead, SJ, Campino, S, Coffey, A, Dunham, A, Fry, AE, Green, A, Gwilliam, R, Hunt, SE, Inouye, M, Jeffreys, AE, Mendy, A, Palotie, A, Potter, S, Ragoussis, J, Rogers, J, Rowlands, K, Somaskantharajah, E, Whittaker, P, Widden, C, Donnelly, P, Howie, B, Marchini, J, Morris, A, SanJoaquin, M, Achidi, EA, Agbenyega, T, Allen, A, Amodu, O, Corran, P, Djimde, A, Dolo, A, Doumbo, OK, Drakeley, C, Dunstan, S, Evans, J & Farrar, J 2009, 'Genome-wide and fine-resolution association analysis of malaria in West Africa', Nature Genetics, vol. 41, no. 6, pp. 657-65. https://doi.org/10.1038/ng.388

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T1 - Genome-wide and fine-resolution association analysis of malaria in West Africa

AU - Wellcome Trust Case Control Consortium

AU - Jallow, Muminatou

AU - Teo, Yik Ying

AU - Small, Kerrin S

AU - Rockett, Kirk A

AU - Deloukas, Panos

AU - Clark, Taane G

AU - Kivinen, Katja

AU - Bojang, Kalifa A

AU - Conway, David J

AU - Pinder, Margaret

AU - Sirugo, Giorgio

AU - Sisay-Joof, Fatou

AU - Usen, Stanley

AU - Auburn, Sarah

AU - Bumpstead, Suzannah J

AU - Campino, Susana

AU - Coffey, Alison

AU - Dunham, Andrew

AU - Fry, Andrew E

AU - Green, Angela

AU - Gwilliam, Rhian

AU - Hunt, Sarah E

AU - Inouye, Michael

AU - Jeffreys, Anna E

AU - Mendy, Alieu

AU - Palotie, Aarno

AU - Potter, Simon

AU - Ragoussis, Jiannis

AU - Rogers, Jane

AU - Rowlands, Kate

AU - Somaskantharajah, Elilan

AU - Whittaker, Pamela

AU - Widden, Claire

AU - Donnelly, Peter

AU - Howie, Bryan

AU - Marchini, Jonathan

AU - Morris, Andrew

AU - SanJoaquin, Miguel

AU - Achidi, Eric Akum

AU - Agbenyega, Tsiri

AU - Allen, Angela

AU - Amodu, Olukemi

AU - Corran, Patrick

AU - Djimde, Abdoulaye

AU - Dolo, Amagana

AU - Doumbo, Ogobara K

AU - Drakeley, Chris

AU - Dunstan, Sarah

AU - Evans, Jennifer

AU - Farrar, Jeremy

PY - 2009

Y1 - 2009

N2 - We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

AB - We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

U2 - 10.1038/ng.388

DO - 10.1038/ng.388

M3 - Article

C2 - 19465909

VL - 41

SP - 657

EP - 665

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

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