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

被引：271

作者：

Jallow, Muminatou ^{[2
]}

Teo, Yik Ying ^{[1
]}

Small, Kerrin S. ^{[1
]}

Rockett, Kirk A. ^{[1
,3
]}

Deloukas, Panos ^{[3
]}

Clark, Taane G. ^{[1
,3
]}

Kivinen, Katja ^{[3
]}

Bojang, Kalifa A. ^{[2
]}

Conway, David J. ^{[2
]}

Pinder, Margaret ^{[2
]}

Sirugo, Giorgio ^{[2
]}

Sisay-Joof, Fatou ^{[2
]}

Usen, Stanley ^{[2
]}

Auburn, Sarah ^{[1
,3
]}

Bumpstead, Suzannah J. ^{[3
]}

Campino, Susana ^{[1
,3
]}

Coffey, Alison ^{[3
]}

Dunham, Andrew ^{[3
]}

Fry, Andrew E. ^{[1
]}

Green, Angela ^{[1
]}

Gwilliam, Rhian ^{[3
]}

Hunt, Sarah E. ^{[3
]}

Inouye, Michael ^{[3
]}

Jeffreys, Anna E. ^{[1
]}

Mendy, Alieu ^{[1
]}

Palotie, Aarno ^{[3
]}

Potter, Simon ^{[3
]}

Ragoussis, Jiannis ^{[1
]}

Rogers, Jane ^{[1
]}

Rowlands, Kate ^{[1
]}

Somaskantharajah, Elilan ^{[3
]}

Whittaker, Pamela ^{[3
]}

Widden, Claire ^{[3
]}

Donnelly, Peter ^{[1
,4
]}

Howie, Bryan ^{[4
]}

Marchini, Jonathan ^{[1
,4
]}

Morris, Andrew ^{[1
]}

SanJoaquin, Miguel ^{[3
,5
]}

Achidi, Eric Akum ^{[6
]}

Agbenyega, Tsiri ^{[7
]}

Allen, Angela ^{[8
,9
]}

Amodu, Olukemi ^{[10
]}

Corran, Patrick ^{[11
]}

Djimde, Abdoulaye ^{[12
]}

Dolo, Amagana ^{[12
]}

Doumbo, Ogobara K. ^{[12
]}

Drakeley, Chris ^{[13
,14
]}

Dunstan, Sarah ^{[15
]}

Evans, Jennifer ^{[7
,16
]}

Farrar, Jeremy ^{[15
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] MRC Labs, Banjul, Gambia

[3] Wellcome Trust Sanger Inst, Cambridge, England

[4] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[5] Univ Malawi, Coll Med, Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi

[6] Univ Buea, Buea, South West Prov, Cameroon

[7] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana

[8] Papua New Guinea Inst Med Res, Madang, Papua N Guinea

[9] Univ Oxford, Weatherall Inst Mol Med, Oxford, England

[10] Univ Ibadan, Coll Med, Inst Child Hlth, Ibadan, Nigeria

[11] Natl Inst Biol Stand & Controls, Potters Bar, Herts, England

[12] Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali

[13] London Sch Hyg & Trop Med, London WC1, England

[14] Kilimanjaro Christian Med Ctr, Joint Malaria Programme, Moshi, Tanzania

[15] Univ Oxford, Hosp Trop Dis, Clin Res Unit, Ho Chi Minh City, Vietnam

[16] Bernhard Nocht Inst Trop Med, Dept Mol Med, Hamburg, Germany

[17] Univ Colombo, Fac Med, Colombo, Sri Lanka

[18] Univ Khartoum, Inst Endem Dis, Khartoum, Sudan

[19] Kenyan Med Res Inst KEMRI, Wellcome Trust Programme, Kilifi, Kenya

[20] Univ Ghana, Noguchi Mem Inst Med Res, Accra, Ghana

[21] Natl Inst Med Res, Dar Es Salaam, Tanzania

[22] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania

[23] Univ Roma La Sapienza, Rome, Italy

[24] Univ Oxford, Dept Publ Hlth & Primary Hlth Care, Ethox Ctr, Oxford, England

[25] Blantyre Malaria Project, Blantyre 3, Malawi

[26] Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA

[27] Inst Pasteur, Unite Immunol Mol Parasites, Paris, France

[28] Mahidol Univ, Fac Trop Med, Bangkok, Thailand

[29] Ctr Natl Rech & Format Paludisme, Ouagadougou, Burkina Faso

[30] Inst Pasteur, Dakar, Senegal

[31] Michigan State Univ, Coll Osteopath Med, Dept Internal Med, E Lansing, MI 48824 USA

[32] Stockholm Univ, Wenner Gren Inst, S-10691 Stockholm, Sweden

来源：

NATURE GENETICS | 2009年 / 41卷 / 06期

基金：

比尔及梅琳达.盖茨基金会; 美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

BETA-GLOBIN GENE; LINKAGE DISEQUILIBRIUM; NATURAL-SELECTION; HEMOGLOBIN-C; POPULATION; CHILDREN; POWER; INDICATORS; COVERAGE; ORIGIN;

D O I：

10.1038/ng.388

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-7) to P = 4 x 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.

引用

页码：657 / 665

页数：9

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