Research Area:	Global Health
Technology Exchange:	Bioinformatics, SNP typing and Statistical genetics
Keywords:	human genome, malaria, network, epidemiology, informatics and variation
Web Links:	CGGH website Podcast 'Genomics and Global Health'

Dominic Kwiatkowski is director of the Centre for Genomics and Global Health. He holds a joint position as MRC Clinical Research Professor at Oxford University, and as a Principal Investigator at the Wellcome Trust Sanger Institute.

Dominic's labs at Oxford and Sanger work together as a single group. The overarching goal of their research is to translate advances in genome science into clinical and epidemiological applications that will help to reduce the burden of infectious disease in the developing world. They are developing methods for large-scale analysis of genome variation at the population level and using these to investigate, for example, how children living in malaria-endemic regions develop protective immunity against malaria, or how malaria parasites develop resistance against anti-malarial drugs. They work mainly on malaria, but many of the tools and methodologies that they are developing also have applications for other diseases.

One of the main interests of Dominic's research group is helping to develop data-sharing networks to tackle fundamental scientific problems that can be solved only by engaging many different research groups around the world. As the MalariaGEN Resource Centre, the group provides support and training in genetics, statistics, informatics and ethics for researchers in 15 malaria-endemic countries. The group also serves as the informatics hub of the Worldwide Antimalarial Resistance Network, which works with the WHO to bring together data from researchers, clinicians and public health agencies around the world.

Dominic trained in clinical paediatrics. He started research on cytokines in Charles Dinarello's laboratory in Boston in 1985, and the following year he went to The Gambia to study the molecular mechanism of malaria fever with Brian Greenwood. In 1989 he moved to Oxford University Department of Paediatrics, while maintaining a clinical research programme in The Gambia. His group started working on genetics around 1994, as a way of getting at basic questions about malaria pathogenesis. In 2000 his laboratory moved to the Wellcome Trust Centre for Human Genetics in Oxford, and in 2005 he took up a joint appointment at the Wellcome Trust Sanger Institute.

Name	Department	Institution	Country
Sodiomon Sirima		Centre National de Recherche et de Formation sur le Paludisme (CNRFP)	Burkina Faso
Eric Akum Achidi		University of Buea	Cameroon
David Conway		MRC Laboratories	The Gambia
Tsiri Agbenyega		Kwame Nkrumah University of Science and Technology	Ghana
Kwadwo Koram		Noguchi Memorial Institute for Medical Research	Ghana
David Modiano		University of Rome 'La Sapienza',	Italy
Malcolm Molyneux		Blantyre Malaria Project	Malawi
Ogobara Doumbo		University of Bamako	Mali
Pascal Michon		Institute for Medical Research	Papua New Guinea
Nadira Karunaweera		University of Colombo	Sri Lanka
Muntaser Ibrahim		University of Khartoum	Sudan
Dr Julie Makani	Tropical Medicine	Oxford University	UK
Martha Lemnge		National Institute for Medical Research	Tanzania
Pratap Sinhasivanon		Mahidol University	Thailand
Prof Jeremy Farrar	Tropical Medicine	Oxford University	UK

Clark TG, Fry AE, Auburn S, Campino S, Diakite M, Green A, Richardson A, Teo YY, Small K, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Sabeti P, Kwiatkowski DP, Rockett KA et al. 2009. Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility. Eur J Hum Genet, 17 (8), pp. 1080-1085. Read abstract | Read more

Several lines of evidence link glucose-6-phosphate dehydrogenase (G6PD) deficiency to protection from severe malaria. Early reports suggested most G6PD deficiency in sub-Saharan Africa was because of the 202A/376G G6PD A- allele, and recent association studies of G6PD deficiency have employed genotyping as a convenient way to determine enzyme status. However, further work has suggested that other G6PD deficiency alleles are relatively common in some regions of West Africa. To investigate the consequences of unrecognized allelic heterogeneity on association studies, in particular studies of G6PD deficiency and malaria, we carried out a case-control analysis of 2488 Gambian children with severe malaria and 3875 controls. No significant association was found between severe malaria and the 202A/376G G6PD A- allele when analyzed alone, but pooling 202A/376G with other deficiency alleles revealed the signal of protection (male odds ratio (OR) 0.77, 95% CI 0.62-0.95, P=0.016; female OR 0.71, 95% CI 0.56-0.89, P=0.004). We have identified the 968C mutation as the most common G6PD A- allele in The Gambia. Our results highlight some of the consequences of allelic heterogeneity, particularly the increased type I error. They also suggest that G6PD-deficient male hemizygotes and female heterozygotes are protected from severe malaria. Hide abstract

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, Fernando D, Hien TT, Horstmann RD, Ibrahim M, Karunaweera N, Kokwaro G, Koram KA, Lemnge M, Makani J, Marsh K, Michon P, Modiano D, Molyneux ME, Mueller I, Parker M, Peshu N, Plowe CV, Puijalon O, Reeder J, Reyburn H, Riley EM, Sakuntabhai A, Singhasivanon P, Sirima S, Tall A, Taylor TE, Thera M, Troye-Blomberg M, Williams TN, Wilson M, Kwiatkowski DP, Wellcome Trust Case Control Consortium, Malaria Genomic Epidemiology Network et al. 2009. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet, 41 (6), pp. 657-665. Read abstract | Read more

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. Hide abstract

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, Rockett KA, Kwiatkowski DP et al. 2009. Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations. J Infect Dis, 199 (4), pp. 569-575. Read abstract | Read more

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. Hide abstract

Diakite M, Clark TG, Auburn S, Campino S, Fry AE, Green A, Morris AP, Richardson A, Jallow M, Sisay-Joof F, Pinder M, Kwiatkowski DP, Rockett KA et al. 2009. A genetic association study in the Gambia using tagging polymorphisms in the major histocompatibility complex class III region implicates a HLA-B associated transcript 2 polymorphism in severe malaria susceptibility. Hum Genet, 125 (1), pp. 105-109. Read abstract | Read more

The tumour necrosis factor (TNF) gene and other genes flanking it in the major histocompatibility complex (MHC) class III region are potentially important mediators of both immunity and pathogenesis of malaria. We investigated the association of severe malaria with 11 haplotype tagging-polymorphisms for 11 MHC class III candidate genes, including TNF, lymphotoxin alpha (LTA), allograft inflammatory factor 1 (AIF1), and HLA-B associated transcript 2 (BAT2). An analysis of 2,162 case-controls demonstrated the first evidence of association between a BAT2 polymorphism (rs1046089) and severe malaria. Hide abstract

Teo YY, Small KS, Fry AE, Wu Y, Kwiatkowski DP, Clark TG. 2009. Power consequences of linkage disequilibrium variation between populations. Genet Epidemiol, 33 (2), pp. 128-135. Read abstract | Read more

We quantify the degree to which LD differences exist in the human genome and investigates the consequences that variations in patterns of LD between populations can have on the power of case-control or family-trio association studies. Although only a small proportion of SNPs show significant LD differences (0.8-5%), these can introduce artificial signals of associations and reduce the power to detect true associations in case-control designs, even when meta-analytic approaches are used to account for stratification. We show that combining trios from different populations in the presence of significant LD differences can adversely affect power even though the number of trios has increased. Our results have implications on genetic studies conducted in populations with substantial population structure and show that the use of meta-analytic approaches or family-based designs to protect Type 1 error does not prevent loss of power due to differences in LD across populations. Hide abstract

Mangano VD, Clark TG, Auburn S, Campino S, Diakite M, Fry AE, Green A, Richardson A, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Newton C, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, Modiano D, Kwiatkowski DP, Rockett KA et al. 2009. Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations. PLoS One, 4 (1), pp. e4206. Read abstract | Read more

Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria. Hide abstract

Campino S, Forton J, Auburn S, Fry A, Diakite M, Richardson A, Hull J, Jallow M, Sisay-Joof F, Pinder M, Molyneux ME, Taylor TE, Rockett K, Clark TG, Kwiatkowski DP et al. 2009. TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression. Malar J, 8 (1), pp. 44. Read abstract | Read more

During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. Hide abstract

Malaria Genomic Epidemiology Network. 2008. A global network for investigating the genomic epidemiology of malaria. Nature, 456 (7223), pp. 732-737. Read abstract | Read more

Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries. Hide abstract