Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Opi, D. Herbert; Swann, Olivia; Macharia, Alexander; Uyoga, Sophie; Band, Gavin; Ndila, Carolyne; Thera, Mahamadou A.; Koné, Abdoulaye K.; Diallo, Dapa A.; Doumbo, Ogobara K.; Lyke, Kirsten E.; Plowe, Christopher V.; Moulds, Joann M.; Mohammed, Shebe; Mturi, Neema; Peshu, Norbert; Maitland, Kathryn; Ahmed, Rayaz; Kwiatkowski, Dominic P.; Rockett, Kirk A.; Williams, Thomas N.; Rowe, J. Alexandra

doi:10.7554/elife.31579

Cited by 29 publications

(27 citation statements)

References 66 publications

(130 reference statements)

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“…Across each ancestry-specific subgroup, our findings overlap with results from other work showing evidence for the importance of epistasis in human immunity, particularly involving the Major Histocompatibility Complex (MHC) [101][102][103][104][105][106][107], as well as the key roles metabolic processes and cellular signaling play in trait architecture for model systems [108][109][110][111][112][113][114]. Most notably, however, the majority of our results occurred within the African subgroup: 165 out of 245 significant pathways across all analyses.…”

Section: Multiethnic Analyses Enables the Detection Of Pathway-level supporting

confidence: 78%

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Turchin

Darnell

Crawford

et al. 2020

Preprint

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Genome-wide association (GWA) studies have identified thousands of significant genetic associations in humans across a number of complex traits. However, the majority of these studies focus on linear additive relationships between genotypic and phenotypic variation. Epistasis, or non-additive genetic interactions, has been identified as a major driver of both complex trait architecture and evolution in multiple model organisms; yet, this same phenomenon is not considered to be a significant factor underlying human complex traits. There are two possible reasons for this assumption. First, most large GWA studies are conducted solely with European cohorts; therefore, our understanding of broad-sense heritability for many complex traits is limited to just one ancestry group. Second, current epistasis mapping methods commonly identify significant genetic interactions by exhaustively searching across all possible pairs of SNPs. In these frameworks, estimated epistatic effects size are often small and power can be low due to the multiple testing burden. Here, we present a case study that uses a novel region-based mapping approach to analyze sets of variants for the presence of epistatic effects across six diverse subgroups within the UK Biobank. We refer to this method as the “MArginal ePIstasis Test for Regions” or MAPIT-R. Even with limited sample sizes, we find a total of 245 pathways within the KEGG and REACTOME databases that are significantly enriched for epistatic effects in height and body mass index (BMI), with 67% of these pathways being detected within individuals of African ancestry. As a secondary analysis, we introduce a novel region-based “leave-one-out” approach to localize pathway-level epistatic signals to specific interacting genes in BMI. Overall, our results indicate that non-European ancestry populations may be better suited for the discovery of non-additive genetic variation in human complex traits — further underscoring the need for publicly available, biobank-sized datasets of diverse groups of individuals.

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Section: Multiethnic Analyses Enables the Detection Of Pathway-level supporting

confidence: 78%

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Turchin

Darnell

Crawford

et al. 2020

Preprint

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“…This locus provides an exciting potential therapeutic target for P. falciparum therapies because, akin to the story of P. vivax malaria, the glycophorins have been shown to act as invasion ligands for the Duffy-Binding-Like (DBL) domains of a range of P. falciparum merozoite proteins (Sim et al 1994;Tolia et al 2005;Mayer et al 2001Mayer et al , 2002Mayer et al , 2004Mayer et al , 2006Mayer et al , 2009. In homozygotes, Dantu confers a strongly protective effect size of 74% against all forms of severe falciparum malaria (Band et al 2015, Leffler et al 2017, Ndila et al 2018, MalariaGEN 2019. Curiously, this polymorphism is found at highest frequencies in East Africa, specifically in the coastal region of Kilifi, and is rare or absent in other malaria endemic regions.…”

Section: Novel Resistance Loci Identified By Genome-wide Association mentioning

confidence: 99%

“…Both the thalassaemias and HbS are disorders of haemoglobin that are caused by various mutations in the α-and β-globin genes (HBA and HBB). It took many years for the veracity of these hypotheses to be established beyond reasonable doubt, but it is now clear that the HbS variant confers the strongest protective effect against severe malaria that has yet been described, with an effect size of > 80% in heterozygous carriers (HbAS; sickle cell trait), while α-thalassaemia confers a protective effect of approximately 40% in homozygotes (MalariaGEN 2014;Ndila et al 2018). Other protective red blood cell (RBC) polymorphisms have also been shown to occur at their highest frequencies in malaria endemic populations, including glucose-6-phosphatase (G6PD) deficiency, the O blood group, and variants of the gene for complement receptor 1 (CR1) (Kwiatkowski 2005;Williams 2016;Rowe et al 1997;Opi et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Human genetics and malaria resistance

2020

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Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells. They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and several variants related to the immune response. Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria. Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research.

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“…In other areas of medicine (such as malaria, HCV and HIV) have successfully delivered clinical trials that integrate molecular or genotypic testing to enable molecular determinants of disease response to be identified in LMICs ( 82 ). Malaria is a good example, where trials often collect data on genotypes and information on microsatellites of malaria parasites from DNA isolated from blood films or spots.…”

Section: Barriers To Global Research In Precision Medicinementioning

confidence: 99%

Global Inequities in Precision Medicine and Molecular Cancer Research

2018

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Precision medicine based upon molecular testing is heralded as a revolution in how cancer is prevented, diagnosed, and treated. Large efforts across the world aim to conduct comprehensive molecular profiling of disease to inform preclinical models, translational research studies and clinical trials. However, most studies have only been performed in patients from high-income countries. As the burden on non-communicable diseases increases, cancer will become a pressing burden across the world, disproportionately affecting low-middle income settings. There is emerging evidence that the molecular landscape of disease differs geographically and by genetic ancestry, which cannot be explained by environmental factors alone. There is a lack of good quality evidence that characterises the molecular landscape of cancers found in low-middle income countries. As cancer medicine becomes increasingly driven by molecular alterations in high-income settings, low-income settings may become left behind. Further efforts on an international scale must be made by researchers, funders, and policymakers to ensure cancer research addresses disease across the world, so models are not limited to subtypes of disease found in high-income countries. In this review, we discuss differences found in the molecular profiles of tumours worldwide and the implication this has for the future of global cancer care. Finally, we identify several barriers currently limiting progress in this field and innovative solutions, which may address these shortcomings.

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Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Cited by 29 publications

References 66 publications

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Human genetics and malaria resistance

Global Inequities in Precision Medicine and Molecular Cancer Research

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