Publications by authors named "Gavin Band"

29 Publications

  • Page 1 of 1

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

Wellcome Open Res 2020 22;5:287. Epub 2021 Sep 22.

Department of Epidemiology and Demography, KEMRI-Wellcome Trust Research Programme, Kilifi, PO BOX 230-80108, Kenya.

The -α -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. 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. We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha ( ) 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. We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.
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http://dx.doi.org/10.12688/wellcomeopenres.16320.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474104PMC
September 2021

Using de novo assembly to identify structural variation of eight complex immune system gene regions.

PLoS Comput Biol 2021 08 3;17(8):e1009254. Epub 2021 Aug 3.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14+ monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a de novo assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data. Continued reductions in the cost of these technologies will enable application of these methods to larger samples and provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.
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http://dx.doi.org/10.1371/journal.pcbi.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363018PMC
August 2021

Evidence of the interplay of genetics and culture in Ethiopia.

Nat Commun 2021 06 11;12(1):3581. Epub 2021 Jun 11.

Research Department of Genetics, Evolution & Environment, University College London, London, UK.

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with-and shape-genetic structure in human populations. Using primarily new genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals' birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors on the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic affiliation, but also identify pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting that shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, we identify the most important cultural and geographic predictors of genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.
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http://dx.doi.org/10.1038/s41467-021-23712-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196081PMC
June 2021

The ferroportin Q248H mutation protects from anemia, but not malaria or bacteremia.

Sci Adv 2019 09 4;5(9):eaaw0109. Epub 2019 Sep 4.

Kenya Medical Research Institute (KEMRI) Wellcome Trust Research Programme, Kilifi, Kenya.

Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the gene results in hemolytic anemia and increased fatality in malaria-infected mice. The Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.
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http://dx.doi.org/10.1126/sciadv.aaw0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726445PMC
September 2019

Bayesian meta-analysis across genome-wide association studies of diverse phenotypes.

Genet Epidemiol 2019 07 28;43(5):532-547. Epub 2019 Mar 28.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic basis of diseases and traits, but most studies have been conducted in isolation, with a focus on either a single or a set of closely related phenotypes. We describe MetABF, a simple Bayesian framework for performing integrative meta-analysis across multiple GWAS using summary statistics. The approach is applicable across a wide range of study designs and can increase the power by 50% compared with standard frequentist tests when only a subset of studies have a true effect. We demonstrate its utility in a meta-analysis of 20 diverse GWAS which were part of the Wellcome Trust Case Control Consortium 2. The novelty of the approach is its ability to explore, and assess the evidence for a range of possible true patterns of association across studies in a computationally efficient framework.
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http://dx.doi.org/10.1002/gepi.22202DOI Listing
July 2019

The UK Biobank resource with deep phenotyping and genomic data.

Nature 2018 10 10;562(7726):203-209. Epub 2018 Oct 10.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.
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http://dx.doi.org/10.1038/s41586-018-0579-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786975PMC
October 2018

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.

Lancet Haematol 2018 Aug 20;5(8):e333-e345. Epub 2018 Jul 20.

KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya; Department of Medicine, Imperial College, St Mary's Hospital, London, UK. Electronic address:

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] 0·15, 95% CI 0·11-0·20; p=2·61 × 10), blood group O (0·74, 0·66-0·82; p=6·26 × 10), and -α-thalassaemia (0·83, 0·76-0·90; p=2·06 × 10). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63-0·92; p=0·001) and FREM3 (0·64, 0·53-0·79; p=3·18 × 10). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49-0·68; p=3·22 × 10), as was homozygosity (0·26, 0·11-0·62; p=0·002).

Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health.

Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.
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http://dx.doi.org/10.1016/S2352-3026(18)30107-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069675PMC
August 2018

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with αthalassaemia.

Elife 2018 04 25;7. Epub 2018 Apr 25.

Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.

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 () gene, named and , 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 and and malaria phenotypes, and find they have opposing associations. The polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between and αthalassaemia, with the protective association of 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.
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http://dx.doi.org/10.7554/eLife.31579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953541PMC
April 2018

Resistance to malaria through structural variation of red blood cell invasion receptors.

Science 2017 06 18;356(6343). Epub 2017 May 18.

International Blood Group Reference Laboratory, National Health Service (NHS) Blood and Transplant, 500 North Bristol Park, Filton, Bristol BS34 7QH, UK.

The malaria parasite invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes and We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of and gain of two hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.
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http://dx.doi.org/10.1126/science.aam6393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575826PMC
June 2017

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Elife 2017 01 9;6. Epub 2017 Jan 9.

University of Ibadan, Ibadan, Nigeria.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
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http://dx.doi.org/10.7554/eLife.15085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222559PMC
January 2017

Admixture into and within sub-Saharan Africa.

Elife 2016 06 21;5. Epub 2016 Jun 21.

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.

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.
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http://dx.doi.org/10.7554/eLife.15266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915815PMC
June 2016

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

Am J Hum Genet 2016 Jun 26;98(6):1092-1100. Epub 2016 May 26.

KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908194PMC
June 2016

Environmental Correlation Analysis for Genes Associated with Protection against Malaria.

Mol Biol Evol 2016 05 6;33(5):1188-204. Epub 2016 Jan 6.

Department of Epidemiology and Demography, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya Department of Medicine, Imperial College, London, United Kingdom INDEPTH Network, Kanda, Accra, Ghana.

Genome-wide searches for loci involved in human resistance to malaria are currently being conducted on a large scale in Africa using case-control studies. Here, we explore the utility of an alternative approach-"environmental correlation analysis, ECA," which tests for clines in allele frequencies across a gradient of an environmental selection pressure-to identify genes that have historically protected against death from malaria. We collected genotype data from 12,425 newborns on 57 candidate malaria resistance loci and 9,756 single nucleotide polymorphisms (SNPs) selected at random from across the genome, and examined their allele frequencies for geographic correlations with long-term malaria prevalence data based on 84,042 individuals living under different historical selection pressures from malaria in coastal Kenya. None of the 57 candidate SNPs showed significant (P < 0.05) correlations in allele frequency with local malaria transmission intensity after adjusting for population structure and multiple testing. In contrast, two of the random SNPs that had highly significant correlations (P < 0.01) were in genes previously linked to malaria resistance, namely, CDH13, encoding cadherin 13, and HS3ST3B1, encoding heparan sulfate 3-O-sulfotransferase 3B1. Both proteins play a role in glycoprotein-mediated cell-cell adhesion which has been widely implicated in cerebral malaria, the most life-threatening form of this disease. Other top genes, including CTNND2 which encodes δ-catenin, a molecular partner to cadherin, were significantly enriched in cadherin-mediated pathways affecting inflammation of the brain vascular endothelium. These results demonstrate the utility of ECA in the discovery of novel genes and pathways affecting infectious disease.
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http://dx.doi.org/10.1093/molbev/msw004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839215PMC
May 2016

A novel locus of resistance to severe malaria in a region of ancient balancing selection.

Nature 2015 Oct 30;526(7572):253-7. Epub 2015 Sep 30.

The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60-0.76, P value = 9.5 × 10(-11)) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees. Taken together with previous observations on the malaria-protective role of blood group O, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host-parasite interactions that are critical in determining the outcome of malaria infection.
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http://dx.doi.org/10.1038/nature15390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629224PMC
October 2015

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

Malar J 2015 Aug 28;14:333. Epub 2015 Aug 28.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.

Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels.

Methods: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels.

Results: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2.

Conclusion: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.
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http://dx.doi.org/10.1186/s12936-015-0833-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552443PMC
August 2015

The correlation between reading and mathematics ability at age twelve has a substantial genetic component.

Nat Commun 2014 Jul 8;5:4204. Epub 2014 Jul 8.

1] Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK [2] Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve.
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http://dx.doi.org/10.1038/ncomms5204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102107PMC
July 2014

A genetic atlas of human admixture history.

Science 2014 Feb;343(6172):747-751

Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.

Modern genetic data combined with appropriate statistical methods have the potential to contribute substantially to our understanding of human history. We have developed an approach that exploits the genomic structure of admixed populations to date and characterize historical mixture events at fine scales. We used this to produce an atlas of worldwide human admixture history, constructed by using genetic data alone and encompassing over 100 events occurring over the past 4000 years. We identified events whose dates and participants suggest they describe genetic impacts of the Mongol empire, Arab slave trade, Bantu expansion, first millennium CE migrations in Eastern Europe, and European colonialism, as well as unrecorded events, revealing admixture to be an almost universal force shaping human populations.
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http://dx.doi.org/10.1126/science.1243518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209567PMC
February 2014

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Nat Genet 2013 Nov 29;45(11):1353-60. Epub 2013 Sep 29.

1] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. [2].

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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http://dx.doi.org/10.1038/ng.2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832895PMC
November 2013

Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Nat Genet 2013 Oct 25;45(10):1150-9. Epub 2013 Aug 25.

1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3].

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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http://dx.doi.org/10.1038/ng.2742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827979PMC
October 2013

A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation.

Biol Psychiatry 2014 Mar 17;75(5):386-97. Epub 2013 Jul 17.

Background: Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories.

Methods: 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of their unaffected relatives, and 2739 healthy controls were genotyped with the Affymetrix 6.0 single nucleotide polymorphism (SNP) array. Analyses of 695,193 SNPs were conducted using UNPHASED, which combines information across families and unrelated individuals. We attempted to replicate signals found in 23 genomic regions using existing data on nonoverlapping samples from the Psychiatric GWAS Consortium and Schizophrenia-GENE-plus cohorts (10,352 schizophrenia patients and 24,474 controls).

Results: No individual SNP showed compelling evidence for association with psychosis in our data. However, we observed a trend for association with same risk alleles at loci previously associated with schizophrenia (one-sided p = .003). A polygenic score analysis found that the Psychiatric GWAS Consortium's panel of SNPs associated with schizophrenia significantly predicted disease status in our sample (p = 5 × 10(-14)) and explained approximately 2% of the phenotypic variance.

Conclusions: Although narrowly defined phenotypes have their advantages, we believe new loci may also be discovered through meta-analysis across broad phenotypes. The novel statistical methodology we introduced to model effect size heterogeneity between studies should help future GWAS that combine association evidence from related phenotypes. Applying these approaches, we highlight three loci that warrant further investigation. We found that SNPs conveying risk for schizophrenia are also predictive of disease status in our data.
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http://dx.doi.org/10.1016/j.biopsych.2013.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923972PMC
March 2014

Imputation-based meta-analysis of severe malaria in three African populations.

PLoS Genet 2013 May 23;9(5):e1003509. Epub 2013 May 23.

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.
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http://dx.doi.org/10.1371/journal.pgen.1003509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662650PMC
May 2013

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis.

Nat Genet 2013 Feb 6;45(2):208-13. Epub 2013 Jan 6.

Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P(combined) = 2.76 × 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
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http://dx.doi.org/10.1038/ng.2518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664012PMC
February 2013

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.

Nat Genet 2012 Dec 11;44(12):1341-8. Epub 2012 Nov 11.

Department of Biostatistics, Center for Statistical Genetics, University of Michigan Ann Arbor, MI, USA.

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
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http://dx.doi.org/10.1038/ng.2467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510312PMC
December 2012

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

Nat Genet 2012 Oct 9;44(10):1131-6. Epub 2012 Sep 9.

Wellcome Trust Centre for Human Genetics, Oxford, UK.

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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http://dx.doi.org/10.1038/ng.2408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459818PMC
October 2012

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

Nat Genet 2012 Feb 5;44(3):328-33. Epub 2012 Feb 5.

Wellcome Trust Centre for Human Genetics, University of Oxford, UK.

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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http://dx.doi.org/10.1038/ng.1081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303115PMC
February 2012

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Nature 2011 Aug 10;476(7359):214-9. Epub 2011 Aug 10.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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http://dx.doi.org/10.1038/nature10251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182531PMC
August 2011

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.

Nat Genet 2011 Jul 10;43(8):761-7. Epub 2011 Jul 10.

Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
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http://dx.doi.org/10.1038/ng.873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640413PMC
July 2011

Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21.

Hum Mol Genet 2011 Jan 2;20(2):345-53. Epub 2010 Nov 2.

Wellcome Trust Centre for Human Genetics, Oxford, UK.

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
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http://dx.doi.org/10.1093/hmg/ddq469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005904PMC
January 2011

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

Nat Genet 2010 Nov 17;42(11):985-90. Epub 2010 Oct 17.

Wellcome Trust Centre for Human Genetics, Oxford, UK.

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
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http://dx.doi.org/10.1038/ng.694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749730PMC
November 2010
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