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1. Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria.

Author: D Herbert Opi, Carolyne M Ndila, Sophie Uyoga, Alex W Macharia, Clare Fennell, Lucy B Ochola, Gideon Nyutu, Bethseba R Siddondo, John Ojal, Mohammed Shebe, Kennedy O Awuondo, Neema Mturi, Norbert Peshu, Benjamin Tsofa, Gavin Band, Kathryn Maitland, Dominic P Kwiatkowski, Kirk A Rockett, Thomas N Williams, and J Alexandra Rowe
Subjects: Genetics, QH426-470
Abstract: Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that "double dose" non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than "single dose" heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO and BO genotypes rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.
Published: 2023
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2. Genome-wide association study of leprosy in Malawi and Mali.

Author: James J Gilchrist, Kathryn Auckland, Tom Parks, Alexander J Mentzer, Lily Goldblatt, Vivek Naranbhai, Gavin Band, Kirk A Rockett, Ousmane B Toure, Salimata Konate, Sibiri Sissoko, Abdoulaye A Djimdé, Mahamadou A Thera, Ogobara K Doumbo, Samba Sow, Sian Floyd, Jörg M Pönnighaus, David K Warndorff, Amelia C Crampin, Paul E M Fine, Benjamin P Fairfax, and Adrian V S Hill
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.
Published: 2022
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3. Evidence of the interplay of genetics and culture in Ethiopia

Author: Saioa López, Ayele Tarekegn, Gavin Band, Lucy van Dorp, Nancy Bird, Sam Morris, Tamiru Oljira, Ephrem Mekonnen, Endashaw Bekele, Roger Blench, Mark G. Thomas, Neil Bradman, and Garrett Hellenthal
Subjects: Science
Abstract: Ethiopia is one of the most ethnically and culturally diverse countries. Here, the authors look at genetic and cultural variation in 1,214 Ethiopians to unravel the relationship between genetic admixture and cultural factors.
Published: 2021
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4. BIRC6 modifies risk of invasive bacterial infection in Kenyan children

Author: James J Gilchrist, Silvia N Kariuki, James A Watson, Gavin Band, Sophie Uyoga, Carolyne M Ndila, Neema Mturi, Salim Mwarumba, Shebe Mohammed, Moses Mosobo, Kaur Alasoo, Kirk A Rockett, Alexander J Mentzer, Dominic P Kwiatkowski, Adrian VS Hill, Kathryn Maitland, J Anthony G Scott, and Thomas N Williams
Subjects: bacteraemia, GWAS, malaria, Medicine, Science, Biology (General), QH301-705.5
Abstract: Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with Plasmodium falciparum parasitaemia. We construct a joint dataset including 1445 bacteraemia cases and 1143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data, we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so, we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.
Published: 2022
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5. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data [version 2; peer review: 2 approved]

Author: Carolyne M. Ndila, Vysaul Nyirongo, Alexander W. Macharia, Anna E. Jeffreys, Kate Rowlands, Christina Hubbart, George B. J. Busby, Gavin Band, Rosalind M. Harding, Kirk A. Rockett, Thomas N. Williams, and MalariaGEN Consortium
Subjects: Medicine, Science
Abstract: Background: The -α3.7I-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. Methods: 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. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (HBA) 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. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.
Published: 2021
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6. Using de novo assembly to identify structural variation of eight complex immune system gene regions.

Author: Jia-Yuan Zhang, Hannah Roberts, David S C Flores, Antony J Cutler, Andrew C Brown, Justin P Whalley, Olga Mielczarek, David Buck, Helen Lockstone, Barbara Xella, Karen Oliver, Craig Corton, Emma Betteridge, Rachael Bashford-Rogers, Julian C Knight, John A Todd, and Gavin Band
Subjects: Biology (General), QH301-705.5
Abstract: 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.
Published: 2021
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7. Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Author: D Herbert Opi, Olivia Swann, Alexander Macharia, Sophie Uyoga, Gavin Band, Carolyne M Ndila, Ewen M Harrison, Mahamadou A Thera, Abdoulaye K Kone, Dapa A Diallo, Ogobara K Doumbo, Kirsten E Lyke, Christopher V Plowe, Joann M Moulds, Mohammed Shebbe, Neema Mturi, Norbert Peshu, Kathryn Maitland, Ahmed Raza, Dominic P Kwiatkowski, Kirk A Rockett, Thomas N Williams, and J Alexandra Rowe
Subjects: Complement receptor 1, Knops blood group, Cerebral malaria, Alpha thalassaemia, Medicine, Science, Biology (General), QH301-705.5
Abstract: 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 (CR1) gene, named Sl2 and McCb, 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 Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 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.
Published: 2018
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8. Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Author: Geraldine M Clarke, Kirk Rockett, Katja Kivinen, Christina Hubbart, Anna E Jeffreys, Kate Rowlands, Muminatou Jallow, David J Conway, Kalifa A Bojang, Margaret Pinder, Stanley Usen, Fatoumatta Sisay-Joof, Giorgio Sirugo, Ousmane Toure, Mahamadou A Thera, Salimata Konate, Sibiry Sissoko, Amadou Niangaly, Belco Poudiougou, Valentina D Mangano, Edith C Bougouma, Sodiomon B Sirima, David Modiano, Lucas N Amenga-Etego, Anita Ghansah, Kwadwo A Koram, Michael D Wilson, Anthony Enimil, Jennifer Evans, Olukemi K Amodu, Subulade Olaniyan, Tobias Apinjoh, Regina Mugri, Andre Ndi, Carolyne M Ndila, Sophie Uyoga, Alexander Macharia, Norbert Peshu, Thomas N Williams, Alphaxard Manjurano, Nuno Sepúlveda, Taane G Clark, Eleanor Riley, Chris Drakeley, Hugh Reyburn, Vysaul Nyirongo, David Kachala, Malcolm Molyneux, Sarah J Dunstan, Nguyen Hoan Phu, Nguyen Ngoc Quyen, Cao Quang Thai, Tran Tinh Hien, Laurens Manning, Moses Laman, Peter Siba, Harin Karunajeewa, Steve Allen, Angela Allen, Timothy ME Davis, Pascal Michon, Ivo Mueller, Síle F Molloy, Susana Campino, Angeliki Kerasidou, Victoria J Cornelius, Lee Hart, Shivang S Shah, Gavin Band, Chris CA Spencer, Tsiri Agbenyega, Eric Achidi, Ogobara K Doumbo, Jeremy Farrar, Kevin Marsh, Terrie Taylor, Dominic P Kwiatkowski, and MalariaGEN Consortium
Subjects: G6PD deficiency, genetic association, infectious disease, selection, Medicine, Science, Biology (General), QH301-705.5
Abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has 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 P. falciparum 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 P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
Published: 2017
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9. Admixture into and within sub-Saharan Africa

Author: George BJ Busby, Gavin Band, Quang Si Le, Muminatou Jallow, Edith Bougama, Valentina D Mangano, Lucas N Amenga-Etego, Anthony Enimil, Tobias Apinjoh, Carolyne M Ndila, Alphaxard Manjurano, Vysaul Nyirongo, Ogobara Doumba, Kirk A Rockett, Dominic P Kwiatkowski, Chris CA Spencer, and Malaria Genomic Epidemiology Network
Subjects: admixture, chromosome painting, Africa, gene-flow, Medicine, Science, Biology (General), QH301-705.5
Abstract: 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.
Published: 2016
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10. Correction: Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations.

Author: Gavin Band, Quang Si Le, Luke Jostins, Matti Pirinen, Katja Kivinen, Muminatou Jallow, Fatoumatta Sisay-Joof, Kalifa Bojang, Margaret Pinder, Giorgio Sirugo, David J. Conway, Vysaul Nyirongo, David Kachala, Malcolm Molyneux, Terrie Taylor, Carolyne Ndila, Norbert Peshu, Kevin Marsh, Thomas N. Williams, Daniel Alcock, Robert Andrews, Sarah Edkins, Emma Gray, Christina Hubbart, Anna Jeffreys, Kate Rowlands, Kathrin Schuldt, Taane G. Clark, Kerrin S. Small, Yik Ying Teo, Dominic P. Kwiatkowski, Kirk A. Rockett, Jeffrey C. Barrett, and Chris C. A. Spencer
Subjects: Genetics, QH426-470
Published: 2013
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11. Imputation-based meta-analysis of severe malaria in three African populations.

Author: Gavin Band, Quang Si Le, Luke Jostins, Matti Pirinen, Katja Kivinen, Muminatou Jallow, Fatoumatta Sisay-Joof, Kalifa Bojang, Margaret Pinder, Giorgio Sirugo, David J Conway, Vysaul Nyirongo, David Kachala, Malcolm Molyneux, Terrie Taylor, Carolyne Ndila, Norbert Peshu, Kevin Marsh, Thomas N Williams, Daniel Alcock, Robert Andrews, Sarah Edkins, Emma Gray, Christina Hubbart, Anna Jeffreys, Kate Rowlands, Kathrin Schuldt, Taane G Clark, Kerrin S Small, Yik Ying Teo, Dominic P Kwiatkowski, Kirk A Rockett, Jeffrey C Barrett, Chris C A Spencer, Malaria Genomic Epidemiology Network, and Malaria Genomic Epidemiological Network
Subjects: Genetics, QH426-470
Abstract: 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.
Published: 2013
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12. Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria

Author: D. Herbert Opi, Carolyne M Ndila, Sophie Uyoga, Alex W Macharia, Clare Fennell, Gideon Nyutu, John Ojal, Mohammed Shebe, Kennedy O Awuondo, Neema Mturi, Norbert Peshu, Benjamin Tsofa, Gavin Band, Kathryn Maitland, Dominic P Kwiatkowski, Kirk A Rockett, Thomas N. Williams, and J. Alexandra Rowe
Abstract: Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (P=0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO genotype rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.
Published: 2022

13. Author response: BIRC6 modifies risk of invasive bacterial infection in Kenyan children

Author: James J Gilchrist, Silvia N Kariuki, James A Watson, Gavin Band, Sophie Uyoga, Carolyne M Ndila, Neema Mturi, Salim Mwarumba, Shebe Mohammed, Moses Mosobo, Kaur Alasoo, Kirk A Rockett, Alexander J Mentzer, Dominic P Kwiatkowski, Adrian VS Hill, Kathryn Maitland, J Anthony G Scott, and Thomas N Williams
Published: 2022

14. ACTR1Ahas pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

Author: James J Gilchrist, Kathryn Auckland, Tom Parks, Alexander J Mentzer, Lily Goldblatt, Vivek Naranbhai, Gavin Band, Kirk A Rockett, Ousmane B Toure, Salimata Konate, Sibiri Sissoko, Abdoulaye A Djimdé, Mahamadou A Thera, Ogobara K Doumbo, Samba Sow, Sian Floyd, Jörg M Pönnighaus, David K Warndorff, Amelia C Crampin, Paul EM Fine, Benjamin P Fairfax, and Adrian VS Hill
Abstract: Leprosy is a chronic infection of the skin and peripheral nerves caused byMycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated five risk loci previously reported in China, Vietnam and India; MHC Class I and II,LACC1(2 independent loci) andSLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583: combinedp= 8.81 × 10−9;OR= 0.51 [95% CI 0.40-0.64]). The leprosy risk locus is a determinant ofACTR1ARNA expression in CD4+T cells (posterior probability of colocalization -PP= 0.96). Furthermore, it demonstrates pleiotropy with established risk loci for inflammatory bowel disease and atopic disease. ReducedACTR1Aexpression decreases susceptibility to leprosy and atopy but increases risk of inflammatory bowel disease. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the evidence that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.Author SummaryLeprosy remains a leading cause of infectious disability globally. Human genetic variation is a major determinant of susceptibility to infection, including leprosy. Large-scale genetic association studies have been pivotal in advancing our understanding of leprosy biology. These studies have been performed in Chinese, Vietnamese and Indian populations, and it remains unclear whether these insights are informative of leprosy susceptibility in African populations. To address this, we performed a genome-wide association study of leprosy susceptibility in Malawi and Mali. In doing so we replicate known leprosy susceptibility loci at MHC class I and II,LACC1andSLC29A3. Furthermore, we identify a novel leprosy susceptibility locus, which modifies expression ofACTR1Ain CD4+T cells and demonstrates pleiotropy with inflammatory bowel disease (IBD) and atopic disease. These data deepen our understanding of leprosy biology, identifyingACTR1Aexpression in CD4+T cells as a determinant of leprosy disease risk, and further define the role of this ancient pathogen in the evolution of immune-mediated diseases in modern populations.
Published: 2022

15. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022

16. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data

Author: Christina Hubbart, Vysaul B. Nyirongo, George B.J. Busby, Thomas N. Williams, Kirk A. Rockett, Anna E. Jeffreys, Gavin Band, Kate Rowlands, Rosalind M. Harding, Carolyne M. Ndila, Alexander Macharia, and Consortium, MalariaGEN
Subjects: 0301 basic medicine, Linkage disequilibrium, haplotypes, viruses, Medicine (miscellaneous), Genome-wide association study, Computational biology, Biology, Genome, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Predictive Models, Genotype, GWAS, Typing, Genotyping, Confounding, Haplotype, virus diseases, α-thalassaemia, Classification and Regression Tree, Articles, biochemical phenomena, metabolism, and nutrition, digestive system diseases, Malaria, 030104 developmental biology, 030220 oncology & carcinogenesis, multinomial regression-model, Research Article
Abstract: Background: The -α3.7I-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. Methods: 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. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (HBA) 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. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.
Published: 2021

17. Evidence of the interplay of genetics and culture in Ethiopia

Author: Neil Bradman, Nancy Bird, Saioa López, Sam Morris, Gavin Band, Lucy van Dorp, Tamiru Oljira, Endashaw Bekele, Mark G. Thomas, Ayele Tarekegn, Roger Blench, Garrett Hellenthal, Ephrem Mekonnen, López, Saioa [0000-0003-2936-4070], Band, Gavin [0000-0002-1710-9024], van Dorp, Lucy [0000-0002-6211-2310], Bird, Nancy [0000-0003-2596-874X], Oljira, Tamiru [0000-0002-8186-1667], Mekonnen, Ephrem [0000-0003-0416-649X], Thomas, Mark G. [0000-0002-2452-981X], Hellenthal, Garrett [0000-0002-5760-8020], Apollo - University of Cambridge Repository, and Thomas, Mark G [0000-0002-2452-981X]
Subjects: 0301 basic medicine, Male, Population genetics, Science, Ethnic group, General Physics and Astronomy, Black People, Ethnic Groups, Big Five personality traits and culture, 631/208/457, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Genetic similarity, Geographical distance, Cultural diversity, Genetic variation, Ethnicity, Humans, 10. No inequality, Social Factors, Language, African Continental Ancestry Group, 2. Zero hunger, Multidisciplinary, 45, article, Genetic Variation, Linguistics, General Chemistry, Cultural Diversity, 631/208/728, Genetic differentiation, Religion, 030104 developmental biology, Geography, Genetics, Population, Haplotypes, Evolutionary biology, 631/208/457/649, Multigene Family, Genetic structure, Female, Ethiopia, 030217 neurology & neurosurgery
Abstract: 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., Ethiopia is one of the most ethnically and culturally diverse countries. Here, the authors look at genetic and cultural variation in 1,214 Ethiopians to unravel the relationship between genetic admixture and cultural factors.
Published: 2021

18. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author: Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology
Subjects: Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.
Published: 2022

19. The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Author: Jim Stalker, Ellen M. Leffler, Kalifa Bojang, Kevin Marsh, Fatoumatta Sisay-Joof, Norbert Peshu, Dominic P. Kwiatkowski, Sónia Gonçalves, Carolyne M. Ndila, Eleanor Drury, Umberto D'Alessandro, Cristina V. Ariani, Roberto Amato, Giorgio Sirugo, Richard D. Pearson, Anna E. Jeffreys, Thuy Nguyen, Thomas N. Williams, Alexander Macharia, Gavin Band, Kate Rowlands, Christina Hubbart, Muminatou Jallow, Kirk A. Rockett, and David J. Conway
Subjects: Genetics, Linkage disequilibrium, education.field_of_study, biology, Population, Plasmodium falciparum, biology.organism_classification, medicine.disease, Structural variation, parasitic diseases, Genetic variation, Genotype, medicine, Parasite hosting, education, Malaria
Abstract: Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. In this study we investigated the correlation between host and parasite genetic variation in 4,171 Gambian and Kenya children ascertained with severe malaria due to Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and variation in three regions of the parasite genome, including nonsynonymous variants in the acyl-CoA synthetase family member PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The HbS-associated parasite alleles are in strong linkage disequilibrium and have frequencies which covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome, and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.
Published: 2021

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

Author: Jia-Yuan Zhang, Helen Lockstone, Olga Mielczarek, David Buck, Karen Oliver, David S. C. Flores, Emma Betteridge, Hannah E. Roberts, Craig Corton, Andrew Brown, Justin P. Whalley, Julian C. Knight, Gavin Band, Barbara Xella, Antony J. Cutler, John A. Todd, and Rachael Bashford-Rogers
Subjects: Structural variation, Haplotype, Sequence assembly, Nanopore sequencing, Computational biology, Human leukocyte antigen, Biology, Gene, Genetic association, Segmental duplication
Abstract: 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; application of these methods to larger samples would 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.
Published: 2021

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

Author: John A. Todd, Justin P. Whalley, Julian C. Knight, Andrew Brown, Hannah E. Roberts, Emma Betteridge, David S. C. Flores, Jia-Yuan Zhang, Antony J. Cutler, Karen Oliver, Barbara Xella, Gavin Band, Olga Mielczarek, Craig Corton, Rachael Bashford-Rogers, Helen Lockstone, and David Buck
Subjects: Heredity, Physiology, Gene Expression, Sequence assembly, Immune Receptors, Biochemistry, Database and Informatics Methods, 0302 clinical medicine, Receptors, KIR, HLA Antigens, Heterochromatin, Immune Physiology, Medicine and Health Sciences, Immunogenetic Phenomena, Biology (General), Segmental duplication, 0303 health sciences, Immune System Proteins, Heterozygosity, Ecology, Chromosome Biology, High-Throughput Nucleotide Sequencing, Genomics, Chromatin, Genetic Mapping, Computational Theory and Mathematics, Modeling and Simulation, Epigenetics, Sequence Analysis, Algorithms, Research Article, Signal Transduction, DNA Copy Number Variations, Bioinformatics, QH301-705.5, Immunology, Receptors, Antigen, T-Cell, Immunoglobulins, Sequence alignment, Computational biology, Human leukocyte antigen, Biology, Research and Analysis Methods, Antibodies, Structural variation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetics, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genome, Human, Haplotype, Biology and Life Sciences, Proteins, Computational Biology, Genetic Variation, Cell Biology, Sequence Analysis, DNA, T Cell Receptors, Haplotypes, Immune System, Nanopore sequencing, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: 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., Author summary The human immune system is incredibly versatile underlying its capacity to defend the body against thousands of pathogens. At a molecular level, it recognizes pathogens using large libraries of antibodies and related protein receptors. These molecules are encoded by gene families that are particularly difficult to analyze due to their unusually complex patterns of similarities and differences between genes and individuals. To overcome this, we applied several sequencing methods to DNA from a single individual and developed methods to reconstruct the underlying sequence at eight of the immune-associated regions. Importantly, we used DNA extracted from monocytes to avoid capturing the further rearrangements that occur in active immune cells. We generated accurate assemblies by integrating multiple complementary data types, although we noted a small subset of locations that remain challenging. Moreover, we found that this individual contains multiple structural differences between the two inherited chromosomes and compared to previously analyzed genomes, affecting the copy number of immune system genes. Application of these methods in larger numbers of individuals will clearly uncover much more variation than is currently known, and might lead to new understanding of the effect of genetic variation on the broad range of human diseases determined by the immune response.
Published: 2021

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

Author: Deepti Gurdasani, James J. Gilchrist, Emily L. Webb, Sodiomon B. Sirima, Thomas N. Williams, Cristina Pomilla, J. Anthony G. Scott, Alison M. Elliott, Dominic P. Kwiatkowski, Anna Rautanen, Swaib A. Lule, Wandia Kimita, Fatou Joof, Reagan M. Mogire, Francis M. Ndungu, Alexander J. Mentzer, Amidou Diarra, Shabir A. Madhi, Philip Bejon, Neema Mturi, Sarah H. Atkinson, Tommy Carstensen, Morgan M. Goheen, Carla Cerami, Adrian V. S. Hill, Alireza Morovat, Kirk A. Rockett, Manjinder S. Sandhu, Andrew M. Prentice, Clare L. Cutland, John Muthii Muriuki, Gavin Band, Muriuki, John Muthii [0000-0003-4369-9547], Mentzer, Alexander J [0000-0002-4502-2209], Band, Gavin [0000-0002-1710-9024], Gilchrist, James J [0000-0003-2045-6788], Carstensen, Tommy [0000-0002-3672-9931], Goheen, Morgan M [0000-0003-2297-3295], Kimita, Wandia [0000-0002-3099-7134], Mogire, Reagan [0000-0001-6454-1613], Cutland, Clare L [0000-0001-8250-8307], Pomilla, Cristina [0000-0002-2581-8365], Gurdasani, Deepti [0000-0001-9996-6929], Rockett, Kirk [0000-0002-6369-9299], Mturi, Neema [0000-0002-6585-2074], Ndungu, Francis M [0000-0002-8977-0030], Sirima, Sodiomon B [0000-0002-0972-4211], Morovat, Alireza [0000-0002-5832-7992], Prentice, Andrew M [0000-0001-5389-451X], Webb, Emily L [0000-0002-4019-7456], Elliott, Alison M [0000-0003-2818-9549], Hill, Adrian VS [0000-0003-0900-9629], Kwiatkowski, Dominic P [0000-0002-5023-0176], Cerami, Carla [0000-0002-7634-0955], Atkinson, Sarah H [0000-0002-8360-4402], Apollo - University of Cambridge Repository, and Wellcome Trust
Subjects: Hemolytic anemia, Male, Erythrocytes, Anemia, Iron, Ferroportin, Mutation, Missense, Bacteremia, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, parasitic diseases, Medicine, Humans, Health and Medicine, Cation Transport Proteins, Research Articles, 030304 developmental biology, 0303 health sciences, Mutation, Multidisciplinary, biology, business.industry, Infant, Newborn, SciAdv r-articles, Infant, Iron deficiency, Iron Deficiencies, medicine.disease, Hemolysis, 3. Good health, Malaria, Glutamine, Amino Acid Substitution, 030220 oncology & carcinogenesis, Immunology, biology.protein, Female, business, Research Article
Abstract: The FPN Q248H mutation protects children from anemia, hemolysis, and iron deficiency, but not malaria or bacterial infection., Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN 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 Plasmodium 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.
Published: 2019

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

Author: Matti Pirinen, Chris C. A. Spencer, Gavin Band, Gilean McVean, Holly Trochet, Luke Jostins, Centre of Excellence in Complex Disease Genetics, Helsinki Institute for Information Technology, Department of Mathematics and Statistics, Institute for Molecular Medicine Finland, Biostatistics Helsinki, Department of Public Health, and Statistical and population genetics
Subjects: SELECTION, Epidemiology, Computer science, Bayesian probability, Correlation and dependence, Genome-wide association study, Computational biology, Polymorphism, Single Nucleotide, DISEASE, GENETIC ASSOCIATION, 03 medical and health sciences, Frequentist inference, pleiotropy, 111 Mathematics, PHEWAS, GWAS, Humans, INVERSION, Computer Simulation, summary statistics, Set (psychology), Genetics (clinical), Selection (genetic algorithm), 030304 developmental biology, Genetic association, RISK, 0303 health sciences, Models, Genetic, Clinical study design, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Novelty, Bayes Theorem, meta-analysis, Phenotype, Case-Control Studies, Meta-analysis, Genome-Wide Association Study
Abstract: 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 to 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.
Published: 2019

24. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author: Corneliu A. Bodea, Benjamin M. Neale, Stephan Ripke, Mark J. Daly, Bernie Devlin, Kathryn Roeder, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombel, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A. Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W. Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M. Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Jane M. Andrews, Peter A. Bampton, Timothy H. Florin, Richard Gearry, Krupa Krishnaprasad, Ian C. Lawrance, Gillian Mahy, Graham Radford-Smith, Rebecca L. Roberts, Lisa A. Simms, Leila Amininijad, Isabelle Cleynen, Olivier Dewit, Denis Franchimont, Michel Georges, Debby Laukens, Emilie Theatre, André Van Gossum, Severine Vermeire, Guy Aumais, Leonard Baidoo, Arthur M. Barrie, Karen Beck, Edmond-Jean Bernard, David G. Binion, Alain Bitton, Steve R. Brant, Judy H. Cho, Albert Cohen, Kenneth Croitoru, Lisa W. Datta, Colette Deslandres, Richard H. Duerr, Debra Dutridge, John Ferguson, Joann Fultz, Philippe Goyette, Gordon R. Greenberg, Talin Haritunians, Gilles Jobin, Seymour Katz, Raymond G. Lahaie, Dermot P. McGovern, Linda Nelson, Sok Meng Ng, Kaida Ning, Pierre Paré, Miguel D. Regueiro, John D. Rioux, Elizabeth Ruggiero, L. Philip Schumm, Marc Schwartz, Regan Scott, Yashoda Sharma, Mark S. Silverberg, Denise Spears, A. Hillary Steinhart, Joanne M. Stempak, Jason M. Swoger, Constantina Tsagarelis, Clarence Zhang, Hongyu Zhao, Jan Aerts, Tariq Ahmad, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Chris Barnes, Jeffrey C. Barrett, Inês Barroso, Anne Barton, Amanda J. Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J. Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Morris J. Brown, Ian N. Bruce, Jaswinder Bull, Oliver S. Burren, John Burton, Jake Byrnes, Sian Caesar, Niall Cardin, Chris M. Clee, Alison J. Coffey, John M.C. Connell, Donald F. Conrad, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Hazel E. Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M. Evans, Gareth Evans, Steve Eyre, Anne Farmer, Nicol Ferrier, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A. Franklyn, Timothy M. Frayling, Rachel M. Freathy, Eleni Giannoulatou, Polly Gibbs, Paul Gilbert, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J. Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A. Hitman, Lynne Hocking, Chris Holmes, Eleanor Howard, Philip Howard, Joanna M.M. Howson, Debbie Hughes, Sarah Hunt, John D. Isaacs, Mahim Jain, Derek P. Jewell, Toby Johnson, Jennifer D. Jolley, Ian R. Jones, Lisa A. Jones, George Kirov, Cordelia F. Langford, Hana Lango-Allen, G. Mark Lathrop, James Lee, Kate L. Lee, Charlie Lees, Kevin Lewis, Cecilia M. Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Jonathan L. Marchini, Paul Martin, Dunecan C.O. Massey, Wendy L. McArdle, Peter McGuffin, Kirsten E. McLay, Gil McVean, Alex Mentzer, Michael L. Mimmack, Ann E. Morgan, Andrew P. Morris, Craig Mowat, Patricia B. Munroe, Simon Myers, William Newman, Elaine R. Nimmo, Michael C. O’Donovan, Abiodun Onipinla, Nigel R. Ovington, Michael J. Owen, Kimmo Palin, Aarno Palotie, Kirstie Parnell, Richard Pearson, David Pernet, John R.B. Perry, Anne Phillips, Vincent Plagnol, Natalie J. Prescott, Inga Prokopenko, Michael A. Quail, Suzanne Rafelt, Nigel W. Rayner, David M. Reid, Anthony Renwick, Susan M. Ring, Neil Robertson, Samuel Robson, Ellie Russell, David St Clair, Jennifer G. Sambrook, Jeremy D. Sanderson, Stephen J. Sawcer, Helen Schuilenburg, Carol E. Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M. Shields, Matthew J. Simmonds, Debbie J. Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E. Stevens, Kathy Stirrups, Millicent A. Stone, David P. Strachan, Zhan Su, Deborah P.M. Symmons, John R. Thompson, Wendy Thomson, Martin D. Tobin, Mary E. Travers, Clare Turnbull, Damjan Vukcevic, Louise V. Wain, Mark Walker, Neil M. Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A. Watkins, John Webster, Michael N. Weedon, Anthony G. Wilson, Matthew Woodburn, B. Paul Wordsworth, Chris Yau, Allan H. Young, Eleftheria Zeggini, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, Alastair Compston, Martin Farrall, Stephen C.L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V.S. Hill, Christopher G. Mathew, Marcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Matthew E. Hurles, Audrey Duncanson, Willem H. Ouwehand, Miles Parkes, Nazneen Rahman, John A. Todd, Nilesh J. Samani, Dominic P. Kwiatkowski, Mark I. McCarthy, Nick Craddock, Panos Deloukas, Peter Donnelly, Jenefer M. Blackwell, Elvira Bramon, Juan P. Casas, Aiden Corvin, Janusz Jankowski, Hugh S. Markus, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Matti Pirinen, Amy Strange, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, Heredity, Genetics, Genetics (clinical), Computer science, Genetic Linkage, Genome-wide association study, VARIANTS, 030105 genetics & heredity, computer.software_genre, Bayes' theorem, Gene Frequency, HISTORY, IMPUTATION, False positive paradox, Genetics(clinical), Disease, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Inheritance (genetic algorithm), Genotype, DATABASE, Genetic genealogy, POWER, Population, Genomics, POPULATION STRATIFICATION, Biology, INHERITANCE, Population stratification, Machine learning, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Allele frequency, FAMILY-BASED ASSOCIATION, 030304 developmental biology, Genetic association, business.industry, Bayes Theorem, DISEASE ASSOCIATION, Human genetics, Hierarchical clustering, Genetics, Population, 030104 developmental biology, Case-Control Studies, 3111 Biomedicine, Artificial intelligence, business, computer, Software, Imputation (genetics)
Abstract: A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.
Published: 2016

25. Environmental Correlation Analysis for Genes Associated with Protection against Malaria

Author: Gavin Band, Robert W. Snow, Carolyne M. Ndila, Alex Macharia, Sophie Uyoga, Kirk A. Rockett, Margaret J. Mackinnon, Dominic P. Kwiatkowski, Anna Rautanen, Thomas N. Williams, and Wellcome Trust
Subjects: 0301 basic medicine, HEPARAN-SULFATE PROTEOGLYCANS, Genome-wide association study, RED-BLOOD-CELLS, 0302 clinical medicine, Gene Frequency, environmental correlation analysis balancing selection malaria local adaptation, Genotype, Malaria, Falciparum, Child, Disease Resistance, Genetics & Heredity, Genetics, biology, INFECTED ERYTHROCYTES, 3. Good health, Cerebral Malaria, Child, Preschool, Life Sciences & Biomedicine, local adaptation, Biochemistry & Molecular Biology, Adolescent, balancing selection, AFRICAN POPULATIONS, Plasmodium falciparum, malaria, Single-nucleotide polymorphism, Environment, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0603 Evolutionary Biology, parasitic diseases, medicine, Humans, Genetic Predisposition to Disease, Selection, Genetic, GENOME-WIDE ASSOCIATION, Allele, Molecular Biology, Allele frequency, Discoveries, Alleles, Genetic Association Studies, Ecology, Evolution, Behavior and Systematics, Evolutionary Biology, 0604 Genetics, Science & Technology, HEMOGLOBIN-VARIANTS, Infant, Newborn, Infant, 0601 Biochemistry And Cell Biology, PLASMODIUM-FALCIPARUM MALARIA, biology.organism_classification, medicine.disease, Kenya, ENDOTHELIAL-CELLS, ALPHA-THALASSEMIA, NATURAL-SELECTION, environmental correlation analysis, 030104 developmental biology, Case-Control Studies, 030217 neurology & neurosurgery, Malaria
Abstract: 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.
Published: 2016

26. The UK Biobank resource with deep phenotyping and genomic data

Author: Jared O'Connell, Olivier Delaneau, Allan Motyer, Samantha Welsh, Peter Donnelly, Mark Effingham, Naomi E. Allen, Jonathan Marchini, Gavin Band, Stephen Leslie, Clare Bycroft, Desislava Petkova, Damjan Vukcevic, Lloyd T. Elliott, Alan Young, Adrian Cortes, Colin Freeman, Gil McVean, and Kevin Sharp
Subjects: Adult, Male, Quality Control, 0301 basic medicine, Databases, Factual, Population genetics, Genomics, Genome-wide association study, Computational biology, Biology, Cohort Studies, Major Histocompatibility Complex, 03 medical and health sciences, Databases, Genetic, Genotype, Electronic Health Records, Humans, Family, Allele, Life Style, Alleles, Aged, Genetic association, Multidisciplinary, Racial Groups, Haplotype, Brain, Middle Aged, Biobank, Body Height, United Kingdom, 3. Good health, Phenotype, 030104 developmental biology, Haplotypes, Female, Biomarkers, Genome-Wide Association Study
Abstract: 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.
Published: 2018

27. Author response: Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Author: Neema Mturi, Carolyne M. Ndila, Norbert Peshu, Dapa A. Diallo, Alexander Macharia, Sophie Uyoga, D. Herbert Opi, Ahmed Raza, Ewen M Harrison, Kirk A. Rockett, Ogobara K. Doumbo, Joann M. Moulds, Mohammed Shebbe, Christopher V. Plowe, Kathryn Maitland, J. Alexandra Rowe, Kirsten E. Lyke, Dominic P. Kwiatkowski, Thomas N. Williams, Gavin Band, Olivia Swann, Mahamadou A. Thera, and Abdoulaye K. Kone
Subjects: Cerebral Malaria, Immunology, Complement receptor, Allele, Biology
Published: 2018

28. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Nicholas G. Martin, René Höhn, Paul Mitchell, Gavin Band, Pamela Whittaker, Michelle Ricketts, Pirro G. Hysi, Jenefer M. Blackwell, Grant W. Montgomery, Elena Rochtchina, Manfred E. Beutel, Richard A. Mills, Anna Rautanen, Alagurevathi Jayakumar, Colin Freeman, Stephen Sawcer, Stuart MacGregor, Irene Schmidtmann, Cornelia M. van Duijn, Nicholas W. Wood, Sayoko E. Moroi, Jonathan L. Haines, Aniket Mishra, Ananth C. Viswanathan, Jie Jin Wang, Donald L. Budenz, Seyhan Yazar, Janey L. Wiggs, Garrett Hellenthal, Kathryn P. Burdon, Jerome I. Rotter, Jamie E Craig, Puya Gharahkhani, Juan P. Casas, R. Rand Allingham, Jost B. Jonas, Ozren Polasek, Julia E. Richards, Sarah Edkins, Rodney J. Scott, Abhishek Nag, Tanja Zeller, Rhian Gwilliam, Chris C. A. Spencer, David S. Friedman, Adriana I Iglesias, Radhi Ravindrarajah, Kent D. Taylor, Caroline Hayward, Eleni Giannoulatou, David A. Mackey, Michael A. Hauser, Paul J. Foster, Emma Gray, Audrey Duncanson, Yih Chung Tham, Murray H. Brilliant, Ching-Yu Cheng, William K. Scott, Robert N. Weinreb, Hugh S. Markus, Xueling Sim, David S. Siscovick, Matti Pirinen, John H. Fingert, Yelena Bykhovskaya, Louis R. Pasquale, Peter Donnelly, Donald J. Zack, Kuldev Singh, Cordelia Langford, Zhan Su, Céline Bellenguez, Joel S. Schuman, Peter Kraft, Christopher G. Mathew, Hannah Blackburn, Sara Widaa, Yuan Shi, Gabriel Cuellar-Partida, André G. Uitterlinden, Naomi Hammond, Panos Deloukas, Richard K. Lee, Robert Plomin, Jessica N. Cooke Bailey, Jae H. Kang, John Attia, Yutao Liu, Simon C. Potter, Jennifer Liddle, Matthew Gillman, Alex W. Hewitt, Margaret A. Pericak-Vance, James F. Wilson, Tien Yin Wong, Elvira Bramon, Janusz Jankowski, Henriët Springelkamp, Sarah E. Hunt, Anthony P Khawaja, Veronique Vitart, Xiaohui Li, Pieter W.M. Bonnemaijer, Damjan Vukcevic, Paul R. Lichter, Aiden Corvin, Sionne E. M. Lucas, Matthew Waller, Caroline C W Klaver, Douglas E. Gaasterland, Terry Gaasterland, Norbert Pfeiffer, Douglas Vollrath, Anthony Realini, Eranga N. Vithana, Gadi Wollstein, Thibaud Boutin, Owen T. McCann, Paul A. Weston, Lisa S. Kearns, Inês Barroso, Richard G. Pearson, Christopher J Hammond, Colin N. A. Palmer, Michael Inouye, Chiea Chuen Khor, Stephanie Loomis, Sandra E Staffieri, Yaron S. Rabinowitz, Richard C. Trembath, Tin Aung, William G. Christen, Paul N. Baird, Jing Xie, Elisabeth M. van Leeuwen, Serge Dronov, Arthur J. Sit, Colin E. Willoughby, Kang Zhang, Matthew A. Brown, Suzannah Bumpstead, Amy Strange, Elizabeth G. Holliday, Clinical Genetics, Epidemiology, Ophthalmology, Internal Medicine, Experimental Immunology, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iglesias, Adriana I [0000-0001-5532-764X], Gharahkhani, Puya [0000-0002-4203-5952], Bailey, Jessica N Cooke [0000-0002-4001-8702], Li, Xiaohui [0000-0002-5037-3572], Khawaja, Anthony P [0000-0001-6802-8585], Haines, Jonathan L [0000-0002-4351-4728], Hayward, Caroline [0000-0002-9405-9550], Bonnemaijer, Pieter [0000-0001-5154-6765], Staffieri, Sandra E [0000-0003-3131-9359], Jonas, Jost B [0000-0003-2972-5227], Kang, Jae H [0000-0003-4812-0557], Wilson, James F [0000-0001-5751-9178], Foster, Paul J [0000-0002-4755-177X], Hysi, Pirro G [0000-0001-5752-2510], Hewitt, Alex W [0000-0002-5123-5999], Khor, Chiea Chuen [0000-0002-1128-4729], Pasquale, Louis R [0000-0002-5835-3496], Montgomery, Grant W [0000-0002-4140-8139], Klaver, Caroline CW [0000-0002-2355-5258], Hammond, Christopher J [0000-0002-3227-2620], Wiggs, Janey L [0000-0003-1890-3278], Burdon, Kathryn P [0000-0001-8217-1249], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Lumican, Candidate gene, genetic structures, Fibrillin-1, Gene Expression, General Physics and Astronomy, Glaucoma, Genome-wide association study, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, 0302 clinical medicine, Myopia, lcsh:Science, Corneal Dystrophies, Hereditary, Genetics, Multidisciplinary, Eye Diseases, Hereditary, Mendelian Randomization Analysis, 3. Good health, medicine.anatomical_structure, Proteoglycans, Decorin, Glaucoma, Open-Angle, Keratoconus, Science, Quantitative Trait Loci, 610 Medicine & health, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Transforming Growth Factor beta2, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Quantitative Trait, Heritable, Asian People, medicine, Humans, CHROMATIN STATES, GENE-EXPRESSION, RISK-FACTOR, MUTATIONS, LUMICAN, MOUSE, KERATOCONUS, DECORIN, POLYMORPHISMS, HERITABILITY, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Loeys-Dietz Syndrome, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genome, Human, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, lcsh:Q, Ehlers-Danlos Syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018

29. Inferring adaptive gene-flow in recent African history

Author: George Busby, Ryan Christ, Gavin Band, Ellen Leffler, Quang Si Le, Kirk Rockett, Dominic Kwiatkowski, and Chris Spencer
Subjects: Genetics, 0303 health sciences, biology, Ethnic group, Major histocompatibility complex, Genome, Phenotype, Gene flow, History of Africa, 03 medical and health sciences, 0302 clinical medicine, Null phenotype, parasitic diseases, biology.protein, Adaptation, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Gene-flow from an ancestrally differentiated group has been shown to be a powerful source of selectively advantageous variants. To understand whether recent gene-flow may have contributed to adaptation among humans in sub-Saharan Africa, we applied a novel method to identify deviations in ancestry inferred from genome-wide data in 48 populations. Among the signals of ancestry deviation that we find in the Fula, an historically pastoralist ethnic group from the Gambia, are the region that encodes the lactose persistence phenotype, LCT/MCM6, which has the highest proportion of Eurasian ancestry in the genome. The region with the lowest proportion of non-African ancestry is across DARC, which encodes the Duffy null phenotype and is protective for Plasmodium vivax malaria. In the Jola from the Gambia and a Khoesan speaking group from Namibia we find multiple regions with inferred ancestry deviation including the Major Histocompatibility Complex. Our analysis shows the potential for adaptive gene-flow in recent human history.
Published: 2017
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30. Genome-wide genetic data on ~500,000 UK Biobank participants

Author: Clare Bycroft, Colin Freeman, Desislava Petkova, Gavin Band, Lloyd T. Elliott, Kevin Sharp, Allan Motyer, Damjan Vukcevic, Olivier Delaneau, Jared O’Connell, Adrian Cortes, Samantha Welsh, Gil McVean, Stephen Leslie, Peter Donnelly, and Jonathan Marchini
Subjects: 0303 health sciences, Haplotype, Genome-wide association study, Computational biology, Biology, computer.software_genre, Biobank, 03 medical and health sciences, 0302 clinical medicine, Cohort, Genotype, Trait, Data mining, computer, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology, Genetic association
Abstract: The UK Biobank project is a large prospective cohort study of ~500,000 individuals from across the United Kingdom, aged between 40-69 at recruitment. A rich variety of phenotypic and health-related information is available on each participant, making the resource unprecedented in its size and scope. Here we describe the genome-wide genotype data (~805,000 markers) collected on all individuals in the cohort and its quality control procedures. Genotype data on this scale offers novel opportunities for assessing quality issues, although the wide range of ancestries of the individuals in the cohort also creates particular challenges. We also conducted a set of analyses that reveal properties of the genetic data – such as population structure and relatedness – that can be important for downstream analyses. In addition, we phased and imputed genotypes into the dataset, using computationally efficient methods combined with the Haplotype Reference Consortium (HRC) and UK10K haplotype resource. This increases the number of testable variants by over 100-fold to ~96 million variants. We also imputed classical allelic variation at 11 human leukocyte antigen (HLA) genes, and as a quality control check of this imputation, we replicate signals of known associations between HLA alleles and many common diseases. We describe tools that allow efficient genome-wide association studies (GWAS) of multiple traits and fast phenome-wide association studies (PheWAS), which work together with a new compressed file format that has been used to distribute the dataset. As a further check of the genotyped and imputed datasets, we performed a test-case genome-wide association scan on a well-studied human trait, standing height.
Published: 2017

31. Reappraisal of known malaria resistance loci in a large multicenter study

Author: Malcolm E. Molyneux, Peter Siba, Andre Ndi, Valentina D. Mangano, Cao Quang Thai, Vysaul Nyirongo, Subulade A. Olaniyan, Angie Green, Mahamadou A. Thera, Timothy M. E. Davis, Síle F. Molloy, Kathryn Fitzpatrick, Giorgio Sirugo, Edith C. Bougouma, Chris Drakeley, Anthony Enimil, Angela Allen, Olukemi K. Amodu, Christina Hubbart, Nuno Sepúlveda, Nguyen Hoan Phu, M Jallow, Carolyne M. Ndila, Stanley Usen, Kimberly J. Johnson, Hugh Reyburn, Taane G. Clark, Dominic P. Kwiatkowski, Si Quang Le, Tobias O. Apinjoh, Kalifa Bojang, Jennifer R Evans, Michael D. Wilson, Lee Hart, Sophie Uyoga, Angeliki Kerasidou, Eric A. Achidi, Steve Allen, Kirk A. Rockett, Pascal Michon, Ivo Mueller, Anna E. Jeffreys, Belco Poudiougou, Anita Ghansah, Norbert Peshu, Fatoumatta Sisay-Joof, David Kachala, Sodiomon B. Sirima, David J. Conway, Geraldine M. Clarke, Regina N. Mugri, Moses Laman, Aaron Vanderwal, Miguel A. Sanjoaquin, Sibiry Sissoko, Ousmane Touré, Laurens Manning, Chris C. A. Spencer, Matti Pirinen, David Modiano, Sarah J. Dunstan, Harin Karunajeewa, Alexander Macharia, Tran Tinh Hien, Tsiri Agbenyega, Gavin Band, Kate Rowlands, Salimata Konate, Rachel Craik, L. Amenga-Etego, Nguyen Ngoc Quyen, Kwadwo A. Koram, Amadou Niangaly, Margaret Pinder, Alphaxard Manjurano, Terrie E. Taylor, Ogobara K. Doumbo, Eleanor M. Riley, Jeremy Farrar, Victoria Cornelius, Kevin Marsh, and Thomas N. Williams
Subjects: medicine.medical_specialty, Genome-wide association study, Glucosephosphate Dehydrogenase, Polymorphism, Single Nucleotide, Article, Papua New Guinea, Plasma Membrane Calcium-Transporting ATPases, Polymorphism (computer science), ABO blood group system, parasitic diseases, Epidemiology, Genetics, medicine, Humans, Malaria, Falciparum, Africa South of the Sahara, Genetic Association Studies, Disease Resistance, biology, Transmission (medicine), Case-control study, Plasmodium falciparum, medicine.disease, biology.organism_classification, 3. Good health, Glucosephosphate Dehydrogenase Deficiency, Logistic Models, Vietnam, Genetic Loci, Case-Control Studies, Malaria
Abstract: Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.
Published: 2014

32. A Genetic Atlas of Human Admixture History

Author: George B.J. Busby, James F. Wilson, Daniel Falush, Cristian Capelli, Simon Myers, Gavin Band, and Garrett Hellenthal
Subjects: Genotyping Techniques, Human Migration, media_common.quotation_subject, Population, Population genetics, Bantu languages, Biology, Polymorphism, Single Nucleotide, Article, Chromosome Painting, Middle East, European colonialism, Genetic drift, Humans, Computer Simulation, Europe, Eastern, education, Alleles, History, Ancient, media_common, Genetics, education.field_of_study, Multidisciplinary, Models, Genetic, Human migration, business.industry, Genetic Drift, Empire, Historical Article, DNA, Mongolia, Genealogy, Haplotypes, business, Software
Abstract: 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.
Published: 2014

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

Author: Kate Rowlands, Eleanor M. Riley, David Modiano, David Kachala, Nicole Thornton, Muminatou Jallow, Edith C. Bougouma, Anna E. Jeffreys, Carolyne M. Ndila, Jim Stalker, Tobias O. Apinjoh, Eleanor Drury, Malcolm E. Molyneux, Alphaxard Manjurano, Ellen M. Leffler, Chris Drakeley, Shane Grimsley, Louise Tilley, George B.J. Busby, Victoria Cornelius, Kevin Marsh, Vysaul Nyirongo, Thomas N. Williams, Geraldine M. Clarke, Terrie Taylor, Fatoumatta Sisay-Joof, Christina Hubbart, Valentina D. Mangano, Kalifa Bojang, Sodiomon B. Sirima, David J. Conway, Katja Kivinen, Hugh Reyburn, Dominic P. Kwiatkowski, Norbert Peshu, Quang Si Le, Eric A. Achidi, Kirk A. Rockett, Chris C. A. Spencer, Gavin Band, Wellcome Trust, and Commission of the European Communities
Subjects: 0301 basic medicine, Models, Molecular, Erythrocytes, Protein Structure, Secondary, 0302 clinical medicine, Gene Frequency, Glycophorins, Copy-number variation, Malaria, Falciparum, Child, Disease Resistance, Genetics, 0303 health sciences, Multidisciplinary, GYPA, biology, GYPB, Research Support, Non-U.S. Gov't, Medicine (all), 3. Good health, Multidisciplinary Sciences, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Malaria Genomic Epidemiology Network, Glycophorin, Adult, multidisciplinary, antigens, cells rbcs, DNA Copy Number Variations, General Science & Technology, Locus (genetics), Receptors, Cell Surface, Host-Parasite Interactions, Structural variation, 03 medical and health sciences, Research Support, N.I.H., Extramural, parasitic diseases, Journal Article, medicine, Humans, 1000 Genomes Project, Gene, Africa South of the Sahara, 030304 developmental biology, Science & Technology, Genome, Human, Haplotype, Plasmodium falciparum, biology.organism_classification, medicine.disease, Red blood cell, 030104 developmental biology, biology.protein, Malaria
Abstract: INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells. In the case of Plasmodium falciparum , this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa. This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system. In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors. RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa. To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus. RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region. In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity. By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association. In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria. To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure. The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA. Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant. CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive. Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus. Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria. This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease.
Published: 2016

34. Author response: Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Author: Gavin Band, Salimata Konate, Muminatou Jallow, Thomas N. Williams, Sibiry Sissoko, Nguyen Hoan Phu, Hugh Reyburn, Nuno Sepúlveda, Ousmane Touré, Christina Hubbart, Chris Drakeley, Dominic P. Kwiatkowski, Sophie Uyoga, Regina N. Mugri, Ivo Mueller, Anna E. Jeffreys, Timothy M. E. Davis, Olukemi K. Amodu, Lee Hart, Geraldine M. Clarke, Anita Ghansah, Eleanor M. Riley, Ogobara K. Doumbo, Kate Rowlands, Tobias O. Apinjoh, Eric A. Achidi, Steve Allen, Kirk A. Rockett, Fatoumatta Sisay-Joof, Síle F. Molloy, Taane G. Clark, Jeremy Farrar, Valentina D. Mangano, Victoria Cornelius, Kevin Marsh, Shivang S. Shah, Kalifa Bojang, Vysaul Nyirongo, Pascal Michon, Alexander Macharia, Angela Allen, Peter Siba, Cao Quang Thai, Carolyne M. Ndila, Subulade A. Olaniyan, Stanley Usen, Andre Ndi, Laurens Manning, Jennifer Evans, Chris C. A. Spencer, Mahamadou A. Thera, Margaret Pinder, Malcolm E. Molyneux, David Kachala, Alphaxard Manjurano, Norbert Peshu, Terrie E. Taylor, Amadou Niangaly, Moses Laman, Katja Kivinen, Tsiri Agbenyega, Lucas Amenga-Etego, Edith C. Bougouma, Nguyen Ngoc Quyen, Giorgio Sirugo, Anthony Enimil, David Modiano, Angeliki Kerasidou, Tran Tinh Hien, Michael D. Wilson, Susana Campino, Sodiomon B. Sirima, David J. Conway, Sarah J. Dunstan, Kwadwo A. Koram, Harin Karunajeewa, and Belco Poudiougou
Subjects: Cerebral Malaria, business.industry, Immunology, Medicine, business
Published: 2016

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

Author: Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.
Subjects: Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; 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.
Published: 2016

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

Author: Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences
Subjects: Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: 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.
Published: 2016

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

Author: Olivia Sousa, Stephen Sawcer, Janusz Jankowski, Serge Dronov, Aiden Corvin, Panos Deloukas, Leena Peltonen, Damjan Vukcevic, Cordelia Langford, Nicholas W. Wood, Nubia N. Pontes, Campbell S. Witt, Richard C. Trembath, Gloria R. Monteiro, Anshuman Mishra, Peter Donnelly, Audrey Duncanson, Matthew A. Brown, Heather J. Cordell, Mary E. Wilson, Elvira Bramon, Selma M. B. Jeronimo, Sarah E. Hunt, Sarah Edkins, Ananth C. Viswanathan, Christopher G. Mathew, Colin Freeman, Gavin Band, Chris C. A. Spencer, Henio G. Lacerda, Eleni Giannoulatou, Frank T. Christiansen, A. Strange, Hugh S. Markus, Céline Bellenguez, Michaela Fakiola, Zhan Su, Jenefer M. Blackwell, Matti Pirinen, Shyam Sundar, Robert Plomin, Shri Prakash Singh, Sanjana Mehrotra, L.K. Smith, Madhukar Rai, Emma Gray, Richard G. Pearson, E. Nancy Miller, Colin N. A. Palmer, Juan P. Casas, and Anna Rautanen
Subjects: Genotype, India, Genome-wide association study, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Article, HLA-DQ alpha-Chains, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetics, medicine, Genetic predisposition, Odds Ratio, Humans, Genetic Predisposition to Disease, Allele frequency, HLA-DRB1, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, Electrophoresis, Agar Gel, 0303 health sciences, Leishmaniasis, Odds ratio, medicine.disease, Visceral leishmaniasis, Haplotypes, Linear Models, Leishmaniasis, Visceral, Brazil, 030215 immunology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: 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.
Published: 2016

38. Author response: Admixture into and within sub-Saharan Africa

Author: Chris C. A. Spencer, Ogobara Doumba, Valentina D. Mangano, Carolyne M. Ndila, Quang Si Le, Gavin Band, George B.J. Busby, Edith Bougama, Tobias O. Apinjoh, Muminatou Jallow, Kirk A. Rockett, Vysaul Nyirongo, Alphaxard Manjurano, Anthony Enimil, Dominic P. Kwiatkowski, and Lucas Amenga-Etego
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Geography, Sub saharan, Socioeconomics
Published: 2016

39. The Burau estimate for the entropy of a braid

Author: Gavin Band and Philip Boyland
Subjects: Pure mathematics, Mathematics::Dynamical Systems, 37E30, Root of unity, Braid group, 20F36, Dynamical Systems (math.DS), Topological entropy, Mathematics - Geometric Topology, Mathematics::Group Theory, Mathematics::Category Theory, Mathematics::Quantum Algebra, Dynamical systems, FOS: Mathematics, Braid, Mathematics - Dynamical Systems, Burau representation, 37E30 (Primary) 37B40, 20F36, 20F29 (Secondary), Mathematics, 20F29, 37B40, Geometric Topology (math.GT), Mathematics::Geometric Topology, Bounded function, Isotopy, Geometry and Topology, Complex number
Abstract: The topological entropy of a braid is the infimum of the entropies of all homeomorphisms of the disc which have a finite invariant set represented by the braid. When the isotopy class represented by the braid is pseudo-Anosov or is reducible with a pseudo-Anosov component, this entropy is positive. Fried and Kolev proved that the entropy is bounded below by the logarithm of the spectral radius of the braid's Burau matrix, $B(t)$, after substituting a complex number of modulus~1 in place of $t$. In this paper we show that for a pseudo-Anosov braid the estimate is sharp for the substitution of a root of unity if and only if it is sharp for $t=-1$. Further, this happens if and only if the invariant foliations of the pseudo-Anosov map have odd order singularities at the strings of the braid and all interior singularities have even order. An analogous theorem for reducible braids is also proved., Comment: 28 pages, 8 figures
Published: 2007

40. Identifying points of a pseudo-Anosov homeomorphism

Author: Gavin Band
Subjects: Discrete mathematics, Algebra and Number Theory, Gravitational singularity, Homeomorphism, Mathematics
Published: 2003

41. Complement receptor 1 polymorphism is associated with cerebral malaria in two discrete populations, but no evidence that human brain endothelial cells express the molecule

Author: Joann M. Moulds, Ahmed Raza, Alexandros Constantinou, Carolyne M. Ndila, J. Alexandra Rowe, Gavin Band, Kirsten E. Lyke, Ogobara K. Doumbo, Dapa A. Diallo, Abdoulaye K. Kone, Ewen M Harrison, D. Herbert Opi, Thomas N. Williams, Mahamadou A. Thera, Christopher V. Plowe, and Olivia Swann
Subjects: Genetics, medicine.anatomical_structure, biology, Cerebral Malaria, Complement receptor 1, Immunology, medicine, Human brain, biology.gene, Molecular Biology
Published: 2017

42. Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations

Author: Norbert Peshu, Emma Gray, Gavin Band, Giorgio Sirugo, Chris C. A. Spencer, Kirk A. Rockett, Sarah Edkins, Kate Rowlands, Kathrin Schuldt, Matti Pirinen, David Kachala, Quang Si Le, Kevin Marsh, Luke Jostins, Daniel Alcock, Malcolm E. Molyneux, Vysaul Nyirongo, Anna E. Jeffreys, Robert Andrews, Dominic P. Kwiatkowski, Thomas N. Williams, Terrie E. Taylor, Kalifa Bojang, Muminatou Jallow, Yik Ying Teo, Carolyne M. Ndila, David J. Conway, Margaret Pinder, Christina Hubbart, Taane G. Clark, Kerrin S. Small, Fatoumatta Sisay-Joof, Katja Kivinen, and Jeffrey C. Barrett
Subjects: Cancer Research, medicine.medical_specialty, lcsh:QH426-470, Correction, Biology, medicine.disease, lcsh:Genetics, Meta-analysis, parasitic diseases, Epidemiology, Genetics, Correct name, medicine, Severe Malaria, Molecular Biology, psychological phenomena and processes, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Imputation (genetics), Malaria, Demography
Abstract: The last author's name was spelled incorrectly. The correct name is: Malaria Genomic Epidemiology Network
Published: 2013

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

Author: Nicholas W. Wood, Chris C. A. Spencer, Konrad Koss, Heike I. Grabsch, Ananth C. Viswanathan, Simon C. Potter, Thomas L. Vaughan, Brian J. Reid, Céline Bellenguez, Kimberley Howarth, Claire Brooks, Michael Gibbons, Geoffrey Liu, David Ferry, Ian Tomlinson, Chuka U. Nwokolo, John de Caestecker, Barrie Rathbone, Francesco Lescai, Anna Rautanen, Weimin Ye, Nicholas I. Church, Nigel C. Bird, Laura J. Hardie, Peter H. Watson, Ross McManus, Peter Donnelly, David Cunningham, Peter Sasieni, Aiden Corvin, Cisca Wijmenga, Sarah Edkins, Amy Strange, Sheldon C. Cooper, Audrey Duncanson, Harvey A. Risch, Ian Sargeant, Christopher Macdonald, Pradeep Bhandari, Sarah E. Hunt, Matthew D. Rutter, John V. Reynolds, Nigel Trudgill, Rebecca Harrison, Anna H. Wu, Scott Sanders, Christopher G. Mathew, Mark S. Anderson, Raf Bisschops, Cathryn Edwards, Avazeh Tashakkori-Ghanbaria, Praful Patel, Wong Ho Chow, Anouk Van Der Winkel, Panos Deloukas, Kishor Vaidya, Manoj Nanji, Nichola L. Gellatly, Leena Peltonen, Iain A. Murray, Matthew A. Brown, Deborah Glancy, Marilie D. Gammon, Robert Plomin, Julie Hapeshi, Elia Stupka, Janusz Jankowski, Liam J. Murray, Alan G. Casson, Hugh McMurtry, Haythem Ali, Douglas A. Corley, Kausila Krishnadath, Hugh Barr, David Johnston, Derek Alderson, Ruth E Langley, Elvira Bramon, Saj Wajed, Sharon Love, Peter D. Siersema, Ernst J. Kuipers, Simon Panter, Mark R. Middleton, Ian D. Penman, Peter Isaacs, Krish Ragunath, David K. Levine, Paul Atherfold, Maikel P. Peppelenbosch, Joost P.H. Drenth, Claire Palles, Art Tucker, Stephen Attwood, Cordelia Langford, Rui Zhang, Matti Pirinen, Colin Freeman, Stephen Sawcer, Stuart MacGregor, Hugh S. Markus, S Paterson, Anna M. Nicholson, M Griffin, Nicola Burch, Colin Rodgers, Helen Winter, Anjan Dhar, Zhan Su, Emma Gray, Jantine W. P. M. van Baal, Richard C. Trembath, David Monk, Paul Mullins, Danielle Morris, Ashref Tawil, Serge Dronov, Hans Prenen, Yeng Ang, Dermot Kelleher, Gavin Band, Leslie Bernstein, Weronica E. Ek, H Smart, Luc J. W. van der Laan, Colin N. A. Palmer, Jenefer M. Blackwell, Wilbert H.M. Peters, David C. Whiteman, Tore Lind, Gosia Trynka, Helen Dallal, Paul Moayyedi, Russell D. Petty, Richard S. Gillies, Nicholas J. Shaheen, Chris Haigh, Sue Cullen, Gareth E. Davies, Julia Brown, Jean-Baptiste Cazier, Juan P. Casas, Yvonne Romero, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Gastroenterology & Hepatology, and Surgery
Subjects: Male, Linkage disequilibrium, Genome-wide association study, GASTROESOPHAGEAL-REFLUX DISEASE, Barrett’s Esophagus, Gastroenterology, Linkage Disequilibrium, Major Histocompatibility Complex, 0302 clinical medicine, Gene Frequency, Metaplasia, Molecular gastro-enterology and hepatology Membrane transport and intracellular motility [IGMD 2], POPULATION, Gastro-esophageal reflux disease (GERD), Genetics, education.field_of_study, Single nucleotide polymorphisms (SNPs), Middle Aged, CANCER, 3. Good health, Esophageal adenocarcinoma (EAC), medicine.anatomical_structure, 030220 oncology & carcinogenesis, OBESITY, Adenocarcinoma, Female, 030211 gastroenterology & hepatology, medicine.symptom, Molecular gastro-enterology and hepatology Translational research [IGMD 2], Adult, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Genome-wide association (GWA) study, Barrett Esophagus, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Esophagus, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, Aged, Models, Genetic, ADENOCARCINOMA, medicine.disease, digestive system diseases, Genetic Loci, Case-Control Studies, Barrett's esophagus, RISK-FACTORS, METAPLASIA, Human medicine, Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract: 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 (P combined = 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 (P combined = 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. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

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

Author: Chris C. A. Spencer, Panos Deloukas, Sarah Edkins, Amy Strange, Gavin Hudson, John Hardy, Aiden Corvin, Mark I. McCarthy, Karen E. Morrison, Robert Plomin, Nigel W. Williams, Patrick F. Chinnery, Simon C. Potter, Hannah Blackburn, Coro Paisán-Ruiz, Richard C. Trembath, Stephen Sawcer, Carl E Clarke, Juan-Pablo Casas, Gavin Band, Leena Peltonen, Matti Pirinen, Matthew A. Brown, Anna Rautanen, Martin A. Brown, Nicholas W. Wood, Cordelia Langford, Janusz Jankowski, David J. Burn, Kailash P. Bhatia, Roger A. Barker, Michelle Gardner, Peter Donnelly, J. P. Pearson, Sarah E. Hunt, Nicholas John Craddock, J.M. Evans, Elvira Bramon, Hugh S. Markus, Zhan Su, Colin Freeman, Colin N. A. Palmer, Andrew J. Lees, Christopher G. Mathew, Emma Gray, Vincent Plagnol, Huw R. Morris, Ananth C. Viswanathan, Jennie M. Blackwell, and Céline Bellenguez
Subjects: Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Genetics, SNP, Humans, Genetic Predisposition to Disease, Age of Onset, Molecular Biology, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Haplotype, Case-control study, Parkinson Disease, General Medicine, Articles, LRRK2, 3. Good health, Haplotypes, Case-Control Studies, Sample Size, alpha-Synuclein, Age of onset, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: 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.
Published: 2011

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

Author: Gilean McVean, Lena Samuelsson, Stephen Sawcer, Ananth C. Viswanathan, Lotus Mallbris, Leena Peltonen, Audrey Duncanson, Brian Kirby, Céline Bellenguez, Eva Riveira-Muñoz, Mona Ståhle, Åsa Torinsson Naluai, Wolfgang Weger, Sarah E. Hunt, Robert Plomin, Peter Donnelly, Juan P. Casas, Judith G.M. Bergboer, Emiliano Giardina, Simon C. Potter, Anne Barton, W.H. Irwin McLean, Alexander T. Dilthey, A. David Burden, Ramon M. Pujol, Hugh S. Markus, Giuseppe Novelli, Adrian Hayday, Richard C. Trembath, Michael E. Weale, Cordelia Langford, Stephen Leslie, Nicholas W. Wood, Panos Deloukas, Catherine H. Smith, Anna Rautanen, Jane Worthington, Katarina Wolk, Zhan Su, Elvira Bramon, Aiden Corvin, Suzannah Bumpstead, Anthony W. Ryan, Alan D. Irvine, Juha Kere, Ross McManus, Jesús Lascorz, Jonathan Barker, Matthew A. Brown, Christopher E.M. Griffiths, Michael H. Allen, Janusz Jankowski, Loukas Moutsianas, Joyce Leman, Patrick L.J.M. Zeeuwen, Colin Freeman, Alexandros Onoufriadis, Francesca Capon, Oliver FitzGerald, Matti Pirinen, Sarah Edkins, Jo Knight, Wolfgang Salmhofer, Amy Strange, André Reis, Joost Schalkwijk, Rachid Tazi-Ahnini, Frank O. Nestle, Angelika Hofer, Xavier Estivill, Helen S. Young, Gavin Band, Jenefer M. Blackwell, Ulrike Hüffmeier, Colin N. A. Palmer, Carlo Perricone, Chris C. A. Spencer, Emma Gray, Heiko Traupe, Rotraut Mössner, Michael J. Cork, Richard B. Warren, David M. Evans, and Christopher G. Mathew
Subjects: Genome-wide association study, Single-nucleotide polymorphism, HLA-C Antigens, Biology, medicine.disease_cause, Aminopeptidases, Polymorphism, Single Nucleotide, Risk Assessment, Chromosomes, Article, Major Histocompatibility Complex, Minor Histocompatibility Antigens, 03 medical and health sciences, HLA-C, 0302 clinical medicine, Gene interaction, Reference Values, Psoriasis, Chromosome Mapping, Chromosomes, Human, Genetic Variation, Humans, Europe, Genome-Wide Association Study, Genetic Predisposition to Disease, Chromosomes, Human, X, Genetics, medicine, Polymorphism, 030304 developmental biology, Genetic association, 0303 health sciences, NFKBIA Gene, Single Nucleotide, Immune dysregulation, medicine.disease, 3. Good health, Settore MED/03 - Genetica Medica, 030220 oncology & carcinogenesis, Infection and autoimmunity [NCMLS 1], Human
Abstract: Contains fulltext : 89179.pdf (Publisher’s version ) (Closed access) 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 x 10 and two loci with a combined P < 5 x 10). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 x 10). 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. 01 november 2010
Published: 2010

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

Author: Paul A. Weston, Emma Gray, Robert W. Ike, Sarah Rogers, Wolfgang Weger, Justin Paschall, Andreas Ruether, Anthony W. Ryan, James T. Elder, Robert Andrews, Ciara Coleman, Amy Perlmutter, Marin Aurand, Eva Riveira-Muñoz, Kati Kainu, G. Mark Lathrop, Per Hoffmann, Peter C.M. van de Kerkhof, Suzannah Bumpstead, Thomas Illig, Matthew W. Gillman, Gavin Band, Enno Christophers, Agnieszka Zawirska, Giuseppe Novelli, Jenefer M. Blackwell, Wilson Liao, Christopher G. Mathew, Steven J. Schrodi, Henry W. Lim, Sara Widaa, Lena Samuelsson, Cordelia Langford, Sari Suomela, Andre Franke, Jonathan Barker, Lotus Mallbris, Leena Peltonen, Ross McManus, Judith G.M. Bergboer, Radhi Ravindrarajah, Colin N. A. Palmer, O. T. McCann, Ggoncalo R. Abecasis, Ravi Hiremagalore, Tiziana Lepre, Rajan P. Nnair, Garrett Hellenthal, Brian Kirby, Richard D. Pearson, Linda E. Campbell, Stefan Schreiber, Eva Ellinghaus, Michael E. Weale, Sampath Prahalad, Stephen L. Guthery, Johann E. Gudjonsson, Janusz Jankowski, Simon C. Potter, Judith Fischer, Werner Kurrat, Michael J. Cork, Sean Ennis, Åsa Torinsson Naluai, Peter Donnelly, Raimund Erbel, Gosia Trynka, Audrey Duncanson, Martin den Heijer, Cindy Helms, Christian Gieger, Markward Ständer, Ulrike Hüffmeier, Mark I. McCarthy, Wolfgang Salmhofer, Yanming Li, Juan P. Casas, Nilesh J. Samani, Ramon M. Pujol, Peter Wolf, James Tt Eelder, Joost Schalkwijk, Katarina Wolk, Matthew Waller, Alan D. Irvine, Petra Badorf, Gemma Martin-Ezquerra, Dafna D. Gladman, Rotraut Mössner, Matthew A. Brown, Patrick L.J.M. Zeeuwen, Jonathan Nn Barker, Anne Barton, H.-Erich Wichmann, Hannah Blackburn, Emiliano Giardina, Wolfgang Küster, Heiko Traupe, Richard B. Warren, Aiden Corvin, Jennifer M. Gardner, Joe McPartlin, Alan Menter, Anna Rautanen, Jane Worthington, John J. Voorhees, Andrew Henschel, Külli Kingo, Proton Rahman, Jennifer Liddle, Hugh S. Markus, Catherine H. Smith, Cisca Wijmenga, Vinod Chandran, Richard Ttrembath, Ananth C. Viswanathan, Hyun Min Kang, David E. Goldgar, Fawnda Pellett, Joyce Leman, Jesús Lascorz, M. Perez, Sarah Edkins, Ulpu Saarialho-Kere, Alexandros Onoufriadis, Stephan Weidinger, Amy Strange, Funda Schürmeier-Horst, Michael H. Allen, Angelika Hofer, Lam C. Tsoi, Karl-Heinz Jöckel, Jun Ding, Adrian Hayday, Trilokraj Tejasvi, Mary J. Malloy, Susanne Moebus, Kristina Callis Duffin, Rachid Tazi-Ahnini, Zhan Su, Gerald G. Krueger, Trevor Markham, Richard C. Trembath, Philip E. Stuart, Gonçalo R. Abecasis, Nicholas Craddock, Céline Bellenguez, Serge Dronov, Clive R. Pullinger, Eleni Giannoulatou, A. David Burden, Damjan Vukcevic, Andrew Miner, Cheryl F. Rosen, L. Barnes, Sarah L. Spain, Mona Ståhle, Naomi Hammond, Rhian Gwilliam, Sarah E. Hunt, Frank O. Nestle, Xavier Estivill, Panos Deloukas, Phil Gallagher, Annica Inerot, Judith Conroy, Helen S. Young, Stephen J. Sawcer, Bruce F. Bebo, Isis Ricaño-Ponce, Juha Kere, Pamela Whittaker, John P. Kane, Anne M. Bowcock, Christopher E.M. Griffiths, W.H. Irwin McLean, Tilo Henseler, Juliane Winkelmann, Michael Weichenthal, Tõnu Esko, Ulrich Mrowietz, Jo Knight, Bing Jian Feng, André Reis, Sulev Kõks, Elvira Bramon, Nicholas W. Wood, Alagurevathi Jayakumar, Colin Freeman, Carlo Perricone, Yun Li, Chris C. A. Spencer, Pui Kwok, Robert Plomin, Ann B. Begovich, Francesca Capon, Carol Wise, Andres Metspalu, Caitriona Cusack, Oliver FitzGerald, Matti Pirinen, Michelle Ricketts, Rajan P. Neir, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Candidate gene, T-Lymphocytes, Genome-wide association study, Disease, DEAD-box RNA Helicases, 0302 clinical medicine, T-CELL DEVELOPMENT, Receptors, Immunologic, MULTIPLE COMMON, Oligonucleotide Array Sequence Analysis, Skin, GENE-EXPRESSION, Genetics, 0303 health sciences, GTPase-Activating Proteins, CELIAC-DISEASE, COMMON VARIANTS, 3. Good health, 030220 oncology & carcinogenesis, DEAD Box Protein 58, STAT3 Transcription Factor, Biology, Polymorphism, Single Nucleotide, White People, Article, TH17 DIFFERENTIATION, SIGNALING PATHWAYS, 03 medical and health sciences, Psoriasis, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Genetic association, Innate immune system, INTERFERON-GAMMA, Membrane Proteins, Pathogenesis and modulation of inflammation Infection and autoimmunity [N4i 1], NEGATIVE REGULATOR, medicine.disease, Immunity, Innate, Genetic architecture, CARD Signaling Adaptor Proteins, Core Binding Factor Alpha 3 Subunit, Settore MED/03 - Genetica Medica, Genetic Loci, Guanylate Cyclase, Genome-Wide Association Study
Abstract: 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. © 2012 Nature America, Inc. All rights reserved.
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