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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, 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
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3. BIRC6 modifies risk of invasive bacterial infection in Kenyan children

Author

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

Subjects
parasitic diseases
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 P. falciparum parasitaemia. We construct a joint dataset including 1,445 bacteraemia cases and 1,143 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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4. 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, Adrian V. S. Hill, and Wellcome Trust

Subjects
Malawi, Immunology, Nucleoside Transport Proteins, Mali, Inflammatory Bowel Diseases, Microbiology, Polymorphism, Single Nucleotide, 1107 Immunology, 1108 Medical Microbiology, Virology, Leprosy, Genetics, Humans, Parasitology, Genetic Predisposition to Disease, Child, Molecular Biology, 0605 Microbiology, Genome-Wide Association Study
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 four risk loci previously reported in China, Vietnam and India; MHC Class I and II,LACC1andSLC29A3. 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]). Using publicly-available data we characterise regulatory activity at this locus, identifyingACTR1Aas 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

5. 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
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6. 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

7. 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
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8. 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
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9. 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
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10. 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
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11. 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

12. 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
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13. 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

14. 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
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15. 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
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16. 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
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17. 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
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18. 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
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19. 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
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20. 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
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21. 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
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22. 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
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23. 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
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25. 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
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26. 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
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27. 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
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