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1. Genome wide association study of clinical duration and age at onset of sporadic CJD

Author

Hummerich, Holger, Speedy, Helen, Campbell, Tracy, Darwent, Lee, Hill, Elizabeth, Collins, Steven, Stehmann, Christiane, Kovacs, Gabor G., Geschwind, Michael D., Frontzek, Karl, Budka, Herbert, Gelpi, Ellen, Aguzzi, Adriano, van der Lee, Sven J., van Duijn, Cornelia M., Liberski, Pawel P., Calero, Miguel, Sanchez-Juan, Pascual, Bouaziz-Amar, Elodie, Laplanche, Jean Louis, Haïk, Stéphane, Brandel, Jean Phillipe, Mammana, Angela, Capellari, Sabina, Poleggi, Anna, Ladogana, Anna, Pocchiari, Maurizio, Zafar, Saima, Booth, Stephanie, Jansen, Gerard H., Areškevičiūtė, Aušrinė, Lund, Eva Løbner, Glisic, Katie, Parchi, Piero, Hermann, Peter, Zerr, Inga, Appleby, Brian S., Safar, Jiri, Gambetti, Pierluigi, Collinge, John, Mead, Simon, Hummerich, Holger, Speedy, Helen, Campbell, Tracy, Darwent, Lee, Hill, Elizabeth, Collins, Steven, Stehmann, Christiane, Kovacs, Gabor G., Geschwind, Michael D., Frontzek, Karl, Budka, Herbert, Gelpi, Ellen, Aguzzi, Adriano, van der Lee, Sven J., van Duijn, Cornelia M., Liberski, Pawel P., Calero, Miguel, Sanchez-Juan, Pascual, Bouaziz-Amar, Elodie, Laplanche, Jean Louis, Haïk, Stéphane, Brandel, Jean Phillipe, Mammana, Angela, Capellari, Sabina, Poleggi, Anna, Ladogana, Anna, Pocchiari, Maurizio, Zafar, Saima, Booth, Stephanie, Jansen, Gerard H., Areškevičiūtė, Aušrinė, Lund, Eva Løbner, Glisic, Katie, Parchi, Piero, Hermann, Peter, Zerr, Inga, Appleby, Brian S., Safar, Jiri, Gambetti, Pierluigi, Collinge, John, and Mead, Simon

Abstract

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5–9 (months)) was available in 3,773 and age at onset (median:67, IQR:61–73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10−6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

Published
2024

2. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Author

Jones, Emma, Hummerich, Holger, Viré, Emmanuelle, Uphill, James, Dimitriadis, Athanasios, Speedy, Helen, Campbell, Tracy, Norsworthy, Penny, Quinn, Liam, Whitfield, Jerome, Linehan, Jacqueline, Jaunmuktane, Zane, Brandner, Sebastian, Jat, Parmjit, Nihat, Akin, How Mok, Tze, Ahmed, Parvin, Collins, Steven, Stehmann, Christiane, Sarros, Shannon, Kovacs, Gabor G, Geschwind, Michael D, Golubjatnikov, Aili, Frontzek, Karl, Budka, Herbert, Aguzzi, Adriano, Karamujić-Čomić, Hata, van der Lee, Sven J, Ibrahim-Verbaas, Carla A, van Duijn, Cornelia M, Sikorska, Beata, Golanska, Ewa, Liberski, Pawel P, Calero, Miguel, Calero, Olga, Sanchez-Juan, Pascual, Salas, Antonio, Martinón-Torres, Federico, Bouaziz-Amar, Elodie, Haïk, Stéphane, Laplanche, Jean-Louis, Brandel, Jean-Phillipe, Amouyel, Phillipe, Lambert, Jean-Charles, Parchi, Piero, Bartoletti-Stella, Anna, Capellari, Sabina, Poleggi, Anna, Ladogana, Anna, Pocchiari, Maurizio, Aneli, Serena, Matullo, Giuseppe, Knight, Richard, Zafar, Saima, Zerr, Inga, Booth, Stephanie, Coulthart, Michael B, Jansen, Gerard H, Glisic, Katie, Blevins, Janis, Gambetti, Pierluigi, Safar, Jiri, Appleby, Brian, Collinge, John, and Mead, Simon

Published
2020
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4. Genome wide association study of clinical duration and age at onset of sporadic CJD

Author

Hummerich, Holger, primary, Speedy, Helen, additional, Campbell, Tracy, additional, Darwent, Lee, additional, Hill, Elizabeth, additional, Collins, Steven, additional, Stehmann, Christiane, additional, Kovacs, Gabor G, additional, Geschwind, Michael D, additional, Frontzek, Karl, additional, Budka, Herbert, additional, Gelpi, Ellen, additional, Aguzzi, Adriano, additional, van der Lee, Sven J, additional, van Duijn, Cornelia M, additional, Liberski, Pawel P, additional, Calero, Miguel, additional, Sanchez Juan, Pascual, additional, Bouaziz Amar, Elodie, additional, Laplanche, Jean Louis, additional, Haik, Stephane, additional, Brandel, Jean Phillipe, additional, Mammana, Angela, additional, Capellari, Sabina, additional, Poleggi, Anna, additional, Ladogana, Anna, additional, Pocchiari, Maurizio, additional, Zafar, Saima, additional, Booth, Stephanie, additional, Jansen, Gerard H, additional, Areskeviciute, Ausrine, additional, Lobner Lund, Eva, additional, Glisic, Katie, additional, Parchi, Piero, additional, Hermann, Peter, additional, Zerr, Inga, additional, Appleby, Brian S, additional, Collinge, John, additional, and Mead, Simon, additional

Published
2023
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5. Genetic and functional studies provide insights into the aetiologies of familial combined hyperlipidemia

Author

Speedy, Helen Elizabeth

Subjects
616.3997, Medicine, Familial Combined Hyperlipidemia, Hyperlipidemia, Atherosclerosis
Abstract

The integration of biological and genetic data has established that diverse biological processes, involving multiple effectors, influence circulating levels of triglyceride and cholesterol. This diversity may underlie the genetic complexity of human dyslipidemias, including the common and highly atherogenic condition, Familial Combined Hyperlipidemia (FCHL). The aetiologies of FCHL are currently undetermined. In this thesis, a multi-pronged approach was employed to identify genes/variants contributing to the linkage observed between the chromosome 21q22.2-22.3 interval and lipid traits, in white-British FCHL families. Additionally GPIHBP1, which encodes glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, was studied. GPIHBP1 represents a strong FCHL candidate gene due to its role in the lipolytic processing of triglyceride-rich lipoproteins. Combined genetic and gene expression analyses, focussed upon a refined 3.8Mb interval on chromosome 21q22.3 that was linked to lipid abnormalities in subsets of FCHL families, identified two genes (COL18A1 and PKNOX1 ) that warrant further investigation with regard to their contribution to FCHL. Promising results were also obtained for C21orf57, which resides just outside the 3.8Mb interval. Genetic association analyses in 1725 members of 239 FCHL families identified nominal association (P=0.0009) between a TSPEAR variant, rs34163868, and plasma triglyceride levels. Furthermore, transcript levels of CBS and TRPM2 were significantly altered by treatment with the PPAR-agonist bezafibrate in a rat hepatoma cell line, thus implicating these genes in triglyceride/fatty acid metabolism. In combined analysis of five independent cohorts, the minor allele of the GPIHBP1 variant, rs11538388 was protective against hypertriglyceridemia (P=2.98x10-4). The same allele was associated with decreased risk of coronary heart disease in the prospective Northwick Park Heart Study II (hazard ratio for carriers=0.76, P=0.0480) and delayed age of onset in the Southampton Atherosclerosis Study (odds ratio=0.76, P=0.0146). Collectively, these data demonstrate that the rs11538388 minor allele, or variant in linkage disequilibrium, is associated with more favourable processing of atherogenic lipoproteins.

Published
2012

8. Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Author

Went, Molly, Sud, Amit, Speedy, Helen, Sunter, Nicola J., Försti, Asta, Law, Philip J., Johnson, David C., Mirabella, Fabio, Holroyd, Amy, Li, Ni, Orlando, Giulia, Weinhold, Niels, van Duin, Mark, Chen, Bowang, Mitchell, Jonathan S., Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Rosenquist, Richard, Kuiper, Rowan, Stephens, Owen W., Bertsch, Uta, Broderick, Peter, Einsele, Hermann, Gregory, Walter M., Hillengass, Jens, Hoffmann, Per, Jackson, Graham H., Jöckel, Karl-Heinz, Nickel, Jolanta, Nöthen, Markus M., da Silva Filho, Miguel Inacio, Thomsen, Hauke, Walker, Brian A., Broyl, Annemiek, Davies, Faith E., Hansson, Markus, Goldschmidt, Hartmut, Dyer, Martin J. S., Kaiser, Martin, Sonneveld, Pieter, Morgan, Gareth J., Hemminki, Kari, Nilsson, Björn, Catovsky, Daniel, Allan, James M., and Houlston, Richard S.

Published
2019
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10. Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

Author

Aikio, Mari, Elamaa, Harri, Vicente, David, Izzi, Valerio, Kaur, Inderjeet, Seppinen, Lotta, Speedy, Helen E., Kaminska, Dorota, Kuusisto, Sanna, Sormunen, Raija, Heljasvaara, Ritva, Jones, Emma L., Muilu, Mikko, Jauhiainen, Matti, Pihlajamäki, Jussi, Savolainen, Markku J., Shoulders, Carol C., and Pihlajaniemi, Taina

Published
2014
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12. CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients

Author

Horswell, Stuart D., Fryer, Lee G.D., Hutchison, Claire E., Zindrou, Dlear, Speedy, Helen E., Town, Margaret-M., Duncan, Emma J., Sivapackianathan, Rasheeta, Patel, Hetal N., Jones, Emma L., Braithwaite, Adam, Salm, Max P.A., Neuwirth, Claire K.Y., Potter, Elizabeth, Anderson, Jonathan R., Taylor, Kenneth M., Seed, Mary, Betteridge, D. John, Crook, Martin A., Wierzbicki, Anthony S., Scott, James, Naoumova, Rossi P., and Shoulders, Carol C.

Published
2013
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13. Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

Author

Law, Philip J., Sud, Amit, Mitchell, Jonathan S., Henrion, Marc, Orlando, Giulia, Lenive, Oleg, Broderick, Peter, Speedy, Helen E., Johnson, David C., Kaiser, Martin, Weinhold, Niels, Cooke, Rosie, Sunter, Nicola J., Jackson, Graham H., Summerfield, Geoffrey, Harris, Robert J., Pettitt, Andrew R., Allsup, David J., Carmichael, Jonathan, Bailey, James R., Pratt, Guy, Rahman, Thahira, Pepper, Chris, Fegan, Chris, von Strandmann, Elke Pogge, Engert, Andreas, Försti, Asta, Chen, Bowang, Filho, Miguel Inacio da Silva, Thomsen, Hauke, Hoffmann, Per, Noethen, Markus M., Eisele, Lewin, Jöckel, Karl-Heinz, Allan, James M., Swerdlow, Anthony J., Goldschmidt, Hartmut, Catovsky, Daniel, Morgan, Gareth J., Hemminki, Kari, and Houlston, Richard S.

Published
2017
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15. Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion

Author

Brennecke, Nicholas, Cali, Ignazio, Mok, Tze, Speedy, Helen, Consortium, Genomics England Research, Hosszu, Laszlo, Stehmann, Christiane, Cracco, Laura, Puoti, Gianfranco, Prior, Thomas, Cohen, Mark, Collins, Steven, Mead, Simon, Appleby, Brian, Brennecke, N., Cali, I., Mok, T. H., Speedy, H., Consortium, G. E. R., Hosszu, L. L. P., Stehmann, C., Cracco, L., Puoti, G., Prior, T. W., Cohen, M. L., Collins, S. J., Mead, S., and Appleby, B. S.

Subjects
Male, Prions, animal diseases, Population, prion disease, Disease, Biology, octapeptide repeat insertion, Microbiology, Asymptomatic, Article, Creutzfeldt-Jakob Syndrome, Prion Proteins, Prion Diseases, Methionine, Genetic, National Prion Clinic, Virology, mental disorders, medicine, Humans, genetics, Allele, education, Alleles, Aged, Genetic testing, Aged, 80 and over, Genetics, education.field_of_study, medicine.diagnostic_test, Brain, Middle Aged, Penetrance, QR1-502, Creutzfeldt-Jakob disease, nervous system diseases, Mutagenesis, Insertional, Infectious Diseases, Female, genetic Creutzfeldt-Jakob disease, medicine.symptom, Oligopeptides, Asymptomatic carrier
Abstract

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.

Published
2021
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17. Genome-wide association study identifies risk variants for sporadic Creutzfeldt-Jakob disease in STX6 and GAL3ST1

Author

Jones, Emma, primary, Hummerich, Holger, additional, Viré, Emmanuelle, additional, Uphill, James, additional, Dimitriadis, Athanasios, additional, Speedy, Helen, additional, Campbell, Tracy, additional, Norsworthy, Penny, additional, Quinn, Liam, additional, Whitfield, Jerome, additional, Linehan, Jacqueline, additional, Jaunmuktane, Zane, additional, Brandner, Sebastian, additional, Jat, Parmjit, additional, Nihat, Akin, additional, Mok, Tze How, additional, Ahmed, Parvin, additional, Collins, Steven, additional, Stehmann, Christiane, additional, Sarros, Shannon, additional, Kovacs, Gabor, additional, Geschwind, Michael, additional, Golubjatnikov, Aili, additional, Fronztek, Karl, additional, Budka, Herbert, additional, Aguzzi, Adriano, additional, Karamujić-Čomić, Hata, additional, van der Lee, Sven, additional, Ibrahim-Verbaas, Carla A, additional, Van Duijn, Cornelia, additional, Sikorska, Beata, additional, Golanska, Ewa, additional, Liberski, Pawel, additional, Calero, Miguel, additional, Calero, Olga, additional, Juan, Pascual Sanchez, additional, Salas, Antonio, additional, Martinón-Torres, Federico, additional, Bouaziz-Amar, Elodie, additional, Haik, Stephane, additional, Laplanche, Jean-Louis, additional, Brandel, Jean-Phillipe, additional, Amouyel, Phillipe, additional, Lambert, Jean-Charles, additional, Parchi, Piero, additional, Bartoletti-Stella, Anna, additional, Capellari, Sabina, additional, Poleggi, Anna, additional, Ladogana, Anna, additional, Pocchiari, Maurizio, additional, Aneli, Serena, additional, Matullo, Giuseppe, additional, Knight, Richard, additional, Zafar, Saima, additional, Zerr, Inga, additional, Booth, Stephanie, additional, Coulthart, Michael B, additional, Jansen, Gerard H, additional, Glisic, Katie, additional, Blevins, Janis, additional, Gambetti, Pierluigi, additional, Safar, Jiri, additional, Appleby, Brian, additional, Collinge, John, additional, and Mead, Simon, additional

Published
2020
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18. Additional file 2: of Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand, Holmes, Michael, Preiss, David, Swerdlow, Daniel, Denaxas, Spiros, Ghazaleh Fatemifar, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Zammy Fairhurst-Hunter, Hartwig, Fernando, Horta, Bernardo, Hypponen, Elina, Power, Christine, Moldovan, Max, Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Goya Wanamethee, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie, Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Andrie Panayiotou, N. Onland-Moret, Schouw, Yvonne, Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas, Langenberg, Claudia, Scott, Robert, Jian’An Luan, Bobak, Martin, Malyutina, Sofia, K, Andrzej PajÄ, Ruzena Kubinova, Abdonas Tamosiunas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve, Brilliant, Murray, Kitchner, Terrie, Hakon Hakonarson, Carrell, David, McCarty, Catherine, Kirchner Lester, Larson, Eric, Crosslin, David, Mariza Andrade, Roden, Dan, Denny, Joshua, Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O’Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Harst, Pim, M. Said, Eppinga, Ruben, Verweij, Niek, Snieder, Harold, Christen, Tim, D. Mook-Kanamori, Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Raha Pazoki, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, DĂśrr, Marcus, Lerch, Markus, VĂślker, Uwe, VĂślzke, Henry, Ward, Joey, Pell, Jill, Meade, Tom, Christophersen, Ingrid, Zee, Anke Maitland-Van Der, Baranova, Ekaterina, Young, Robin, Ford, Ian, Campbell, Archie, Sandosh Padmanabhan, Bots, Michiel, Grobbee, Diederick, Froguel, Philippe, DorothĂŠe Thuillier, Roussel, Ronan, AmĂŠlie Bonnefond, Cariou, Bertrand, Smart, Melissa, Yanchun Bao, Kumari, Meena, Anubha Mahajan, Hopewell, Jemma, Seshadri, Sudha, Dale, Caroline, Costa, Rui, Ridker, Paul, Chasman, Daniel, Reiner, Alex, Ritchie, Marylyn, Lange, Leslie, Cornish, Alex, Dobbins, Sara, Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, BjĂśrn Nilsson, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert, Riyaz Patel, Keating, Brendan, Sattar, Naveed, Houlston, Richard, Casas, Juan, and Aroon Hingorani

Abstract

Supplemental figures and study acknowledgments. (PDF 154 kb)

Published
2019
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19. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, van der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., de Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, van der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Doerr, Marcus, Lerch, Markus M., Voelker, Uwe, Voelzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-van der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothee, Roussel, Ronan, Bonnefond, Amelie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Bjorn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., Hingorani, Aroon D., Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, van der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., de Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, van der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Doerr, Marcus, Lerch, Markus M., Voelker, Uwe, Voelzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-van der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothee, Roussel, Ronan, Bonnefond, Amelie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Bjorn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., and Hingorani, Aroon D.

Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Published
2019
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20. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Planningssecretariaat HCK, Onderzoek Precision medicine, Cardiovasculaire Epi Team 3, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Brain, Cancer, Cardiovasculaire Epidemiologie, Epi Methoden Team 6, Aios en Stafsecr. Cardiologie, Cardiovasculaire Epi Team 5, Cardiovasculaire Epi Team 9, Team Medisch, Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'An, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., De Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M., Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-Van Der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., Hingorani, Aroon D., Planningssecretariaat HCK, Onderzoek Precision medicine, Cardiovasculaire Epi Team 3, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Brain, Cancer, Cardiovasculaire Epidemiologie, Epi Methoden Team 6, Aios en Stafsecr. Cardiologie, Cardiovasculaire Epi Team 5, Cardiovasculaire Epi Team 9, Team Medisch, Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'An, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., De Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M., Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-Van Der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., and Hingorani, Aroon D.

Published
2019

21. Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Author

Went, Molly, Sud, Amit, Speedy, Helen, Sunter, Nicola J., Försti, Asta, Law, Philip J., Johnson, David C., Mirabella, Fabio, Holroyd, Amy, Li, Ni, Orlando, Giulia, Weinhold, Niels, van Duin, Mark, Chen, Bowang, Mitchell, Jonathan S., Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Rosenquist, Richard, Kuiper, Rowan, Stephens, Owen W., Bertsch, Uta, Broderick, Peter, Einsele, Hermann, Gregory, Walter M., Hillengass, Jens, Hoffmann, Per, Jackson, Graham H., Jöckel, Karl-Heinz, Nickel, Jolanta, Nöthen, Markus M., da Silva Filho, Miguel Inacio, Thomsen, Hauke, Walker, Brian A., Broyl, Annemiek, Davies, Faith E., Hansson, Markus, Goldschmidt, Hartmut, Dyer, Martin J. S., Kaiser, Martin, Sonneveld, Pieter, Morgan, Gareth J., Hemminki, Kari, Nilsson, Björn, Catovsky, Daniel, Allan, James M., Houlston, Richard S., and Hematology

Subjects
Cancer och onkologi, Genetic Linkage, Quantitative Trait Loci, Medizin, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Leukemia, Lymphocytic, Chronic, B-Cell, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Organ Specificity, Cancer and Oncology, hemic and lymphatic diseases, Case-Control Studies, Databases, Genetic, Humans, Genetic Predisposition to Disease, Hematologi, Multiple Myeloma, Alleles, Genetic Association Studies, Genome-Wide Association Study
Abstract

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Published
2018

23. Abstract 906: COSMIC: Describing the world’s knowledge of somatic mutations in cancer

Author

Forbes, Simon Andrew, primary, beare, david, additional, boutselakis, charalampos, additional, bamford, sally, additional, noble, kate, additional, rye, claire, additional, tate, john, additional, kok, chai yin, additional, hathaway, charlie, additional, ponting, laura, additional, ramshaw, christopher, additional, stefancsik, raymund, additional, thompson, samantha, additional, harsha, bhavana, additional, bindal, nidhi, additional, wang, shicai, additional, jupe, steven, additional, speedy, helen, additional, creatore, celestino, additional, fish, peter, additional, ward, sari, additional, cole, charlotte, additional, dawson, elisabeth, additional, and sondka, zbyslaw, additional

Published
2019
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24. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Law, Philip J, Berndt, Sonja I, Speedy, Helen E, Camp, Nicola J, Sava, Georgina P, Skibola, Christine F, Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J, Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R, Clot, Guillem, Teras, Lauren R, Quintela, Inés, Birmann, Brenda M, Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E, Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G, Purdue, Mark P, Mainou-Fowler, Tryfonia, Vajdic, Claire M, Jackson, Graham H, Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G, Lawrence, Charles, Call, Timothy G, Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W Ryan, Link, Brian K, Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C H, Southey, Melissa C, Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J, Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M, Harris, Robert J, Miligi, Lucia, Pettitt, Andrew R, North, Kari E, Allsup, David J, Fraumeni, Joseph F, Bailey, James R, Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Christopher, Chanock, Stephen J, Fegan, Chris, Rosenquist, Richard, de Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J S, Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M, Rothman, Nathanial, Houlston, Richard, Slager, Susan, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], Department of Physics, Loyola College, Nungambakkam, Chennai – 600 034, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Aleppo [Aleppo], Sea Mammal Research Unit [University of St Andrews] (SMRU), School of Biology [University of St Andrews], University of St Andrews [Scotland]-University of St Andrews [Scotland]-Natural Environment Research Council (NERC), Department of Chemical Engineering, Imperial College London, De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), The Cancer Council Victoria, University of Oulu, Uppsala Universitet [Uppsala], Université Paris Nanterre (UPN), University of Iowa [Iowa City], Registre des hémopathies malignes de Côte d'Or, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), B.B. Brodie Department of Neuroscience, Pennsylvania State University (Penn State), Penn State System, University of Newcastle [Australia] (UoN), Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Department of Haematology, School of Medicine, Cardiff University, CIBER de Enfermedades Raras (CIBERER), University of Leeds, Haemato-oncology, Institute of cancer research, Mayo Clinic [Rochester], Northern Institute for Cancer Research [Newcastle] (NICR), Newcastle University [Newcastle], Institute of Cancer Research, Belmont, Sutton, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Sea Mammal Research Unit, Scottish Oceans Institute, University of St Andrews [Scotland], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Cardiff, Équipe Instrumentation embarquée et systèmes de surveillance intelligents (LAAS-S4M), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), University of Newcastle [Callaghan, Australia] (UoN), Astrophysique Interprétation Modélisation (AIM (UMR7158 / UMR_E_9005 / UM_112)), LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Adult, Male, RM, Cancer och onkologi, B-Lymphocytes, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Science, Chromosome Mapping, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, Polymorphism, Single Nucleotide, Article, Young Adult, Cancer and Oncology, Case-Control Studies, Antibody Formation, Chromosomes, Human, Humans, Female, Genetic Predisposition to Disease, RC, Genome-Wide Association Study
Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response., Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

Published
2017
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25. COSMIC: the Catalogue Of Somatic Mutations In Cancer

Author

Tate, John G, primary, Bamford, Sally, additional, Jubb, Harry C, additional, Sondka, Zbyslaw, additional, Beare, David M, additional, Bindal, Nidhi, additional, Boutselakis, Harry, additional, Cole, Charlotte G, additional, Creatore, Celestino, additional, Dawson, Elisabeth, additional, Fish, Peter, additional, Harsha, Bhavana, additional, Hathaway, Charlie, additional, Jupe, Steve C, additional, Kok, Chai Yin, additional, Noble, Kate, additional, Ponting, Laura, additional, Ramshaw, Christopher C, additional, Rye, Claire E, additional, Speedy, Helen E, additional, Stefancsik, Ray, additional, Thompson, Sam L, additional, Wang, Shicai, additional, Ward, Sari, additional, Campbell, Peter J, additional, and Forbes, Simon A, additional

Published
2018
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26. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand F, primary, Holmes, Michael V, additional, Preiss, David, additional, Swerdlow, Daniel, additional, Denaxas, Spiros, additional, Fatemifar, Ghazaleh, additional, Faraway, Rupert, additional, Finan, Chris, additional, Lumbers, Tom, additional, Henry, Albert, additional, Valentine, Dennis, additional, Fairhurst-Hunter, Zammy, additional, Hartwig, Fernando Pires, additional, Horta, Bernardo Lessa, additional, Hypponen, Elina, additional, Power, Christine, additional, Moldovan, Max, additional, van Iperen, Erik, additional, Hovingh, Kees, additional, Demuth, Ilja, additional, Norman, Kristina, additional, Steinhagen-Thiessen, Elisabeth, additional, Demuth, Juri, additional, Bertram, Lars, additional, Lill, Christina M, additional, Coassin, Stefan, additional, Willeit, Johann, additional, Kiechl, Stefan, additional, Willeit, Karin, additional, Mason, Dan, additional, Wright, John, additional, Morris, Richard, additional, Wanamethee, Goya, additional, Whincup, Peter, additional, Ben-Shlomo, Yoav, additional, McLachlan, Stela, additional, Price, Jackie F., additional, Kivimaki, Mika, additional, Welch, Catherine, additional, Sanchez-Galvez, Adelaida, additional, Marques-Vidal, Pedro, additional, Nicolaides, Andrew, additional, Panayiotou, Andrie G., additional, Onland-Moret, N. Charlotte, additional, van der Schouw, Yvonne T., additional, Matullo, Giuseppe, additional, Fiorito, Giovanni, additional, Guarrera, Simonetta, additional, Sacerdote, Carlotta, additional, Wareham, Nicholas J, additional, Langenberg, Claudia, additional, Scott, Robert A, additional, Luan, Jian’an, additional, Bobak, Martin, additional, Malyutina, Sofia, additional, Pajak, Andrzej, additional, Kubinova, Ruzena, additional, Tamosiunas, Abdonas, additional, Pikhart, Hynek, additional, Grarup, Niels, additional, Pedersen, Oluf, additional, Hansen, Torben, additional, Linneberg, Allan, additional, Jess, Tine, additional, Cooper, Jackie, additional, Humphries, Steve E, additional, Brilliant, Murray, additional, Kitchner, Terrie, additional, Hakonarson, Hakon, additional, Carrell, David S., additional, McCarty, Catherine A., additional, Lester, Kirchner H, additional, Larson, Eric B., additional, Crosslin, David R., additional, Andrade, Mariza de, additional, Roden, Dan M, additional, Denny, Joshua C, additional, Carty, Cara, additional, Hancock, Stephen, additional, Attia, John, additional, Holliday, Elizabeth, additional, Scott, Rodney, additional, Schofield, Peter, additional, O’Donnell, Martin, additional, Yusuf, Salim, additional, Chong, Michael, additional, Pare, Guillaume, additional, van der Harst, Pim, additional, Said, M. Abdullah, additional, Eppinga, Ruben N., additional, Verweij, Niek, additional, Snieder, Harold, additional, Christen, Tim, additional, Mook-Kanamori, D.O., additional, Gustafsson, Stefan, additional, Lind, Lars, additional, Ingelsson, Erik, additional, Pazoki, Raha, additional, Franco, Oscar, additional, Hofman, Albert, additional, Uitterlinden, Andre, additional, Dehghan, Abbas, additional, Teumer, Alexander, additional, Baumeister, Sebastian, additional, Dörr, Marcus, additional, Lerch, Markus M., additional, Völker, Uwe, additional, Völzke, Henry, additional, Ward, Joey, additional, Pell, Jill P, additional, Meade, Tom, additional, Christophersen, Ingrid E., additional, Maitland-van der Zee, Anke H., additional, Baranova, Ekaterina V., additional, Young, Robin, additional, Ford, Ian, additional, Campbell, Archie, additional, Padmanabhan, Sandosh, additional, Bots, Michiel L, additional, Grobbee, Diederick E., additional, Froguel, Philippe, additional, Thuillier, Dorothée, additional, Roussel, Ronan, additional, Bonnefond, Amelie, additional, Cariou, Bertrand, additional, Smart, Melissa, additional, Bao, Yanchun, additional, Kumari, Meena, additional, Mahajan, Anubha, additional, Hopewell, Jemma C., additional, Seshadri, Sudha, additional, Dale, Caroline, additional, Costa, Rui Providencia E, additional, Ridker, Paul M, additional, Chasman, Daniel I., additional, Reiner, Alex P., additional, Ritchie, Marylyn D, additional, Lange, Leslie A, additional, Cornish, Alex J., additional, Dobbins, Sara E., additional, Hemminki, Kari, additional, Kinnersley, Ben, additional, Sanson, Marc, additional, Labreche, Karim, additional, Simon, Matthias, additional, Bondy, Melissa, additional, Law, Philip, additional, Speedy, Helen, additional, Allan, James, additional, Li, Ni, additional, Went, Molly, additional, Weinhold, Niels, additional, Morgan, Gareth, additional, Sonneveld, Pieter, additional, Nilsson, Björn, additional, Goldschmidt, Hartmut, additional, Sud, Amit, additional, Engert, Andreas, additional, Hansson, Markus, additional, Hemingway, Harry, additional, Asselbergs, Folkert W, additional, Patel, Riyaz S, additional, Keating, Brendan J, additional, Sattar, Naveed, additional, Houlston, Richard, additional, Casas, Juan P, additional, and Hingorani, Aroon D, additional

Published
2018
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27. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Law, Phillip J., Berndt, Sonja I., Speedy, Helen E., Camp, Nicola J., Sava, Georgina P., Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J., Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R., Clot, Guillem, Teras, Lauren R., Quintela, Ines, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E., Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G., Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H., Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C. H., Southey, Melissa C., Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J., Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M., Harris, Robert J., Miligi, Lucia, Pettitt, Andrew R., North, Kari E., Allsup, David J., Fraumeni, Joseph F., Jr., Bailey, James R., Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, de Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J. S., Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M., Rothman, Nathanial, Houlston, Richard, Slager, Susan L., Law, Phillip J., Berndt, Sonja I., Speedy, Helen E., Camp, Nicola J., Sava, Georgina P., Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J., Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R., Clot, Guillem, Teras, Lauren R., Quintela, Ines, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E., Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G., Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H., Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C. H., Southey, Melissa C., Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J., Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M., Harris, Robert J., Miligi, Lucia, Pettitt, Andrew R., North, Kari E., Allsup, David J., Fraumeni, Joseph F., Jr., Bailey, James R., Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, de Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J. S., Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M., Rothman, Nathanial, Houlston, Richard, and Slager, Susan L.

Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P = 5.04 X 10 (-) (13)), 1q42.13 (rs41271473, P = 1.06 X 10 (-) (10)), 4q24 (rs71597109, P = 1.37 X 10 (-) (10)), 4q35.1 (rs57214277, P = 3.69 X 10 (-) (8)), 6p21.31 (rs3800461, P = 1.97 X 10 (-) (8)), 11q23.2 (rs61904987, P = 2.64 X 10 (-) (11)), 18q21.1 (rs1036935, P = 3.27 X 10 (-) (8)), 19p13.3 (rs7254272, P = 4.67 X 10 (-) (8)) and 22q13.33 (rs140522, P = 2.70 X 10 (-) (9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

Published
2017
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28. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, Law, Philip J, Berndt, Sonja I., Speedy, Helen E, Camp, Nicola J, Sava, Georgina P, Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J, Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R, Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E, Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G, Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H, Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E, Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C H, Southey, Melissa C., Milne, Roger L, Clavel, Jacqueline, Topka, Sabine, Spinelli, John, Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M, Harris, Robert J, Miligi, Lucia, Pettitt, Andrew R, North, Kari E., Allsup, David J, Fraumeni, Joseph F., Bailey, James R, Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, De Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J S, Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M, Rothman, Nathanial, Houlston, Richard S, Slager, Susan L., LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, Law, Philip J, Berndt, Sonja I., Speedy, Helen E, Camp, Nicola J, Sava, Georgina P, Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J, Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R, Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E, Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G, Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H, Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E, Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C H, Southey, Melissa C., Milne, Roger L, Clavel, Jacqueline, Topka, Sabine, Spinelli, John, Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M, Harris, Robert J, Miligi, Lucia, Pettitt, Andrew R, North, Kari E., Allsup, David J, Fraumeni, Joseph F., Bailey, James R, Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, De Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J S, Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M, Rothman, Nathanial, Houlston, Richard S, and Slager, Susan L.

Published
2017

29. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Law, Philip J., Berndt, Sonja I., Speedy, Helen E., Camp, Nicola J., Sava, Georgina P., Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J., Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R., Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E., Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G., Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H., Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C.H., Southey, Melissa C., Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J., Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M., Harris, Robert J., Miligi, Lucia, Pettitt, Andrew R., North, Kari E., Allsup, David J., Fraumeni, Joseph F., Bailey, James R., Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, De Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J.S., Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M., Rothman, Nathanial, Houlston, Richard, Slager, Susan, Law, Philip J., Berndt, Sonja I., Speedy, Helen E., Camp, Nicola J., Sava, Georgina P., Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J., Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R., Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E., Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G., Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H., Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C.H., Southey, Melissa C., Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J., Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M., Harris, Robert J., Miligi, Lucia, Pettitt, Andrew R., North, Kari E., Allsup, David J., Fraumeni, Joseph F., Bailey, James R., Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, De Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J.S., Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M., Rothman, Nathanial, Houlston, Richard, and Slager, Susan

Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10 -10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

Published
2017

30. Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

Author

Jäger, Roland, Migliorini, Gabriele, Henrion, Marc, Kandaswamy, Radhika, Speedy, Helen E, Heindl, Andreas, Whiffin, Nicola, Carnicer, Maria J, Broome, Laura, Dryden, Nicola, Nagano, Takashi, Schoenfelder, Stefan, Enge, Martin, Yuan, Yinyin, Taipale, Jussi, Fraser, Peter, Fletcher, Olivia, Houlston, Richard S, Schoenfelder, Stefan [0000-0002-3200-8133], and Apollo - University of Cambridge Repository

Subjects
Genetic Loci, Risk Factors, Cell Line, Tumor, Statistics as Topic, Humans, Genetic Predisposition to Disease, Molecular Sequence Annotation, Nucleotide Motifs, Colorectal Neoplasms, Base Pairing, Chromatin, In Situ Hybridization, Fluorescence, Chromosomes, Human, Pair 8
Abstract

Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci.

Published
2015
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31. COSMIC: the Catalogue Of Somatic Mutations In Cancer.

Author

Tate, John G, Bamford, Sally, Jubb, Harry C, Sondka, Zbyslaw, Beare, David M, Bindal, Nidhi, Boutselakis, Harry, Cole, Charlotte G, Creatore, Celestino, Dawson, Elisabeth, Fish, Peter, Harsha, Bhavana, Hathaway, Charlie, Jupe, Steve C, Kok, Chai Yin, Noble, Kate, Ponting, Laura, Ramshaw, Christopher C, Rye, Claire E, and Speedy, Helen E

Published
2019
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32. Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism

Author

Kandaswamy, Radhika, primary, Sava, Georgina P., additional, Speedy, Helen E., additional, Beà, Sílvia, additional, Martín-Subero, José I., additional, Studd, James B., additional, Migliorini, Gabriele, additional, Law, Philip J., additional, Puente, Xose S., additional, Martín-García, David, additional, Salaverria, Itziar, additional, Gutiérrez-Abril, Jesús, additional, López-Otín, Carlos, additional, Catovsky, Daniel, additional, Allan, James M., additional, Campo, Elías, additional, and Houlston, Richard S., additional

Published
2016
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33. Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

Author

Jäger, Roland, primary, Migliorini, Gabriele, additional, Henrion, Marc, additional, Kandaswamy, Radhika, additional, Speedy, Helen E., additional, Heindl, Andreas, additional, Whiffin, Nicola, additional, Carnicer, Maria J., additional, Broome, Laura, additional, Dryden, Nicola, additional, Nagano, Takashi, additional, Schoenfelder, Stefan, additional, Enge, Martin, additional, Yuan, Yinyin, additional, Taipale, Jussi, additional, Fraser, Peter, additional, Fletcher, Olivia, additional, and Houlston, Richard S., additional

Published
2015
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34. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia

Author

Speedy, Helen E., Di Bernardo, Maria Chiara, Sava, Georgina P., Dyer, Martin J. S., Holroyd, Amy, Wang, Yufei, Sunter, Nicola J., Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E., Roos, Groan, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Hall, Andrew G., Mainou-Fowler, Tryfonia, Jackson, Graham H., Summerfield, Geoffrey, Harris, Robert J., Pettitt, Andrew R., Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Rosenquist, Richard, Catovsky, Daniel, Allan, James M., Houlston, Richard S., Speedy, Helen E., Di Bernardo, Maria Chiara, Sava, Georgina P., Dyer, Martin J. S., Holroyd, Amy, Wang, Yufei, Sunter, Nicola J., Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E., Roos, Groan, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Hall, Andrew G., Mainou-Fowler, Tryfonia, Jackson, Graham H., Summerfield, Geoffrey, Harris, Robert J., Pettitt, Andrew R., Allsup, David J., Bailey, James R., Pratt, Guy, Pepper, Chris, Fegan, Chris, Rosenquist, Richard, Catovsky, Daniel, Allan, James M., and Houlston, Richard S.

Abstract

Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 x 10(-9)), 4q26 (rs6858698, P = 3.07 x 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 x 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 x 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 x 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 x 10(-10)) and 8q22.3 (rs2511714, P = 2.90 x 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

Published
2014
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35. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia

Author

Speedy, Helen E, primary, Di Bernardo, Maria Chiara, additional, Sava, Georgina P, additional, Dyer, Martin J S, additional, Holroyd, Amy, additional, Wang, Yufei, additional, Sunter, Nicola J, additional, Mansouri, Larry, additional, Juliusson, Gunnar, additional, Smedby, Karin E, additional, Roos, Göran, additional, Jayne, Sandrine, additional, Majid, Aneela, additional, Dearden, Claire, additional, Hall, Andrew G, additional, Mainou-Fowler, Tryfonia, additional, Jackson, Graham H, additional, Summerfield, Geoffrey, additional, Harris, Robert J, additional, Pettitt, Andrew R, additional, Allsup, David J, additional, Bailey, James R, additional, Pratt, Guy, additional, Pepper, Chris, additional, Fegan, Chris, additional, Rosenquist, Richard, additional, Catovsky, Daniel, additional, Allan, James M, additional, and Houlston, Richard S, additional

Published
2013
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38. Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMFSuper-Enhancer Polymorphism

Author

Kandaswamy, Radhika, Sava, Georgina P., Speedy, Helen E., Beà, Sílvia, Martín-Subero, José I., Studd, James B., Migliorini, Gabriele, Law, Philip J., Puente, Xose S., Martín-García, David, Salaverria, Itziar, Gutiérrez-Abril, Jesús, López-Otín, Carlos, Catovsky, Daniel, Allan, James M., Campo, Elías, and Houlston, Richard S.

Abstract

Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10−13, odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMFexpression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMFexpression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.

Published
2016
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39. Candidate gene association studies and risk of chronic lymphocytic leukemia: a systematic review and meta-analysis.

Author

Sava, Georgina P., Speedy, Helen E., and Houlston, Richard S.

Subjects
*CHRONIC lymphocytic leukemia, *GENETIC polymorphisms, *HUMAN genetic variation, *LINKAGE disequilibrium, *META-analysis, *ALLELES, *CANCER risk factors
Abstract

To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to chronic lymphocytic leukemia (CLL), we conducted a systematic review and meta-analysis of published case-control studies. We identified 36 studies which reported on polymorphic variation in 19 genes and CLL risk. Out of the 23 polymorphic variants, significant associations ( p < 0.05) were seen in pooled analyses for only four variants: MDR1, rs1045642; LTA, rs2239704; CD38, rs6449182; and IFNGR1, rs4896243. These findings should be interpreted cautiously, as the estimated false positive report probabilities (FPRPs) for each association were not noteworthy (i.e. FPRP > 0.2). While studies of candidate polymorphisms may be an attractive means of identifying risk factors for CLL, the limited power of published studies to demonstrate statistically significant associations makes it essential that future analyses be based on sample sizes well-powered to identify variants having modest effects on CLL risk. [ABSTRACT FROM AUTHOR]

Published
2014
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40. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.

Author

Speedy, Helen E, Di Bernardo, Maria Chiara, Sava, Georgina P, Dyer, Martin J S, Holroyd, Amy, Wang, Yufei, Sunter, Nicola J, Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E, Roos, Göran, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Hall, Andrew G, Mainou-Fowler, Tryfonia, Jackson, Graham H, Summerfield, Geoffrey, Harris, Robert J, and Pettitt, Andrew R

Subjects
*GENOMES, *DISEASE susceptibility, *CHRONIC lymphocytic leukemia, *HUMAN genetic variation, *META-analysis, *RISK assessment, *GENETICS
Abstract

Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10−9), 4q26 (rs6858698, P = 3.07 × 10−9), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10−10) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10−8). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10−7) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10−10) and 8q22.3 (rs2511714, P = 2.90 × 10−9). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL. [ABSTRACT FROM AUTHOR]

Published
2014
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41. CDKN2Bexpression in adipose tissue of familial combined hyperlipidemia patients[S]

Author

Horswell, Stuart D., Fryer, Lee G.D., Hutchison, Claire E., Zindrou, Dlear, Speedy, Helen E., Town, Margaret-M., Duncan, Emma J., Sivapackianathan, Rasheeta, Patel, Hetal N., Jones, Emma L., Braithwaite, Adam, Salm, Max P.A., Neuwirth, Claire K.Y., Potter, Elizabeth, Anderson, Jonathan R., Taylor, Kenneth M., Seed, Mary, Betteridge, D. John, Crook, Martin A., Wierzbicki, Anthony S., Scott, James, Naoumova, Rossi P., and Shoulders, Carol C.

Abstract

The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2Bwere increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2Bknockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B3′UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2BmRNA in the MuTHERadipose tissue dataset, family studies suggest the association between increased CDKN2Bexpression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis.

Published
2013
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42. Genome wide association study of clinical duration and age at onset of sporadic CJD.

Author

Hummerich H, Speedy H, Campbell T, Darwent L, Hill E, Collins S, Stehmann C, Kovacs GG, Geschwind MD, Frontzek K, Budka H, Gelpi E, Aguzzi A, van der Lee SJ, van Duijn CM, Liberski PP, Calero M, Sanchez-Juan P, Bouaziz-Amar E, Laplanche JL, Haïk S, Brandel JP, Mammana A, Capellari S, Poleggi A, Ladogana A, Pocchiari M, Zafar S, Booth S, Jansen GH, Areškevičiūtė A, Løbner Lund E, Glisic K, Parchi P, Hermann P, Zerr I, Appleby BS, Safar J, Gambetti P, Collinge J, and Mead S

Subjects
Humans, Aged, Middle Aged, Female, Male, Phenotype, Genotype, Creutzfeldt-Jakob Syndrome genetics, Creutzfeldt-Jakob Syndrome pathology, Age of Onset, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci., Competing Interests: Stéphane Haik reports grants from Santé Publique France, during the conduct of the study; grants from LFB Biomedicaments, grants from Institut de Recherche Servier, grants from MedDay Pharmaceuticals, outside the submitted work; In addition, Stéphane Haik has a patent Method for treating prion diseases (PCT/EP2019/070457) pending. Brian Appleby has received funding from CDC, NIH, CJD Foundation, Alector, and Ionis. He has served as a consultant for Ionis, Sangamo, and Gate Biosciences. He has received royalties from Wolter Kluwers. Karl Fronztek reports grants from Ono Pharmaceuticals outside the submitted work. Simon Mead reports grants from Medical Research Council (UK) and grants from National Institute of Health Research’s Biomedical Research Centre at University College London Hospitals NHS Foundation Trust during the conduct of the study. Gabor G Kovacs reports personal fees from Biogen, outside the submitted work. John Collinge reports grants from Medical Research Council, grants from NIHR UCLH Biomedical Research Centre, during the conduct of the study; and is a Director and shareholder of D-Gen Limited, an academic spinout in the field of prion disease diagnostics, decontamination and therapeutics. Inga Zerr reports grants from the Bundesministerium für Gesundheit via Robert Koch institute, JPND and personal fees (not related to the content of the manuscript) from Ferring Pharmaceuticals and IONIS, speaking honoraria for medical lectures from Lilly, Biogen, Medfora, DGLN (German Society for cerebrospinal fluid diagnostics in Neurology). Maurizio Pocchiari reports personal fees from Ferring Pharmaceuticals, personal fees from CNCCS (Collection of National Chemical Compounds and Screening Center), non-financial support from Fondazione Cellule Staminali, outside the submitted work. Michael D Geschwind has consulted for3D Communications, Adept Field Consulting, Advanced Medical Inc., Best Doctors Inc., Second Opinion Inc., Gerson Lehrman Group Inc., Guidepoint Global LLC, InThought Consulting Inc., Market Plus, Trinity Partners LLC, Biohaven Pharmaceuticals, Quest Diagnostics and various medical-legal consulting. He has received speaking honoraria for various medical center lectures and from Oakstone publishing. He has received past research support from Alliance Biosecure, CurePSP, the Tau Consortium, and Quest Diagnostics. Michael D Geschwind serves on the board of directors for San Francisco Bay Area Physicians for Social Responsibility and on the editorial board of Dementia & Neuropsychologia., (Copyright: © 2024 Hummerich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2024
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43. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

Author

Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, and Hingorani AD

Subjects
Anticholesteremic Agents adverse effects, Biomarkers blood, Brain Ischemia epidemiology, Brain Ischemia prevention & control, Down-Regulation, Dyslipidemias blood, Dyslipidemias epidemiology, Genome-Wide Association Study, Humans, Myocardial Infarction epidemiology, Myocardial Infarction prevention & control, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Serine Proteinase Inhibitors adverse effects, Stroke epidemiology, Stroke prevention & control, Treatment Outcome, Anticholesteremic Agents therapeutic use, Cholesterol, LDL blood, Dyslipidemias drug therapy, Dyslipidemias genetics, PCSK9 Inhibitors, Polymorphism, Single Nucleotide, Proprotein Convertase 9 genetics, Serine Proteinase Inhibitors therapeutic use
Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9., Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration., Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable., Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Published
2019
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44. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

Author

Law PJ, Berndt SI, Speedy HE, Camp NJ, Sava GP, Skibola CF, Holroyd A, Joseph V, Sunter NJ, Nieters A, Bea S, Monnereau A, Martin-Garcia D, Goldin LR, Clot G, Teras LR, Quintela I, Birmann BM, Jayne S, Cozen W, Majid A, Smedby KE, Lan Q, Dearden C, Brooks-Wilson AR, Hall AG, Purdue MP, Mainou-Fowler T, Vajdic CM, Jackson GH, Cocco P, Marr H, Zhang Y, Zheng T, Giles GG, Lawrence C, Call TG, Liebow M, Melbye M, Glimelius B, Mansouri L, Glenn M, Curtin K, Diver WR, Link BK, Conde L, Bracci PM, Holly EA, Jackson RD, Tinker LF, Benavente Y, Boffetta P, Brennan P, Maynadie M, McKay J, Albanes D, Weinstein S, Wang Z, Caporaso NE, Morton LM, Severson RK, Riboli E, Vineis P, Vermeulen RC, Southey MC, Milne RL, Clavel J, Topka S, Spinelli JJ, Kraft P, Ennas MG, Summerfield G, Ferri GM, Harris RJ, Miligi L, Pettitt AR, North KE, Allsup DJ, Fraumeni JF, Bailey JR, Offit K, Pratt G, Hjalgrim H, Pepper C, Chanock SJ, Fegan C, Rosenquist R, de Sanjose S, Carracedo A, Dyer MJ, Catovsky D, Campo E, Cerhan JR, Allan JM, Rothman N, Houlston R, and Slager S

Subjects
Adult, B-Lymphocytes immunology, B-Lymphocytes physiology, Case-Control Studies, Chromosome Mapping, Female, Genome-Wide Association Study, Humans, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Antibody Formation genetics, Chromosomes, Human genetics, Genetic Predisposition to Disease, Leukemia, Lymphocytic, Chronic, B-Cell genetics
Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10 -13 ), 1q42.13 (rs41271473, P=1.06 × 10 -10 ), 4q24 (rs71597109, P=1.37 × 10 -10 ), 4q35.1 (rs57214277, P=3.69 × 10 -8 ), 6p21.31 (rs3800461, P=1.97 × 10 -8 ), 11q23.2 (rs61904987, P=2.64 × 10 -11 ), 18q21.1 (rs1036935, P=3.27 × 10 -8 ), 19p13.3 (rs7254272, P=4.67 × 10 -8 ) and 22q13.33 (rs140522, P=2.70 × 10 -9 ). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response., Competing Interests: The authors declare no competing financial interests.

Published
2017
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