20 results on '"Crisp Hihn, A"'
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2. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
- Author
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Dixon, Peter H., Levine, Adam P., Cebola, Inês, Chan, Melanie M. Y., Amin, Aliya S., Aich, Anshul, Mozere, Monika, Maude, Hannah, Mitchell, Alice L., Zhang, Jun, Adlard, Julian, Ahmed, Munaza, Aitman, Tim, Alachkar, Hana, Allsup, David, Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Astle, William, Attwood, Anthony, Babbs, Chris, Bakchoul, Tamam, Bariana, Tadbir, Barwell, Julian, Bennett, David, Bentley, David, Bierzynska, Agnieszka, Biss, Tina, Bleda, Marta, Bogaard, Harm, Bourne, Christian, Boyce, Sara, Bradley, John, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Michael, Buchan, Rachel, Buckland, Matthew, Bueser, Teofila, Burns, Siobhan, Burren, Oliver, Calleja, Paul, Carr-White, Gerald, Carss, Keren, Casey, Ruth, Caulfield, Mark, Chambers, John, Chambers, Jennifer, Cheng, Floria, Chinnery, Patrick F., Christian, Martin, Church, Colin, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor, Collins, Janine, Collins, Peter, Colombo, Camilla, Condliffe, Robin, Cook, Stuart, Cook, Terry, Cooper, Nichola, Corris, Paul, Crisp-Hihn, Abigail, Curry, Nicola, Danesino, Cesare, Daniels, Matthew, Daugherty, Louise, Davis, John, Deevi, Sri V. V., Dent, Timothy, Dewhurst, Eleanor, Dixon, Peter, Downes, Kate, Drazyk, Anna, Drewe, Elizabeth, Dutt, Tina, Edgar, David, Edwards, Karen, Egner, William, Erber, Wendy, Erwood, Marie, Estiu, Maria C., Evans, Gillian, Evans, Dafydd Gareth, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Fletcher, Debra, Fox, James, Frary, Amy, French, Courtney, Freson, Kathleen, Frontini, Mattia, Gale, Daniel, Gall, Henning, Geoghegan, Claire, Gerighty, Terry, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, Simon, Gilmour, Kimberley, Girerd, Barbara, Goddard, Sarah, Gomez, Keith, Gordins, Pavels, Gosal, David, Gräf, Stefan, Grassi, Luigi, Greene, Daniel, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell, Grozeva, Detelina, Hackett, Scott, Hadinnapola, Charaka, Hague, William, Haimel, Matthias, Hall, Matthew, Hanson, Helen, Harkness, Kirsty, Harper, Andrew, Harris, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Hoffmann, Jonathan, Horvath, Rita, Houweling, Arjan, Howard, Luke, Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud, Humbert, Marc, Humphray, Sean, Hunter, Sarah, Hurles, Matthew, Izatt, Louise, James, Roger, Johnson, Sally, Jolles, Stephen, Jolley, Jennifer, Jurkute, Neringa, Kasanicki, Mary, Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kiely, David, Kingston, Nathalie, Klima, Robert, Kostadima, Myrto, Kovacs, Gabor, Koziell, Ania, Kreuzhuber, Roman, Kuijpers, Taco, Kumar, Ajith, Kumararatne, Dinakantha, Kuria, Manju, Laffa, Michael, Lalloo, Fiona, Lamber, Michele, Alle, Hana Lango, Lawrie, Allan, Layton, Mark, Lentaigne, Claire, Levine, Adam, Linger, Rachel, Longhurst, Hilary, Louka, Eleni, Ross, Robert MacKenzie, Madan, Bella, Maher, Eamonn, Maimaris, Jesmeen, Mangles, Sarah, Mapeta, Rutendo, Marchbank, Kevin, Marks, Stephen, Markus, Hugh S., Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark, Meacham, Stuart, Mead, Adam, Megy, Karyn, Mehta, Sarju, Michaelides, Michel, Millar, Carolyn, Moledina, Shahin, Montani, David, Moor, Tony, Morrell, Nicholas, Muir, Keith, Mumford, Andrew, Newnham, Michael, O'Sullivan, Jennifer, Obaji, Samya, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Ormondroy, Elizabeth, Ouwehan, Willem, Papadi, Sofia, Park, Soo-Mi, Parry, David, Paterson, Joan, Peacock, Andrew, Peden, John, Peerlinck, Kathelijne, Penkett, Christopher, Pepke-Zaba, Joanna, Petersen, Romina, Pyle, Angela, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthew, Paula, Rees, Christine, Rendon, Augusto, Renton, Tara, Rice, Andrew, Richardson, Sylvia, Richter, Alex, Roberts, Irene, Roughley, Catherine, Roy, Noemi, Sadeghi-Alavijeh, Omid, Saleem, Moin, Samani, Nilesh, Sanchis-Juan, Alba, Sargur, Ravishankar, Satchell, Simon, Savic, Sinisa, Scelsi, Laura, Schulman, Sol, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, Carrock, Seyres, Denis, Shapiro, Susie, Sharmardina, Olga, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael, Sivapalaratnam, Suthesh, Skytte, Anne-Bine, Smith, Katherine, Smith, Kenneth G. C., Snape, Katie, Soubrier, Florent, Staines, Simon, Staples, Emily, Stark, Hannah, Stephens, Jonathan, Stirrups, Kathleen, Stock, Sophie, Suntharalingam, Jay, Swietlik, Emilia, Tait, R. Campbell, Talks, Kate, Tan, Rhea, Thaventhiran, James, Themistocleous, Andreas, Thomas, Moira, Thomson, Kate, Thrasher, Adrian, Thys, Chantal, Tischkowitz, Marc, Titterton, Catherine, Toh, Cheng-Hock, Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Trembath, Richard, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Vale, Tom, Van Geet, Chris, Van Zuydam, Natalie, Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Waisfisz, Quintin, Walker, Suellen, Ware, James, Watkins, Hugh, Watt, Christopher, Webster, Andrew, Wei, Wei, Welch, Steven, Wessels, Julie, Westbury, Sarah, Westwood, John-Paul, Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Wong, Edwin, Wood, Nicholas, Wood, Yvette, Woods, Geoff, Woodward, Emma, Wort, Stephen, Worth, Austen, Yates, Katherine, Yong, Patrick, Young, Tim, Yu, Ping, Yu-Wai-Man, Patrick, Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M. A., Caulfield, M. J., Chan, G. C., Fowler, T., Giess, A., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O'Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Chambers, Jenny, Syngelaki, Argyro, Donnelly, Jennifer, Cooley, Sharon, Geary, Michael, Nicolaides, Kypros, Thorsell, Malin, Hague, William M., Estiu, Maria Cecilia, Marschall, Hanns-Ulrich, Gale, Daniel P., Williamson, Catherine, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Pediatrics, Foundation for the National Institutes of Health (FNIH), The Academy of Medical Sciences, British Heart Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Paediatric Infectious Diseases / Rheumatology / Immunology, and ARD - Amsterdam Reproduction and Development
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VARIANT ,LOCI ,INTEGRATIVE ANALYSIS ,General Physics and Astronomy ,Cholestasis, Intrahepatic ,TRIGLYCERIDE LEVELS ,DISEASE ,General Biochemistry, Genetics and Molecular Biology ,Bile Acids and Salts ,Pregnancy ,Humans ,MUTATION ,Science & Technology ,Multidisciplinary ,Genomics England Research Consortium Collaborators ,Infant, Newborn ,NIHR BioResource ,General Chemistry ,GLUCOCORTICOID-RECEPTOR ,Multidisciplinary Sciences ,ALKALINE SPHINGOMYELINASE ,Pregnancy Complications ,INSIGHTS ,Science & Technology - Other Topics ,Premature Birth ,Female ,FASTING GLUCOSE ,Genome-Wide Association Study - Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published
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- 2022
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3. Publisher Correction:Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)
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Thaventhiran, James E.D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H.R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V.V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel J., Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H., Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Chandra, Anita, Edgar, J. David M., Herwadkar, Archana, Cooper, Nichola, Grigoriadou, Sofia, Huissoon, Aarnoud P., Goddard, Sarah, Jolles, Stephen, Schuetz, Catharina, Boschann, Felix, Abbs, Stephen, Adhya, Zoe, Adlard, Julian, Afzal, Maryam, Ahmed, Irshad, Ahmed, Munaza, Ahmed, Saeed, Aitman, Timothy J., Alachkar, Hana, Alamelu, Jayanthi, Alikhan, Raza, Allen, Carl E., Allen, Louise, Allsup, David J., Alvi, Arif, Ambegaonkar, Gautam, Anantharachagan, Ariharan, Ancliff, Philip, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Arumugakani, Gururaj, Arya, Rita, Ashford, Sofie, Astle, William J., Attwood, Anthony, Austin, Steve, Aydinok, Yesim, Ayub, Waqar, Babbs, Christian, Bacchelli, Chiara, Baglin, Trevor, Bakchoul, Tamam, Bariana, Tadbir K., Barratt, Jonathan, Barwell, Julian, Baski, John, Bates, Rachel W., Batista, Joana, Baynam, Gareth, Bennett, David L., Bethune, Claire, Bhatnagar, Neha, Bibi, Shahnaz, Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Bleda, Marta, Blesneac, Iulia, Boardman, Barbara, Boddana, Preetham, Bogaard, Harm J., Booth, Claire, Boyce, Sara, Bradley, John R., Brady, Angela, Breen, Gerome, Brennan, Paul, Brewer, Carole, Briley, Annette, Brown, Richard, Browning, Michael J., Brownlie, Mary, Bryson, Christine J., Buchan, Rachel J., Buck, Jackie, Bueser, Teofila, Diz, Carmen Bugarin, Burns, Siobhan O., Calleja, Paul, Carmichael, Jenny, Carr-White, Gerald, Carss, Keren J., Casey, Ruth, Chalmers, Elizabeth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Chan, Melissa V., Cheng, Floria, Chinn, Ivan K., Chinnery, Patrick F., Chitre, Manali, Chong, Sam, Christian, Martin T., Church, Colin, Clement, Emma M., Brod, Naomi Clements, Clifford, Hayley, Clowes, Virginia E., Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine H., Collins, Peter W., Condliffe, Robin, Cook, H. Terence, Cook, Stuart, Cookson, Victoria, Corris, Paul A., Creaser-Myers, Amanda, Crisp-Hihn, Abigail, Curry, Nicola S., Da Costa, Rosa, Danesino, Cesare, Daniels, Matthew J., Darby, Damaris, Daugherty, Louise C., Davies, E. G., Davies, Sophie, Davis, John, de Bree, Godelieve J., Deacock, Sarah, Deegan, Patrick B., Dempster, John, Dent, Timothy, Deshpande, Charu, Devlin, Lisa A., Dewhurst, Eleanor F., Dixit, Anand K., Dixon, Peter H., Doffinger, Rainer, Dolling, Helen, Dormand, Natalie, Downes, Kate, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edwards, Karen E., Egner, William, Ekani, Melanie N., El-Shanawany, Tariq, Elkhalifa, Shuayb, Elston, Tony, Emmerson, Ingrid, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Firth, Helen V., Fitzpatrick, Maggie M., Fletcher, Debra, Flinter, Frances A., Fox, James C., Frary, Amy J., French, Courtney E., Freson, Kathleen, Frontini, Mattia, Furie, Bruce, Gale, Daniel P., Gall, Henning J., Gardham, Alice, Gaspar, H. Bobby, Gattens, Michael, Ghali, Neeti, Ghataorhe, Pavandeep K., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Ghurye, Rohit, Gibbs, J. Simon R., Gilbert, Rodney D., Girerd, Barbara, Girling, Joanna C., Gissen, Paul, Gorman, Kathleen M., Gosal, David, Graf, Stefan, Grassi, Luigi, Greenhalgh, Alan J., Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip G., Griffiths, Sian, Grozeva, Detelina, Hackett, Scott J., Hadden, Robert D.M., Hadinnapola, Charaka, Hague, Rosie, Hague, William M., Haimel, Matthias, Hall, Matthew, Halmagyi, Csaba, Hammerton, Tracey, Hanson, Helen L., Harkness, Kirsty, Harper, Andrew R., Harper, Lorraine, Harris, Claire, Harrison, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Heemskerk, Johan W.M., Hegde, Shivaram, Henderson, Alex, Henderson, Robert H., Hensiek, Anke, Henskens, Yvonne M.C., Hodgson, Joshua, Hoffman, Jonathan, Holden, Simon, Holder, Muriel, Horvath, Rita, Houlden, Henry, Houweling, Arjan C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Sean, Hughes, Stephen, Huis in ‘t Veld, Anna E., Humbert, Marc, Hurles, Matthew E., Hurst, Jane A., Irvine, Val, Izatt, Louise, James, Roger, Jeevaratnam, Praveen, Johnson, Mark, Johnson, Sally A., Jolley, Jennifer D., Jones, Bryony, Jones, Julie, Josifova, Dragana, Jurkute, Neringa, Karim, Yousuf M., Karoshi, Mahantesh A., Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Keeling, David, Kelleher, Peter, Kelly, Anne M., Kempster, Carly, Kennedy, Fiona, Kiani, Sorena, Kiely, David G., Kingston, Nathalie, Kinsey, Sally, Klein, Nigel, Klima, Robert, Knox, Ellen, Kostadima, Myrto A., Kovacs, Gabor, Koziell, Ania B., Kreuzhuber, Roman, Krishnakumar, Deepa, Kuijpers, Taco W., Kumar, Ajith, Kurian, Manju A., Laffan, James, Laffan, Michael A., Lalloo, Fiona, Lambert, Michele P., Lawman, Sarah H.A., Lawrie, Allan, Layton, D. Mark, Lear, Sara E., Lees, Melissa M., Lentaigne, Claire, Levine, Adam P., Lewington, Andrew J.P., Li, Wei, Liesner, Ri, Liu, Bin, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Hadeler, Silvia Lucato, Lyons, Paul A., Macdougall, Malcolm, Machado, Rajiv D., MacKenzie Ross, Robert V., Mackillop, Lucy H., MacLaren, Robert, Madan, Bella, Magee, Laura, Mahdi-Rogers, Mohamed, Maher, Eamonn R., Makris, Mike, Mangles, Sarah, Manson, Ania, Manzur, Adnan, Mapeta, Rutendo, Marchbank, Kevin J., Mark, Patrick B., Marks, Stephen, Markus, Hugh S., Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer M., Masati, Larahmie, Mathias, Mary, Matser, Vera, Matthews, Emma L., Maw, Anna, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McDermott, Elizabeth M., McGowan, Simon J., McJannet, Coleen, McKinney, Harriet, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Meehan, Sharon, Mehta, Sarju, Mercer, Catherine L., Michaelides, Michel, Michell, Anna C., Milford, David, Millar, Carolyn M., Millar, Hazel, Mistry, Anoop, Moenen, Floor, Moledina, Shahin, Montani, David, Moore, Anthony T., Moore, Jason, Morrell, Nicholas W., Morrisson, Valerie, Mozere, Monika, Muir, Keith W., Mumford, Andrew D., Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Newnham, Michael, Ng, Joanne, Ngoh, Adeline, Noorani, Sadia, Noori, Muna, Nurden, Paquita, O’Sullivan, Jennifer M., Obaji, Samya, Okoli, Steven, Oksenhendler, Eric, Olschewski, Andrea, Olschewski, Horst, Ong, Albert C.M., Ong, Kai Ren, Oram, Helen, Ormondroyd, Elizabeth, Othman, Shokri, Ouwehand, Willem H., Pantazis, Antonis, Papadia, Sofia, Papandreou, Apostolos, Park, Soo Mi, Parker, Alasdair P.J., Parry, David, Parsons, Georgina, Pasi, K. John, Paterson, Joan, Payne, Jeanette H., Peacock, Andrew J., Peerlinck, Kathelijne, Pepke-Zaba, Joanna, Perry, David, Petersen, Romina, Piechowski-Jozwiak, Bartlomiej, Pinto, Fernando, Polwarth, Gary J., Ponsford, Mark J., Prasad, Sanjay, Prokopenko, Inga, Psaila, Beth, Pyle, Angela, Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raina, Sanjay, Ranganathan, Lavanya, Rankin, Julia, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rehnstrom, Karola, Reid, Evan, Reilly, Mary M., Renton, Tara, Revel-Vilk, Shoshana, Rhodes, Christopher J., Rice, Andrew S.C., Richards, Emma E., Richards, Mike, Richardson, Sylvia, Richter, Alex, Robert, Leema, Roberts, Irene, Rondina, Matthew T., Rosser, Elisabeth, Rothwell, Peter, Roughley, Catherine, Roy, Noemi B., Rue-Albrecht, Kevin, Sadeghi-Alavijeh, Omid, Saleem, Moin A., Salmon, Richard M., Samani, Nilesh J., Sambrook, Jennifer G., Sandford, Richard, Santra, Saikat, Satchell, Simon C., Savic, Sinisa, Scelsi, Laura, Schotte, Gwen, Schulman, Sol, Schulze, Harald, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, W. A.Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Shapiro, Susan E., Sharma, Pankaj, Shehata, Hassan A., Shipley, Deborah, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simpson, Michael, Sims, Matthew C., Sinha, Manish D., Sivapalaratnam, Suthesh, Skytte, Anne Bine, Smith, Kenneth G.C., Snape, Katie, Sneddon, Linda, Sohal, Aman, Soubrier, Florent, Southgate, Laura, Southwood, Mark, Splitt, Miranda, Staines, Simon, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stein, Daniel, Stein, Penelope E., Stock, Sophie, Stubbs, Matthew J., Suntharalingam, Jay, Swietlik, Emilia M., Symington, Emily, Tait, R. Campbell, Talks, Kate, Tan, Rhea Y.Y., Taylor, Gordon B., Thachil, Jecko, Themistocleous, Andreas C., Thomas, David C., Thomas, Ellen, Thomas, Patrick, Thompson, Dorothy A., Thomson, Kate, Thrasher, Adrian J., Thys, Chantal, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tool, Anton T.J., Toshner, Mark R., Traylor, Matthew, Treacy, Carmen M., Treadaway, Paul, Trembath, Richard C., Trippier, Sarah, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Upton, Paul D., Urniaz, Rafal, Vale, Tom, Van Geet, Chris, van Zuydam, Natalie, Vandersteen, Anthony M., Vazquez-Lopez, Marta, Veltman, Marijcke W.M., Vogt, Julie, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Vora, Ajay, Vries, Minka J.A., Wakeling, Emma L., Walker, Neil, Walker, Suellen M., Walsh, Roddy, Wanjiku, Ivy, Ware, James S., Warner, Timothy Q., Wassmer, Evangeline, Watkins, Hugh, Watson, Henry G., Watt, Christopher, Waugh, Dean, Webb, Nick, Webster, Andrew R., Wei, Wei, Welch, Angela, Welch, Steven B., Werring, David, Wessels, Julie, Westbury, Sarah K., Westwood, John Paul W., Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Willcocks, Lisa, Williams, David J., Williamson, Catherine, Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R., Workman, Sarita, Wort, Stephen J., Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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4. Powerful identification of cis-regulatory SNPs in human primary monocytes using allele-specific gene expression.
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Jonas Carlsson Almlöf, Per Lundmark, Anders Lundmark, Bing Ge, Seraya Maouche, Harald H H Göring, Ulrika Liljedahl, Camilla Enström, Jessy Brocheton, Carole Proust, Tiphaine Godefroy, Jennifer G Sambrook, Jennifer Jolley, Abigail Crisp-Hihn, Nicola Foad, Heather Lloyd-Jones, Jonathan Stephens, Rhian Gwilliam, Catherine M Rice, Christian Hengstenberg, Nilesh J Samani, Jeanette Erdmann, Heribert Schunkert, Tomi Pastinen, Panos Deloukas, Alison H Goodall, Willem H Ouwehand, François Cambien, and Ann-Christine Syvänen
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Medicine ,Science - Abstract
A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.
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- 2012
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5. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
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Heinig, Matthias, Petretto, Enrico, Wallace, Chris, Bottolo, Leonardo, Rotival, Maxime, Lu, Han, Li, Yoyo, Sarwar, Rizwan, Langley, Sarah R., Bauerfeind, Anja, Hummel, Oliver, Lee, Young-Ae, Paskas, Svetlana, Rintisch, Carola, Saar, Kathrin, Cooper, Jason, Buchan, Rachel, Gray, Elizabeth E., Cyster, Jason G., Braund, Peter, Gracey, Jay, Krishnan, Unni, Moore, Jasbir S., Nelson, Chris P., Pollard, Helen, Attwood, Tony, Crisp-Hihn, Abi, Foad, Nicola, Jolley, Jennifer, Lloyd-Jones, Heather, Muir, David, Murray, Elizabeth, O’Leary, Karen, Rankin, Angela, Sambrook, Jennifer, Godfroy, Tiphaine, Brocheton, Jessy, Proust, Carole, Schmitz, Gerd, Heimerl, Susanne, Lugauer, Ingrid, Belz, Stephanie, Gulde, Stefanie, Linsel-Nitschke, Patrick, Sager, Hendrik, Schroeder, Laura, Lundmark, Per, Syvannen, Ann-Christine, Neudert, Jessica, Scholz, Michael, Deloukas, Panos, Gray, Emma, Gwilliams, Rhian, Niblett, David, Erdmann, Jeanette, Hengstenberg, Christian, Maouche, Seraya, Ouwehand, Willem H., Rice, Catherine M., Samani, Nilesh J., Schunkert, Heribert, Goodall, Alison H., Schulz, Herbert, Roider, Helge G., Vingron, Martin, Blankenberg, Stefan, Münzel, Thomas, Zeller, Tanja, Szymczak, Silke, Ziegler, Andreas, Tiret, Laurence, Smyth, Deborah J., Pravenec, Michal, Aitman, Timothy J., Cambien, Francois, Clayton, David, Todd, John A., Hubner, Norbert, and Cook, Stuart A.
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- 2010
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6. Whole-genome sequencing of a sporadic primary immunodeficiency cohort
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Thaventhiran, James E.D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H.R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V.V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel J., Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H., Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Chandra, Anita, Edgar, J. David M., Herwadkar, Archana, Cooper, Nichola, Grigoriadou, Sofia, Huissoon, Aarnoud P., Goddard, Sarah, Jolles, Stephen, Schuetz, Catharina, Boschann, Felix, Abbs, Stephen, Adhya, Zoe, Adlard, Julian, Afzal, Maryam, Ahmed, Irshad, Ahmed, Munaza, Ahmed, Saeed, Aitman, Timothy J., Alachkar, Hana, Alamelu, Jayanthi, Alikhan, Raza, Allen, Carl E., Allen, Louise, Allsup, David J., Alvi, Arif, Ambegaonkar, Gautam, Anantharachagan, Ariharan, Ancliff, Philip, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Arumugakani, Gururaj, Arya, Rita, Ashford, Sofie, Astle, William J., Attwood, Anthony, Austin, Steve, Aydinok, Yesim, Ayub, Waqar, Babbs, Christian, Bacchelli, Chiara, Baglin, Trevor, Bakchoul, Tamam, Bariana, Tadbir K., Barratt, Jonathan, Barwell, Julian, Baski, John, Bates, Rachel W., Batista, Joana, Baynam, Gareth, Bennett, David L., Bethune, Claire, Bhatnagar, Neha, Bibi, Shahnaz, Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Bleda, Marta, Blesneac, Iulia, Boardman, Barbara, Boddana, Preetham, Bogaard, Harm J., Booth, Claire, Boyce, Sara, Bradley, John R., Brady, Angela, Breen, Gerome, Brennan, Paul, Brewer, Carole, Briley, Annette, Brown, Richard, Browning, Michael J., Brownlie, Mary, Bryson, Christine J., Buchan, Rachel J., Buck, Jackie, Bueser, Teofila, Diz, Carmen Bugarin, Burns, Siobhan O., Calleja, Paul, Carmichael, Jenny, Carr-White, Gerald, Carss, Keren J., Casey, Ruth, Chalmers, Elizabeth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Chan, Melissa V., Cheng, Floria, Chinn, Ivan K., Chinnery, Patrick F., Chitre, Manali, Chong, Sam, Christian, Martin T., Church, Colin, Clement, Emma M., Brod, Naomi Clements, Clifford, Hayley, Clowes, Virginia E., Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine H., Collins, Peter W., Condliffe, Robin, Cook, H. Terence, Cook, Stuart, Cookson, Victoria, Corris, Paul A., Creaser-Myers, Amanda, Crisp-Hihn, Abigail, Curry, Nicola S., Da Costa, Rosa, Danesino, Cesare, Daniels, Matthew J., Darby, Damaris, Daugherty, Louise C., Davies, E. G., Davies, Sophie, Davis, John, de Bree, Godelieve J., Deacock, Sarah, Deegan, Patrick B., Dempster, John, Dent, Timothy, Deshpande, Charu, Devlin, Lisa A., Dewhurst, Eleanor F., Dixit, Anand K., Dixon, Peter H., Doffinger, Rainer, Dolling, Helen, Dormand, Natalie, Downes, Kate, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edwards, Karen E., Egner, William, Ekani, Melanie N., El-Shanawany, Tariq, Elkhalifa, Shuayb, Elston, Tony, Emmerson, Ingrid, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Firth, Helen V., Fitzpatrick, Maggie M., Fletcher, Debra, Flinter, Frances A., Fox, James C., Frary, Amy J., French, Courtney E., Freson, Kathleen, Frontini, Mattia, Furie, Bruce, Gale, Daniel P., Gall, Henning J., Gardham, Alice, Gaspar, H. Bobby, Gattens, Michael, Ghali, Neeti, Ghataorhe, Pavandeep K., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Ghurye, Rohit, Gibbs, J. Simon R., Gilbert, Rodney D., Girerd, Barbara, Girling, Joanna C., Gissen, Paul, Gorman, Kathleen M., Gosal, David, Graf, Stefan, Grassi, Luigi, Greenhalgh, Alan J., Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip G., Griffiths, Sian, Grozeva, Detelina, Hackett, Scott J., Hadden, Robert D.M., Hadinnapola, Charaka, Hague, Rosie, Hague, William M., Haimel, Matthias, Hall, Matthew, Halmagyi, Csaba, Hammerton, Tracey, Hanson, Helen L., Harkness, Kirsty, Harper, Andrew R., Harper, Lorraine, Harris, Claire, Harrison, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Heemskerk, Johan W.M., Hegde, Shivaram, Henderson, Alex, Henderson, Robert H., Hensiek, Anke, Henskens, Yvonne M.C., Hodgson, Joshua, Hoffman, Jonathan, Holden, Simon, Holder, Muriel, Horvath, Rita, Houlden, Henry, Houweling, Arjan C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Sean, Hughes, Stephen, Huis in ‘t Veld, Anna E., Humbert, Marc, Hurles, Matthew E., Hurst, Jane A., Irvine, Val, Izatt, Louise, James, Roger, Jeevaratnam, Praveen, Johnson, Mark, Johnson, Sally A., Jolley, Jennifer D., Jones, Bryony, Jones, Julie, Josifova, Dragana, Jurkute, Neringa, Karim, Yousuf M., Karoshi, Mahantesh A., Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Keeling, David, Kelleher, Peter, Kelly, Anne M., Kempster, Carly, Kennedy, Fiona, Kiani, Sorena, Kiely, David G., Kingston, Nathalie, Kinsey, Sally, Klein, Nigel, Klima, Robert, Knox, Ellen, Kostadima, Myrto A., Kovacs, Gabor, Koziell, Ania B., Kreuzhuber, Roman, Krishnakumar, Deepa, Kuijpers, Taco W., Kumar, Ajith, Kurian, Manju A., Laffan, James, Laffan, Michael A., Lalloo, Fiona, Lambert, Michele P., Lawman, Sarah H.A., Lawrie, Allan, Layton, D. Mark, Lear, Sara E., Lees, Melissa M., Lentaigne, Claire, Levine, Adam P., Lewington, Andrew J.P., Li, Wei, Liesner, Ri, Liu, Bin, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Hadeler, Silvia Lucato, Lyons, Paul A., Macdougall, Malcolm, Machado, Rajiv D., MacKenzie Ross, Robert V., Mackillop, Lucy H., MacLaren, Robert, Madan, Bella, Magee, Laura, Mahdi-Rogers, Mohamed, Maher, Eamonn R., Makris, Mike, Mangles, Sarah, Manson, Ania, Manzur, Adnan, Mapeta, Rutendo, Marchbank, Kevin J., Mark, Patrick B., Marks, Stephen, Markus, Hugh S., Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer M., Masati, Larahmie, Mathias, Mary, Matser, Vera, Matthews, Emma L., Maw, Anna, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McDermott, Elizabeth M., McGowan, Simon J., McJannet, Coleen, McKinney, Harriet, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Meehan, Sharon, Mehta, Sarju, Mercer, Catherine L., Michaelides, Michel, Michell, Anna C., Milford, David, Millar, Carolyn M., Millar, Hazel, Mistry, Anoop, Moenen, Floor, Moledina, Shahin, Montani, David, Moore, Anthony T., Moore, Jason, Morrell, Nicholas W., Morrisson, Valerie, Mozere, Monika, Muir, Keith W., Mumford, Andrew D., Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Newnham, Michael, Ng, Joanne, Ngoh, Adeline, Noorani, Sadia, Noori, Muna, Nurden, Paquita, O’Sullivan, Jennifer M., Obaji, Samya, Okoli, Steven, Oksenhendler, Eric, Olschewski, Andrea, Olschewski, Horst, Ong, Albert C.M., Ong, Kai Ren, Oram, Helen, Ormondroyd, Elizabeth, Othman, Shokri, Ouwehand, Willem H., Pantazis, Antonis, Papadia, Sofia, Papandreou, Apostolos, Park, Soo Mi, Parker, Alasdair P.J., Parry, David, Parsons, Georgina, Pasi, K. John, Paterson, Joan, Payne, Jeanette H., Peacock, Andrew J., Peerlinck, Kathelijne, Pepke-Zaba, Joanna, Perry, David, Petersen, Romina, Piechowski-Jozwiak, Bartlomiej, Pinto, Fernando, Polwarth, Gary J., Ponsford, Mark J., Prasad, Sanjay, Prokopenko, Inga, Psaila, Beth, Pyle, Angela, Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raina, Sanjay, Ranganathan, Lavanya, Rankin, Julia, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rehnstrom, Karola, Reid, Evan, Reilly, Mary M., Renton, Tara, Revel-Vilk, Shoshana, Rhodes, Christopher J., Rice, Andrew S.C., Richards, Emma E., Richards, Mike, Richardson, Sylvia, Richter, Alex, Robert, Leema, Roberts, Irene, Rondina, Matthew T., Rosser, Elisabeth, Rothwell, Peter, Roughley, Catherine, Roy, Noemi B., Rue-Albrecht, Kevin, Sadeghi-Alavijeh, Omid, Saleem, Moin A., Salmon, Richard M., Samani, Nilesh J., Sambrook, Jennifer G., Sandford, Richard, Santra, Saikat, Satchell, Simon C., Savic, Sinisa, Scelsi, Laura, Schotte, Gwen, Schulman, Sol, Schulze, Harald, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, W. A.Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Shapiro, Susan E., Sharma, Pankaj, Shehata, Hassan A., Shipley, Deborah, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simpson, Michael, Sims, Matthew C., Sinha, Manish D., Sivapalaratnam, Suthesh, Skytte, Anne Bine, Smith, Kenneth G.C., Snape, Katie, Sneddon, Linda, Sohal, Aman, Soubrier, Florent, Southgate, Laura, Southwood, Mark, Splitt, Miranda, Staines, Simon, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stein, Daniel, Stein, Penelope E., Stock, Sophie, Stubbs, Matthew J., Suntharalingam, Jay, Swietlik, Emilia M., Symington, Emily, Tait, R. Campbell, Talks, Kate, Tan, Rhea Y.Y., Taylor, Gordon B., Thachil, Jecko, Themistocleous, Andreas C., Thomas, David C., Thomas, Ellen, Thomas, Patrick, Thompson, Dorothy A., Thomson, Kate, Thrasher, Adrian J., Thys, Chantal, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tool, Anton T.J., Toshner, Mark R., Traylor, Matthew, Treacy, Carmen M., Treadaway, Paul, Trembath, Richard C., Trippier, Sarah, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Upton, Paul D., Urniaz, Rafal, Vale, Tom, Van Geet, Chris, van Zuydam, Natalie, Vandersteen, Anthony M., Vazquez-Lopez, Marta, Veltman, Marijcke W.M., Vogt, Julie, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Vora, Ajay, Vries, Minka J.A., Wakeling, Emma L., Walker, Neil, Walker, Suellen M., Walsh, Roddy, Wanjiku, Ivy, Ware, James S., Warner, Timothy Q., Wassmer, Evangeline, Watkins, Hugh, Watson, Henry G., Watt, Christopher, Waugh, Dean, Webb, Nick, Webster, Andrew R., Wei, Wei, Welch, Angela, Welch, Steven B., Werring, David, Wessels, Julie, Westbury, Sarah K., Westwood, John Paul W., Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Willcocks, Lisa, Williams, David J., Williamson, Catherine, Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R., Workman, Sarita, Wort, Stephen J., Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, Wellcome Trust, Thaventhiran, James [0000-0001-8616-074X], Lango Allen, Hana [0000-0002-7803-8688], Burren, Oliver [0000-0002-3388-5760], Rae, William [0000-0003-0095-2514], Zhang, Zinan [0000-0003-3831-2272], Megy, Karyn [0000-0002-2826-3879], Johnson, Kathleen [0000-0002-6823-3252], Smith, Kenneth [0000-0003-3829-4326], Apollo - University of Cambridge Repository, University of St Andrews. School of Medicine, University of St Andrews. Statistics, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, Ege Üniversitesi, Experimental Immunology, Graduate School, AII - Inflammatory diseases, Infectious diseases, APH - Aging & Later Life, APH - Global Health, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, APH - Quality of Care, ACS - Atherosclerosis & ischemic syndromes, Biochemie, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, Faculteit FHML Centraal, MUMC+: DA CDL Algemeen (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: MA Hematologie (9), Interne Geneeskunde, and Promovendi CD
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0301 basic medicine ,Male ,Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics ,Genome-wide association study ,VARIANTS ,Regulatory Sequences, Nucleic Acid ,medicine.disease_cause ,Genome ,Cohort Studies ,0302 clinical medicine ,RARE ,QR180 Immunology ,Primary Immunodeficiency Consortium for the NIHR Bioresource ,Genetics ,Protein Tyrosine Phosphatase, Non-Receptor Type 2 ,Multidisciplinary ,Suppressor of Cytokine Signaling 1 Protein/genetics ,GENETIC-VARIATION ,RNA-Binding Proteins ,Primary Immunodeficiency Diseases/diagnosis ,ASSOCIATION ,Penetrance ,Multidisciplinary Sciences ,DEFICIENCY ,QR180 ,Science & Technology - Other Topics ,Female ,General Science & Technology ,Primary Immunodeficiency Diseases ,Transcription Factors/genetics ,Genomics ,COMMON VARIABLE IMMUNODEFICIENCY ,QH426 Genetics ,Biology ,Article ,Actin-Related Protein 2-3 Complex ,03 medical and health sciences ,Suppressor of Cytokine Signaling 1 Protein ,SDG 3 - Good Health and Well-being ,SUPPRESSOR ,Actin-Related Protein 2-3 Complex/genetics ,medicine ,Humans ,QH426 ,Whole genome sequencing ,Science & Technology ,Whole Genome Sequencing ,Common variable immunodeficiency ,DAS ,Bayes Theorem ,Immune dysregulation ,Regulatory Sequences, Nucleic Acid/genetics ,medicine.disease ,RNA-Binding Proteins/genetics ,STAT1 MUTATIONS ,030104 developmental biology ,Primary immunodeficiency ,IUIS PHENOTYPIC CLASSIFICATION ,GAIN ,030215 immunology ,Genome-Wide Association Study ,Transcription Factors - Abstract
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans. © 2020, The Author(s), under exclusive licence to Springer Nature Limited., Wellcome Trust, WT: 104807/Z/14/Z University College London, UCL: 100140/Z/12/Z, 107212/Z/15/Z, MR/L019027, 203141/Z/16/Z, 091157/Z/10/Z Bundesministerium für Bildung und Forschung, BMBF: 01ZX1306A University of Cambridge 201250/Z/16/Z 01ZX1709 Seventh Framework Programme, FP7 NIHR Bristol Biomedical Research Centre Deutsche Forschungsgemeinschaft, DFG Deutsche Forschungsgemeinschaft, DFG: EXC 2167-390884018 Juvenile Diabetes Research Foundation United Kingdom, JDRF: 9-2011-253, 5-SRA-2015-130-A-N National Institute for Health Research, NIHR: RG65966 Medical Research Council, MRC: RG95376, MR/L006197/1 Great Ormond Street Hospital for Children, GOSH, Acknowledgements The NBR-RD PID Consortium is part of the NIHR BioResource, for which funding was provided by the NIHR (NIHR, grant number RG65966). We acknowledge the participation of all NIHR BioResource volunteers, and thank the NIHR BioResource centre and staff for their contribution. J.E.D.T. is supported by the Medical Research Council (MRC) (RG95376 and MR/L006197/1); A.J.T. is supported by the Wellcome Trust (104807/Z/14/Z) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; K.G.C.S. is supported by the MRC (programme grant MR/L019027) and is a Wellcome Investigator; A.J.C. was supported by the Wellcome Trust (091157/Z/10/Z, 107212/Z/15/Z, 100140/Z/12/Z, 203141/Z/16/Z), JDRF (9-2011-253, 5-SRA-2015-130-A-N), NIHR Oxford Biomedical Research Centre and NIHR Cambridge Biomedical Research Centre; E.E. has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement number 609020-Scientia Fellows; E.R. is supported by the Wellcome Trust (201250/Z/16/Z); D.E. is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A; GB-XMAP grant 01ZX1709) and funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany’s Excellence Strategy (EXC 2167-390884018). The NIHR Cambridge Biomedical Research Centre (BRC) is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the NIHR. This research was co-funded by the support listed above and the NIHR Cambridge BRC.
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- 2020
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7. Germline selection shapes human mitochondrial DNA diversity
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Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Non-Mendelian inheritance ,Genome ,Mitochondrial/genetics ,DNA, Mitochondrial/genetics ,0302 clinical medicine ,Ovum/growth & development ,MTDNA ,TRANSCRIPTION ,Genetics ,education.field_of_study ,Multidisciplinary ,NIHR BioResource–Rare Diseases ,ASSOCIATION ,Heteroplasmy ,Mitochondrial ,Multidisciplinary Sciences ,GENOME ,REPLACEMENT ,Science & Technology - Other Topics ,Female ,Maternal Inheritance ,Mitochondrial DNA ,General Science & Technology ,Genetic genealogy ,Population ,Biology ,Human mitochondrial genetics ,SEQUENCE ,DNA, Mitochondrial ,03 medical and health sciences ,Genetic ,100,000 Genomes Project–Rare Diseases Pilot ,Genetic variation ,MD Multidisciplinary ,Humans ,Selection, Genetic ,education ,Selection ,Ovum ,Science & Technology ,MUTATIONS ,Genetic Variation ,DNA ,LEIGH-DISEASE ,030104 developmental biology ,REPLICATION ,Genome, Mitochondrial ,HETEROPLASMY ,030217 neurology & neurosurgery - Abstract
INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.
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- 2019
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8. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
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Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Ines, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stephanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, Ross, Robert V MacKenzie, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Noordegraaf, Anton Vonk, Waisfisz, Quinten, Walsworth, Anna K, Walter, Robert E, Wharton, John, White, R James, Wilt, Jeffrey, Wort, Stephen J, Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Tregouet, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Graf, Stefan, Nichols, William C, Trembath, Richard C, Desai, Ankit A, Morrell, Nicholas W, Wilkins, Martin R, Adlard, Julian, Ahmed, Munaza, Aitman, Tim, Alachkar, Hana, Allsup, David, Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Astle, William, Attwood, Anthony, Babbs, Chris, Bakchoul, Tamam, Bariana, Tadbir, Barwell, Julian, Bennett, David, Bentley, David, Bierzynska, Agnieszka, Biss, Tina, Bogaard, Harm, Bourne, Christian, Boyce, Sara, Bradley, John, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Michael, Buchan, Rachel, Buckland, Matthew, Bueser, Teofila, Burns, Siobhan, Burren, Oliver, Calleja, Paul, Carr-White, Gerald, Carss, Keren, Casey, Ruth, Caulfield, Mark, Chambers, John, Chambers, Jennifer, Cheng, Floria, Chinnery, Patrick F, Christian, Martin, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor, Collins, Janine, Collins, Peter, Colombo, Camilla, Cook, Stuart, Cook, Terry, Cooper, Nichola, Corris, Paul, Crisp-Hihn, Abigail, Curry, Nicola, Daniels, Matthew, Daugherty, Louise, Davis, John, Deevi, Sri VV, Dent, Timothy, Dewhurst, Eleanor, Dixon, Peter, Downes, Kate, Drazyk, Anna, Drewe, Elizabeth, Dutt, Tina, Edgar, David, Edwards, Karen, Egner, William, Erber, Wendy, Erwood, Marie, Estiu, Maria C, Evans, Gillian, Evans, Dafydd Gareth, Everington, Tamara, Eyries, Mlanie, Favier, Remi, Fletcher, Debra, Fox, James, Frary, Amy, French, Courtney, Freson, Kathleen, Frontini, Mattia, Gale, Daniel, Geoghegan, Claire, Gerighty, Terry, Gibbs, Simon, Gilmour, Kimberley, Goddard, Sarah, Gomez, Keith, Gordins, Pavels, Gosal, David, Grassi, Luigi, Greene, Daniel, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell, Grozeva, Detelina, Hackett, Scott, Hague, William, Hall, Matthew, Hanson, Helen, Harkness, Kirsty, Harper, Andrew, Harris, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Hoffmann, Jonathan, Horvath, Rita, Houweling, Arjan, Howard, Luke, Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud, Humphray, Sean, Hunter, Sarah, Hurles, Matthew, Izatt, Louise, James, Roger, Johnson, Sally, Jolles, Stephen, Jolley, Jennifer, Jurkute, Neringa, Kasanicki, Mary, Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kiely, David, Kingston, Nathalie, Klima, Robert, Kostadima, Myrto, Koziell, Ania, Kreuzhuber, Roman, Kuijpers, Taco, Kumar, Ajith, Kumararatne, Dinakantha, Kurian, Manju, Laffan, Michael, Lalloo, Fiona, Lambert, Michele, Allen, Hana Lango, Layton, Mark, Lentaigne, Claire, Levine, Adam, Linger, Rachel, Longhurst, Hilary, Louka, Eleni, Ross, Robert MacKenzie, Madan, Bella, Maher, Eamonn, Maimaris, Jesmeen, Mangles, Sarah, Mapeta, Rutendo, Marchbank, Kevin, Marks, Stephen, Markus, Hugh S, Marschall, Hanns-Ulrich, Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark, Meacham, Stuart, Mead, Adam, Megy, Karyn, Mehta, Sarju, Michaelides, Michel, Millar, Carolyn, Moore, Tony, Morrell, Nicholas, Mozere, Monika, Muir, Keith, Mumford, Andrew, O'Sullivan, Jennifer, Obaji, Samya, Okoli, Steven, Ong, Kai Ren, Ormondroyd, Elizabeth, Ouwehand, Willem, Papadia, Sofia, Park, Soo-Mi, Parry, David, Paterson, Joan, Peacock, Andrew, Peden, John, Peerlinck, Kathelijne, Penkett, Christopher, Petersen, Romina, Pyle, Angela, Rankin, Stuart, Rao, Anupama, Raymond, F Lucy, Rayner-Matthews, Paula, Rees, Christine, Rendon, Augusto, Renton, Tara, Rice, Andrew, Richardson, Sylvia, Richter, Alex, Roberts, Irene, Roughley, Catherine, Roy, Noemi, Sadeghi-Alavijeh, Omid, Saleem, Moin, Samani, Nilesh, Sanchis-Juan, Alba, Sargur, Ravishankar, Satchell, Simon, Savic, Sinisa, Schulman, Sol, Scully, Marie, Searle, Claire, Sewell, Carrock, Seyres, Denis, Shapiro, Susie, Sharmardina, Olga, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael, Sivapalaratnam, Suthesh, Skytte, Anne-Bine, Smith, Katherine, Smith, Kenneth GC, Snape, Katie, Staines, Simon, Staples, Emily, Stark, Hannah, Stephens, Jonathan, Stirrups, Kathleen, Stock, Sophie, Swietlik, Emilia, Tait, R Campbell, Talks, Kate, Tan, Rhea, Thaventhiran, James, Themistocleous, Andreas, Thomas, Moira, Thomson, Kate, Thrasher, Adrian, Thys, Chantal, Tischkowitz, Marc, Titterton, Catherine, Toh, Cheng-Hock, Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Trembath, Richard, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Vale, Tom, Van Geet, Chris, Van Zuydam, Natalie, Vazquez-Lopez, Marta, Von Ziegenweidt, Julie, Waisfisz, Quintin, Walker, Suellen, Ware, James, Watkins, Hugh, Watt, Christopher, Webster, Andrew, Wei, Wei, Welch, Steven, Wessels, Julie, Westbury, Sarah, Westwood, John-Paul, Whitehorn, Deborah, Whitworth, James, Williamson, Catherine, Wong, Edwin, Wood, Nicholas, Wood, Yvette, Woods, Geoff, Woodward, Emma, Wort, Stephen, Worth, Austen, Yates, Katherine, Yong, Patrick, Young, Tim, Yu, Ping, Yu-Wai-Man, Patrick, Theuer, Alison, Malur, Anagha, Williams, Ann, Dotson, Anne, Warden, Ashley, Harrington, Brandy, Vang, Brenda, Ziemak, Caitlin, Casanova, Nancy, Caskey, Elizabeth, MacDonald, Catherine, Rowley, Courtney, Larimore, Daniel, Brady, Daniela, Tomer, David, Davis, Anne, Broach, Debra, Devereux, Jane, Lovato, Ellen, Stratton, Eric, Turk, Erin, Jackson, Esperanza, Paciotti, Gina, Peichel, Gretchen, Birru, Hellina, del Junco, Holly, Ingledue, Rebecca, Bruno, Jackie, Drake, Jan, Marks, Jennifer, Pisarcik, Jessica, Spears, Jill, Santiago, Joseph, DeMartino, Jordyn, Beckmann, Joy, Palmer, Julia, Visnaw, Karen, Kennedy, Karla, Lewis, Karlise, Miller-Reed, Kathleen, Hannon, Kelly, McClain, Kimberly, Dillon, Laura, Olanipekun, Lekan, Mendibles, Lillian, Hawke, Lindsey, Brody, Linnea, Durst, Louise, Andrews, Mary, Allahua, Melissa, Stratoberdha, Melissa, Lemma, Merte, Cope, Molly, Franzo, Mya, Feliz, Natalia, Hawkes, Nicholas, Norwood, Tracy, Wilson, Opal, Palmisciano, Amy, Gruhlke, Peggy, Correa, Priscilla, Blake, Randy, Karnekar, Reema, Do, Robyn, Rohwer, Kristal, Ahmed, Sara, Schiltz, Kimberly, Scovel, Page, Cordell, Shannon, Heuerman, Sharon, Ahmad, Shazzra, Szuberla, Sylwia, Roads, Tammy, Iem, Thoeun, Mcgaha, Traci, Urban, Tracy, Aston, Valerie, Ayesh, Waleed, Light, Allison, Arkon, Abby, Tavlarides, Andrea, Anderson, Audrey, Bindu, John, Boekwig, Deedre, Singleton, Donna, Abrea, Inna, Lee, Jennifer, Ormiston, Mark, Whitman, Renesa, Holy, Royanne, Almeida-Peters, Sisama, Igenoza, Tosin, Farber, Hap, Reponen, Auvo, Barve, Mukta, Gygi, Amber, and Winslow, Clayborne
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ALPHA ,Science & Technology ,Critical Care Medicine ,ENDODERM FORMATION ,General & Internal Medicine ,Respiratory System ,SUSCEPTIBILITY ,SOX17 ,Life Sciences & Biomedicine ,DISEASE - Abstract
BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR. ispartof: LANCET RESPIRATORY MEDICINE vol:7 issue:3 pages:227-238 ispartof: location:England status: published
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- 2019
9. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure
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Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van Duijn, Cornelia M. McEniery CM, Wilkinson IB, Cockcroft JR, O'Shaughnessy KM, Newhouse SJ, Yasmin, Smith AV, Eiriksdottir G, Launer LJ, Sigurdsson S, Aspelund T, Gudnason V, De Bacquer D, Rietzschel ER, De Backer GG, Van Bortel L, De Buyzere ML, Segers P, Bekaert S, Gillebert TC, De Meyer T, Ferrucci L, Tanaka T, Johnson AD, Levy D, Benjamin EJ, Mitchell GF, Vita JA, Larson MG, Hamburg NM, Vasan RS, Isaacs A, Schut AF, Oostra BA, van Duijn CM, van Rijn MJ, Sie MP, Newman AB, Herrington DM, Andrews JS, Ding J, Sutton-Tyrrell KC, Harris TB, Howard TD, Liu Y, Parsa A, Shuldiner AR, McArdle PF, Gibson Q, Post WS, Dehghan A, Hofman A, Uitterlinden AG, Sijbrands EJ, Rivadeneira F, Mattace-Raso FU, Verwoert GC, Witteman JC, Scuteri A, Lakatta EG, Jewell E, Abecasis GR, Tarasov KV, Uda M, Najjar SS, Sanna S, Attwood T, Belz S, Braund P, Cambien F, Cooper J, Crisp-Hihn A, Deloukas P, Foad N, Eardman J, Goodall AH, Gracey J, Gray E, Gulde S, Gwilliams R, Heimerl S, Hengstenberg C, Jolley J, Krishnan U, Linsel-Nitschke P, Lloyd-Jones H, Lugauer I, Lundmark P, Maouche S, Moore JS, Muir D, Murray E, Nelson CP, Neudert J, Niblett D, O'Leary K, Ouwehand WH, Pollard H, Rankin A, Rice CM, Sager H, Samani NJ, Sambrook J, Schmitz G, Scholz M, Schroeder L, Schunkert H, Syvannen AC, Wallace C, Kathiresan S, Reilly MP, Erdmann J, Assimes TL, Boerwinkle E, Hall A, König IR, Laaksonen R, McPherson R, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Assime TL, Holm H, Roberts R, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Wild P, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Chen IY, Cupples L, Demissie-Banjaw S, Folsom A, Glazer N, Harris T, Heckbert S, Lumley T, Marciante K, Morrison A, O' Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Uitterlinden A, Gretarsdottir S, Gulcher JR, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Fischer M, Grosshennig A, Lieb W, Stark K, Schreiber S, Wichmann HE, Aherrahrou Z, Bruse P, Doering A, Illig T, Klopp N, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Wagner AK, Willenborg C, Böhm BO, Dobnig H, Grammer TB, Hoffmann MM, Kleber M, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Guiducci C, Burtt N, Gabriel SB, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Dandona S, Jarinova O, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Yang YA, Stricker BH, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Willerson JT, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Gao X, Yang Q, O'Connell JR, Schmidt H, Ketkar S, Hwang SJ, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Siscovick D, Zillikens MC, Feitosa M, Province M, de Andrade M, Turner ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Coresh J, Schmidt R, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Felix SB, Watzinger N, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Reffelmann T, Redfield MM, Werdan K, Arnett DK, Blettner M, Friedrich N, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic N, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Vollenweider P, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Lightstone L, Scott J, Navis G, Elliott P, Kooner JS., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), University of Leicester, Department of Genetics [Leicester], Erasmus University Rotterdam, Netherlands Genomics Initiative, Department of Epidemiology and Biostatistics, School of Public Health, Zahedan University of Medical Sciences, Washington University in Saint Louis (WUSTL), Queen Mary University of London (QMUL), National Heart, Lung and Blood Institute, Partenaires INRAE, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne = University of Lausanne (UNIL), Department of Biostatistics [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Leiden University Medical Center (LUMC), Universiteit Leiden, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Department of Epidemiology, The Netherlands Cancer Institute, Department of Mathematics, Boston University [Boston] (BU), GlaxoSmithKline, Division of Community Health Sciences, St. George's, University of South Florida [Tampa] (USF), Universität Greifswald - University of Greifswald, University of Washington [Seattle], University of Tartu, Institute of Molecular and Cell Biology, Medical Research Council, Institut de Génomique, Centre National de Génotypage, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University Medical Center Groningen, Department of Genetics, University Medical Center Groningen [Groningen] (UMCG), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Massachusetts General Hospital [Boston], Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Università degli studi di Trieste = University of Trieste, Universität zu Lübeck = University of Lübeck [Lübeck], Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, The University of Western Australia (UWA), Department of Twin Research and Genetic Epidemiology, King's College London, London, University of Oxford, Medical University Graz, National Institute on Aging, Centre for population Health Sciences, University of Edinburgh, Uppsala University, Vrije Universiteit Amsterdam [Amsterdam] (VU), Western General Hospital, Harvard Medical School [Boston] (HMS), Brigham and Women's Hospital [Boston], University of Michigan System, University of Groningen, Ealing Hospital, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Medical Genetics Institute, Cedars-Sinai Medical Center, University of Tampere, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Split, The University of Texas Health Science Center at Houston (UTHealth), Johns Hopkins University (JHU), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Swiss Institute of Bioinformatics [Lausanne] (SIB), Finnish Institute of Occupational Health, National Institute of Health and Welfare, University of Oulu, Lapland Central Hospital, University of Bristol [Bristol], Institute for Community Medicine, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), US National Institutes of Health, National Heart, Lung, and Blood Institute, European, Epidemiology, Internal Medicine, Public Health, Clinical Genetics, Université de Lausanne (UNIL), LeidenUniversity Medical Centre, University of Iceland, Università degli studi di Trieste, Universität zu Lübeck [Lübeck], University of Western Australia, University of Oxford [Oxford], VU University Amsterdam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Human genetics, Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Epidemiology and Data Science, Medical Research Council (MRC), Louise V., Wain, Germaine C., Verwoert, Paul F., O'Reilly, Gang, Shi, Toby, Johnson, Andrew D., Johnson, Murielle, Bochud, Kenneth M., Rice, Peter, Henneman, Albert V., Smith, Georg B., Ehret, Najaf, Amin, Martin G., Larson, Vincent, Mooser, David, Hadley, Marcus, Dörr, Joshua C., Bi, Thor, Aspelund, Tõnu, Esko, A. Cecile J. W., Janssen, Jing Hua, Zhao, Simon, Heath, Maris, Laan, Jingyuan, Fu, Giorgio, Pisti, Jian'An, Luan, Pankaj, Arora, Gavin, Luca, Pirastu, Nicola, Irene, Pichler, Anne U., Jackson, Rebecca J., Webster, Feng, Zhang, John F., Peden, Helena, Schmidt, Toshiko, Tanaka, Harry, Campbell, Wilmar, Igl, Yuri, Milaneschi, Jouke Jan, Hottenga, Veronique, Vitart, Daniel I., Chasman, Stella, Trompet, Jennifer L., Bragg Gresham, Behrooz Z., Alizadeh, John C., Chamber, Xiuqing, Guo, Terho, Lehtimäki, Brigitte, Kühnel, Lorna M., Lopez, Ozren, Polašek, Mladen, Boban, Christopher P., Nelson, Alanna C., Morrison, Vasyl, Pihur, Santhi K., Ganesh, Albert, Hofman, Suman, Kundu, Francesco U. S., Mattace Raso, Fernando, Rivadeneira, Eric J. G., Sijbrand, Andre G., Uitterlinden, Shih Jen, Hwang, Ramachandran S., Vasan, Thomas J., Wang, Sven, Bergmann, Peter, Vollenweider, Gérard, Waeber, Jaana, Laitinen, Anneli, Pouta, Paavo, Zitting, Wendy L., Mcardle, Heyo K., Kroemer, Uwe, Völker, Henry, Völzke, Nicole L., Glazer, Kent D., Taylor, Tamara B., Harri, Helene, Alavere, Toomas, Haller, Aime, Kei, Mari Liis, Tammesoo, Yurii, Aulchenko, Inês, Barroso, Kay Tee, Khaw, Pilar, Galan, Serge, Hercberg, Mark, Lathrop, Susana, Eyheramendy, Elin, Org, Siim, Sõber, Xiaowen, Lu, Ilja M., Nolte, Brenda W., Penninx, Tanguy, Corre, Corrado, Masciullo, Cinzia, Sala, Leif, Groop, Benjamin F., Voight, Olle, Melander, Christopher J., O'Donnell, Veikko, Salomaa, D'Adamo, ADAMO PIO, Antonella, Fabretto, Flavio, Faletra, Sheila, Ulivi, Fabiola Del Greco, M, Maurizio, Facheri, Francis S., Collin, Richard N., Bergman, John P., Beilby, Joseph, Hung, A., William Musk, Massimo, Mangino, So Youn, Shin, Nicole, Soranzo, Hugh, Watkin, Anuj, Goel, Anders, Hamsten, Pierre, Gider, Marisa, Loitfelder, Marion, Zeginigg, Dena, Hernandez, Samer S., Najjar, Pau, Navarro, Sarah H., Wild, Anna Maria, Corsi, Andrew, Singleton, Eco J. C., de Geu, Gonneke, Willemsen, Alex N., Parker, Lynda M., Rose, Brendan, Buckley, David, Stott, Marco, Orru, Manuela, Uda, Melanie M., van der Klauw, Weihua, Zhang, Xinzhong, Li, James, Scott, Yii Der Ida, Chen, Gregory L., Burke, Mika, Kähönen, Jorma, Viikari, Angela, Döring, Thomas, Meitinger, Gail, Davie, John M., Starr, Valur, Emilsson, Andrew, Plump, Jan H., Lindeman, Peter A. C., 't Hoen, Inke R., König, Janine F., Felix, Robert, Clarke, Jemma C., Hopewell, Halit, Ongen, Monique, Breteler, Stéphanie, Debette, Anita L., Destefano, Myriam, Fornage, Gary F., Mitchell, Nicholas L., Smith, Hilma, Holm, Kari, Stefansson, Gudmar, Thorleifsson, Unnur, Thorsteinsdottir, Nilesh J., Samani, Michael, Preu, Igor, Rudan, Caroline, Hayward, Ian J., Deary, H., Erich Wichmann, Olli T., Raitakari, Walter, Palma, Jaspal S., Kooner, Ronald P., Stolk, J., Wouter Jukema, Alan F., Wright, Dorret I., Boomsma, Stefania, Bandinelli, Ulf B., Gyllensten, James F., Wilson, Luigi, Ferrucci, Reinhold, Schmidt, Martin, Farrall, Tim D., Spector, Lyle J., Palmer, Jaakko, Tuomilehto, Arne, Pfeufer, Gasparini, Paolo, David, Siscovick, David, Altshuler, Ruth J. F., Loo, Daniela, Toniolo, Harold, Snieder, Christian, Gieger, Pierre, Meneton, Nicholas J., Wareham, Ben A., Oostra, Andres, Metspalu, Lenore, Launer, Rainer, Rettig, David P., Strachan, Jacques S., Beckmann, Jacqueline C. M., Witteman, Jeanette, Erdmann, Ko Willems van, Dijk, Eric, Boerwinkle, Michael, Boehnke, Paul M., Ridker, Marjo Riitta, Jarvelin, Aravinda, Chakravarti, Goncalo R., Abecasi, Vilmundur, Gudnason, Christopher Newton, Cheh, Daniel, Levy, Patricia B., Munroe, Bruce M., Psaty, Mark J., Caulfield, Dabeeru C., Rao, Martin D., Tobin, Paul, Elliott, Cornelia M., van Duijn, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcu, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Mari, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, Mcardle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Tooma, Keis, Aime, Tammesoo, Mari-Lii, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Ander, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, Jame, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thoma, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andre, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willem, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van, Duijn, Cornelia M., McEniery CM, Wilkinson, Ib, Cockcroft, Jr, O'Shaughnessy, Km, Newhouse, Sj, Yasmin, Smith, Av, Eiriksdottir, G, Launer, Lj, Sigurdsson, S, Aspelund, T, Gudnason, V, De Bacquer, D, Rietzschel, Er, De Backer, Gg, Van Bortel, L, De Buyzere, Ml, Segers, P, Bekaert, S, Gillebert, Tc, De Meyer, T, Ferrucci, L, Tanaka, T, Johnson, Ad, Levy, D, Benjamin, Ej, Mitchell, Gf, Vita, Ja, Larson, Mg, Hamburg, Nm, Vasan, R, Isaacs, A, Schut, Af, Oostra, Ba, van Duijn, Cm, van Rijn, Mj, Sie, Mp, Newman, Ab, Herrington, Dm, Andrews, J, Ding, J, Sutton-Tyrrell, Kc, Harris, Tb, Howard, Td, Liu, Y, Parsa, A, Shuldiner, Ar, Mcardle, Pf, Gibson, Q, Post, W, Dehghan, A, Hofman, A, Uitterlinden, Ag, Sijbrands, Ej, Rivadeneira, F, Mattace-Raso, Fu, Verwoert, Gc, Witteman, Jc, Scuteri, A, Lakatta, Eg, Jewell, E, Abecasis, Gr, Tarasov, Kv, Uda, M, Najjar, S, Sanna, S, Attwood, T, Belz, S, Braund, P, Cambien, F, Cooper, J, Crisp-Hihn, A, Deloukas, P, Foad, N, Eardman, J, Goodall, Ah, Gracey, J, Gray, E, Gulde, S, Gwilliams, R, Heimerl, S, Hengstenberg, C, Jolley, J, Krishnan, U, Linsel-Nitschke, P, Lloyd-Jones, H, Lugauer, I, Lundmark, P, Maouche, S, Moore, J, Muir, D, Murray, E, Nelson, Cp, Neudert, J, Niblett, D, O'Leary, K, Ouwehand, Wh, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Samani, Nj, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Schunkert, H, Syvannen, Ac, Wallace, C, Kathiresan, S, Reilly, Mp, Erdmann, J, Assimes, Tl, Boerwinkle, E, Hall, A, König, Ir, Laaksonen, R, Mcpherson, R, Thompson, Jr, Thorsteinsdottir, U, Ziegler, A, Absher, D, Chen, L, Cupples, La, Halperin, E, Li, M, Musunuru, K, Preuss, M, Schillert, A, Thorleifsson, G, Voight, Bf, Wells, Ga, Assime, Tl, Holm, H, Roberts, R, Stewart, Af, Fortmann, S, Go, A, Hlatky, M, Iribarren, C, Knowles, J, Myers, R, Quertermous, T, Sidney, S, Risch, N, Tang, H, Blankenberg, S, Zeller, T, Wild, P, Schnabel, R, Sinning, C, Lackner, K, Tiret, L, Nicaud, V, Bickel, C, Rupprecht, Hj, Perret, C, Proust, C, Münzel, T, Barbalic, M, Bis, J, Chen, Iy, Cupples, L, Demissie-Banjaw, S, Folsom, A, Glazer, N, Harris, T, Heckbert, S, Lumley, T, Marciante, K, Morrison, A, O' Donnell, Cj, Psaty, Bm, Rice, K, Rotter, Ji, Siscovick, D, Smith, N, Smith, A, Taylor, Kd, van Duijn, C, Volcik, K, Whitteman, J, Ramachandran, V, Uitterlinden, A, Gretarsdottir, S, Gulcher, Jr, Kong, A, Stefansson, K, Thorgeirsson, G, Andersen, K, Fischer, M, Grosshennig, A, Lieb, W, Stark, K, Schreiber, S, Wichmann, He, Aherrahrou, Z, Bruse, P, Doering, A, Illig, T, Klopp, N, Loley, C, Medack, A, Meisinger, C, Meitinger, T, Nahrstedt, J, Peters, A, Wagner, Ak, Willenborg, C, Böhm, Bo, Dobnig, H, Grammer, Tb, Hoffmann, Mm, Kleber, M, März, W, Meinitzer, A, Winkelmann, Br, Pilz, S, Renner, W, Scharnagl, H, Stojakovic, T, Tomaschitz, A, Winkler, K, Guiducci, C, Burtt, N, Gabriel, Sb, O'Donnell, Cj, Elosua, R, Peltonen, L, Salomaa, V, Schwartz, Sm, Melander, O, Altshuler, D, Dandona, S, Jarinova, O, Qu, L, Wilensky, R, Matthai, W, Hakonarson, Hh, Devaney, J, Burnett, M, Pichard, Ad, Kent, Km, Satler, L, Lindsay, Jm, Waksman, R, Knouff, Cw, Waterworth, Dm, Walker, Mc, Mooser, V, Epstein, Se, Rader, Dj, Wright, Bj, Balmforth, Aj, Ball, Sg, Smith, Nl, Felix, Jf, Morrison, Ac, Demissie, S, Glazer, Nl, Loehr, Lr, Rosamond, Wd, Bis, Jc, Folsom, Ar, Benjamin, E, Aulchenko, Y, Haritunians, T, Couper, D, Murabito, J, Yang, Ya, Stricker, Bh, Gottdiener, J, Chang, Pp, Wang, Tj, Rice, Km, Heckbert, Sr, Fox, Er, Willerson, Jt, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Gao, X, Yang, Q, O'Connell, Jr, Schmidt, H, Ketkar, S, Hwang, Sj, Teumer, A, Paré, G, Atkinson, Ej, Lohman, K, Cornelis, Mc, Probst-Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Rampersaud, E, Mitchell, Bd, Arking, De, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer, Ih, Zillikens, Mc, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, A, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Prokopenko, I, Wang, W, Coresh, J, Schmidt, R, Shlipak, Mg, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Felix, Sb, Watzinger, N, Homuth, G, Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Reffelmann, T, Redfield, Mm, Werdan, K, Arnett, Dk, Blettner, M, Friedrich, N, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Vollenweider, P, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Lightstone, L, Scott, J, Navis, G, Elliott, P, and Kooner, Js.
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Netherlands Twin Register (NTR) ,Linkage disequilibrium ,pulse pressure ,mean arterial pressure ,genome-wide ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,BLOOD-PRESSURE ,Blood Pressure ,030204 cardiovascular system & hematology ,Linkage Disequilibrium ,0302 clinical medicine ,RELEVANCE ,CardioGram ,Medicine and Health Sciences ,Genetics & Heredity ,ddc:616 ,Genetics ,0303 health sciences ,Genome-wide association ,11 Medical And Health Sciences ,Arteries ,ADRENERGIC-RECEPTOR TRAFFICKING ,Pulse pressure ,EchoGen consortium ,Hypertension ,HEART-FAILURE ,arterial pressure ,Case-Control Studie ,Life Sciences & Biomedicine ,Human ,circulatory and respiratory physiology ,medicine.medical_specialty ,Mean arterial pressure ,Arterie ,AortaGen Consortium ,Cardiogenics consortium ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Article ,Follow-Up Studie ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,METAANALYSIS ,030304 developmental biology ,Genetic association ,Science & Technology ,HYPERTENSION ,MORTALITY ,Case-control study ,CARDIOVASCULAR-DISEASE RISK ,06 Biological Sciences ,GENE ,MICE ,Endocrinology ,Blood pressure ,CKDGen consortium ,Genetic Loci ,Case-Control Studies ,KidneyGen consortium ,CHARGE Consortium Heart Failure Working Group ,LifeLines Cohort Study ,Developmental Biology ,Follow-Up Studies ,Genome-Wide Association Study - Abstract
Les affiliations des 100 premiers auteurs sont renseignées dans la notice. Les affiliations des autres auteurs sont disponibles à la fin de la publication.; International audience; Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
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- 2016
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10. Large-scale gene-centric analysis identifies novel variants for coronary artery disease
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Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)
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Male ,Cancer Research ,Candidate gene ,Epidemiology ,Genome-wide association study ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Cardiovascular ,0302 clinical medicine ,GENETICS & HEREDITY ,Genetics (clinical) ,Genetics ,0303 health sciences ,Cardiovascular diseases [NCEBP 14] ,Middle Aged ,3. Good health ,CYP17A1 ,Genetic Epidemiology ,Genome-wide association ,Myocardial-infarction ,Susceptibility loci ,Risk ,Atherosclerosis ,Metanalysis ,Lipoprotein ,Medicine ,Female ,Life Sciences & Biomedicine ,Research Article ,Asian Continental Ancestry Group ,Adult ,SUSCEPTIBILITY LOCI ,lcsh:QH426-470 ,European Continental Ancestry Group ,Biology ,Polymorphism, Single Nucleotide ,coronary artery disease ,genetics ,White People ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Asian People ,Genetic variation ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Allele ,Molecular Biology ,Gene ,METAANALYSIS ,Ecology, Evolution, Behavior and Systematics ,Genetic Association Studies ,Cardiovascular Disease Epidemiology ,Alleles ,030304 developmental biology ,Aged ,0604 Genetics ,Science & Technology ,Case-control study ,Genetic Variation ,Human Genetics ,Odds ratio ,large-scale gene analysis ,lcsh:Genetics ,LIPOPROTEIN ,MYOCARDIAL-INFARCTION ,ATHEROSCLEROSIS ,Case-Control Studies ,Genetics of Disease ,IBC 50K CAD Consortium ,Developmental Biology ,Genome-Wide Association Study - Abstract
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.
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- 2016
11. Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders
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Westbury, Sarah K, Turro, Ernest, Greene, Daniel, Lentaigne, Claire, Kelly, Anne M, Bariana, Tadbir K, Simeoni, Ilenia, Pillois, Xavier, Attwood, Antony, Austin, Steve, Jansen, Sjoert BG, Bakchoul, Tamam, Crisp-Hihn, Abi, Erber, Wendy N, Favier, Rémi, Foad, Nicola, Gattens, Michael, Jolley, Jennifer D, Liesner, Ri, Meacham, Stuart, Millar, Carolyn M, Nurden, Alan T, Peerlinck, Kathelijne, Perry, David J, Poudel, Pawan, Schulman, Sol, Schulze, Harald, Stephens, Jonathan C, Furie, Bruce, Robinson, Peter N, van Geet, Chris, Rendon, Augusto, Gomez, Keith, Laffan, Michael A, Lambert, Michele P, Nurden, Paquita, Ouwehand, Willem H, Richardson, Sylvia, Mumford, Andrew D, Freson, Kathleen, Medical Research Council (MRC), Medical Research Council, and BRIDGE-BPD Consortium
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Genetics & Heredity ,Science & Technology ,Research ,Clinical Sciences ,Guidelines ,Thrombocytopenia ,Complex ,mental disorders ,Genetics ,Molecular Medicine ,Genetics(clinical) ,Disease ,ddc:610 ,Molecular Biology ,Life Sciences & Biomedicine ,Bridge-BPD Consortium - Abstract
Background Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases. Methods We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes. Results We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician. Conclusions These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0151-5) contains supplementary material, which is available to authorized users.
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- 2015
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12. Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
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Per Lundmark, Abigail Crisp-Hihn, Seraya Maouche, Tiphaine Godefroy, Harald H H Göring, Nilesh J. Samani, Anders Lundmark, Carole Proust, Jonathan Stephens, François Cambien, Jessy Brocheton, Bing Ge, Nicola S. Foad, Heribert Schunkert, Ulrika Liljedahl, Tomi Pastinen, Panos Deloukas, Camilla Enström, Jennifer Jolley, Rhian Gwilliam, Heather Lloyd-Jones, Ann-Christine Syvänen, Alison H. Goodall, Jonas Carlsson Almlöf, Jeanette Erdmann, Willem H. Ouwehand, Jennifer G. Sambrook, Catherine M. Rice, and Christian Hengstenberg
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Medicin och hälsovetenskap ,genetic association ,Microarrays ,genotype ,lcsh:Medicine ,Gene Expression ,Genome-wide association study ,genotyping expression analysis ,genetic analysis ,Regulatory Sequences, Nucleic Acid ,Medical and Health Sciences ,Monocytes ,0302 clinical medicine ,Gene Frequency ,single nucleotide polymorphism ,lcsh:Science ,Genetics ,0303 health sciences ,Multidisciplinary ,messenger RNA ,article ,Chromosome Mapping ,Genomics ,sample size ,Functional Genomics ,quantitative trait locus mapping ,monocyte ,allele specific gene expression analysis ,Research Article ,Genetic Markers ,Genotype ,Quantitative Trait Loci ,DNA flanking region ,Single-nucleotide polymorphism ,Biology ,gene frequency ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Gene mapping ,Genome Analysis Tools ,Genetic Mutation ,Genome-Wide Association Studies ,Humans ,RNA, Messenger ,human ,Allele ,blood donor ,intermethod comparison ,Allele frequency ,Genetic Association Studies ,Alleles ,030304 developmental biology ,Gene Expression Profiling ,human cell ,lcsh:R ,Computational Biology ,Human Genetics ,gene mapping ,Gene expression profiling ,Minor allele frequency ,Gene Expression Regulation ,Expression quantitative trait loci ,Genetic Polymorphism ,gene expression ,lcsh:Q ,Genome Expression Analysis ,Population Genetics ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.
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- 2012
13. Correction: Comprehensive Exploration of the Effects of miRNA SNPs on Monocyte Gene Expression
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Nicolas Greliche, Tanja Zeller, Philipp S. Wild, Maxime Rotival, Arne Schillert, Andreas Ziegler, Tony Attwood, Belz Stephanie, Peter Braund, Jessy Brocheton, Jason Cooper, Abi Crisp-Hihn, Patrick (formerly Linsel-Nitschke) Diemert, Nicola Foad, Tiphaine Godefroy, Jay Gracey, Emma Gray, Rhian Gwilliams, Susanne Heimerl, Jennifer Jolley, Unni Krishnan, Heather Lloyd-Jones, Ulrika Liljedahl, Ingrid Lugauer, Per Lundmark, Seraya Maouche, Jasbir S Moore, Montalescot Gilles, David Muir, Elizabeth Murray, Chris P Nelson, Jessica Neudert, David Niblett, Karen O.Leary, Helen Pollard, Carole Proust, Angela Rankin, Augusto Rendon, Catherine M Rice, Hendrik Sager, Jennifer Sambrook, Schmitz Gerd, Michael Scholz, Laura Schroeder, Jonathan Stephens, Ann-Christine Syvannen, Stefanie (formerlyGulde) Tennstedt, and Chris Wallace
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Multidisciplinary ,business.industry ,Monocyte ,lcsh:R ,Correction ,lcsh:Medicine ,Single-nucleotide polymorphism ,Computational biology ,Bioinformatics ,medicine.anatomical_structure ,microRNA ,Gene expression ,medicine ,lcsh:Q ,business ,lcsh:Science - Abstract
There was an error in the author byline. The correct byline is: Nicolas Greliche1,2, Tanja Zeller3, Philipp S. Wild4, Maxime Rotival1¤, Arne Schillert5, Andreas Ziegler5, the Cardiogenics Consortium¶, Panos Deloukas6, Jeanette Erdmann7, Christian Hengstenberg8, Willem H. Ouwehand6,9, Nilesh J. Samani10,11, Heribert Schunkert7, Thomas Munzel4, Karl J. Lackner12, Francois Cambien1, Alison H. Goodall10,11, Laurence Tiret1, Stefan Blankenberg3, David-Alexandre Tregouet1,13*
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- 2012
14. Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
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Almlöf, Jonas Carlsson, Lundmark, Per, Lundmark, Anders, Ge, B., Maouche, S., Göring, H. H. H., Liljedahl, Ulrika, Enström, Camilla, Brocheton, J., Proust, C., Godefroy, T., Sambrook, J. G., Jolley, J., Crisp-Hihn, A., Foad, N., Lloyd-Jones, H., Stephens, J., Gwilliam, R., Rice, C. M., Hengstenberg, C., Samani, N. J., Erdmann, J., Schunkert, H., Pastinen, T., Deloukas, P., Goodall, A. H., Ouwehand, W. H., Cambien, F., Syvänen, Ann-Christine, Almlöf, Jonas Carlsson, Lundmark, Per, Lundmark, Anders, Ge, B., Maouche, S., Göring, H. H. H., Liljedahl, Ulrika, Enström, Camilla, Brocheton, J., Proust, C., Godefroy, T., Sambrook, J. G., Jolley, J., Crisp-Hihn, A., Foad, N., Lloyd-Jones, H., Stephens, J., Gwilliam, R., Rice, C. M., Hengstenberg, C., Samani, N. J., Erdmann, J., Schunkert, H., Pastinen, T., Deloukas, P., Goodall, A. H., Ouwehand, W. H., Cambien, F., and Syvänen, Ann-Christine
- Abstract
A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.
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- 2012
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15. Large-scale gene-centric analysis identifies novel variants for coronary artery disease
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Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., Wallace, C., Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., and Wallace, C.
- Abstract
Contains fulltext : 98050.pdf (publisher's version ) (Open Access), Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other approximately 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular f
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- 2011
16. Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
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Almlöf, Jonas Carlsson, primary, Lundmark, Per, additional, Lundmark, Anders, additional, Ge, Bing, additional, Maouche, Seraya, additional, Göring, Harald H. H., additional, Liljedahl, Ulrika, additional, Enström, Camilla, additional, Brocheton, Jessy, additional, Proust, Carole, additional, Godefroy, Tiphaine, additional, Sambrook, Jennifer G., additional, Jolley, Jennifer, additional, Crisp-Hihn, Abigail, additional, Foad, Nicola, additional, Lloyd-Jones, Heather, additional, Stephens, Jonathan, additional, Gwilliam, Rhian, additional, Rice, Catherine M., additional, Hengstenberg, Christian, additional, Samani, Nilesh J., additional, Erdmann, Jeanette, additional, Schunkert, Heribert, additional, Pastinen, Tomi, additional, Deloukas, Panos, additional, Goodall, Alison H., additional, Ouwehand, Willem H., additional, Cambien, François, additional, and Syvänen, Ann-Christine, additional
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- 2012
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17. Correction: Comprehensive Exploration of the Effects of miRNA SNPs on Monocyte Gene Expression
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Greliche, Nicolas, primary, Zeller, Tanja, additional, Wild, Philipp S., additional, Rotival, Maxime, additional, Schillert, Arne, additional, Ziegler, Andreas, additional, Attwood, Tony, additional, Stephanie, Belz, additional, Braund, Peter, additional, Brocheton, Jessy, additional, Cooper, Jason, additional, Crisp-Hihn, Abi, additional, Diemert, Patrick (formerly Linsel-Nitschke), additional, Foad, Nicola, additional, Godefroy, Tiphaine, additional, Gracey, Jay, additional, Gray, Emma, additional, Gwilliams, Rhian, additional, Heimerl, Susanne, additional, Jolley, Jennifer, additional, Krishnan, Unni, additional, Lloyd-Jones, Heather, additional, Liljedahl, Ulrika, additional, Lugauer, Ingrid, additional, Lundmark, Per, additional, Maouche, Seraya, additional, Moore, Jasbir S, additional, Gilles, Montalescot, additional, Muir, David, additional, Murray, Elizabeth, additional, Nelson, Chris P, additional, Neudert, Jessica, additional, Niblett, David, additional, O.Leary, Karen, additional, Pollard, Helen, additional, Proust, Carole, additional, Rankin, Angela, additional, Rendon, Augusto, additional, Rice, Catherine M, additional, Sager, Hendrik, additional, Sambrook, Jennifer, additional, Gerd, Schmitz, additional, Scholz, Michael, additional, Schroeder, Laura, additional, Stephens, Jonathan, additional, Syvannen, Ann-Christine, additional, Tennstedt, Stefanie (formerlyGulde), additional, and Wallace, Chris, additional
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- 2012
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18. Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders.
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Westbury, Sarah K., Turro, Ernest, Greene, Daniel, Lentaigne, Claire, Kelly, Anne M., Bariana, Tadbir K., Simeoni, Ilenia, Pillois, Xavier, Attwood, Antony, Austin, Steve, Jansen, Sjoert B. G., Bakchoul, Tamam, Crisp-Hihn, Abi, Erber, Wendy N., Favier, Rémi, Foad, Nicola, Gattens, Michael, Jolley, Jennifer D., Liesner, Ri, and Meacham, Stuart
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HEMORRHAGE ,HUMAN phenotype ,BLOOD platelets ,NERVOUS system ,HUMAN genetics - Abstract
Background: Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases. Methods: We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes. Results: We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician. Conclusions: These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity. [ABSTRACT FROM AUTHOR]
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- 2015
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19. Blood Pressure Loci Identified with a Gene-Centric Array
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Meena Kumari, Claire E. Hastie, Jonathan Stephens, Patricia B. Munroe, Christopher P. Nelson, John M. C. Connell, Martin D. Tobin, Hani Neuvrith, Jean Tichet, Paul Burton, Gudrun Veldre, Daniele Cusi, Anna Levinsson, Paul Elliott, Elin Org, Erika Salvi, Tina Shah, Nabila Devos, Harm-Jan Westra, Juan-Pablo Casas, Olle Melander, Jan A. Staessen, Nilesh J. Samani, Jackie A. Cooper, Peter S. Braund, Neil R Poulter, Alive V. Stanton, Abiodun Onipinla, Marcel G. M. Wolfs, Steve E. Humphries, Philippa J. Talmud, Rebecca Hardy, Fotios Drenos, Maris Laan, Mark J. Caulfield, Richard Dobson, Willem H. Ouwehand, Yun Zhang, Li Chen, SG Wannamethee, Sue Shaw-Hawkins, Christopher Newton-Cheh, Eoin O'Brien, Simon A. McG. Thom, Maria Grazia Franzosi, Charles A. Mein, Mika Kivimäki, Tom R. Gaunt, Jennifer G. Sambrook, Andrea Stucchi, Annika Rosengren, Sonia Shah, Thomas Hedner, George A. Wells, Dag S. Thelle, Debbie A Lawlor, Pierre-François Plouin, Fredrik Nyberg, Richard W Morris, Ian N M Day, Vesela Gateva, Lude Franke, Peter S. Sever, Morris J. Brown, Margus Putku, Sandosh Padmanabhan, John F. Peden, Pim van der Harst, Jutta Palmen, Ioanna Tzoulaki, Alexandre F.R. Stewart, Andrew Wong, Peeter Juhanson, Marciej Tomaszewski, Alison H. Goodall, Martin Farrall, Wai K. Lee, Nicola Glorioso, Hugh Watkins, Xavier Jeunemaitre, Anders Hamsten, Robert Clarke, Anna F. Dominiczak, Mark Lathrop, Stephen Newhouse, Margus Viigimaa, George Davey Smith, Robert Roberts, John C. Whittaker, Michael V. Holmes, Toby Johnson, F. Gerald R. Fowkes, Aroon D. Hingorani, Udo Seedorf, Siim Sõber, Denis C. Shields, Diana Kuh, Chris Wallace, Philip Howard, Peter H. Whincup, Gonçalo R. Abecasis, Anuj Goel, Christian Delles, Björn Wahlstrand, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiogenics Consortium, Global BPgen Consortium, Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M.D., Bochud, M., Coin, L., Najjar, S.S., Hua, J., Heath, S.C., Eyheramendy, S., Papadakis, K., Voight, B.F., Scott, L.J., Zhang, F., Farrall, M., Tanaka, T., Wallace, C., Chambers, J.C., Khaw, K.T., Nilsson, P., van der Harst, P., Polidoro, S., Grobbee, D.E., Onland-Moret, N.C., Bots, M.L., Wain, L.V., Elliott, K.S., Teumer, A., Luan, J., Lucas, G., Kuusisto, J., Burton, P.R., Hadley, D., McArdle, W.L., Wellcome Trust Case Control Consortium, X, Brown, M., Dominiczak, A., Newhouse, S.J., Samani, N.J., Webster, J., Zeggini, E., Beckmann, J.S., Bergmann, S., Lim, N., Song, K., Vollenweider, P., Waeber, G., Waterworth, D.M., Yuan, X., Groop, L., Orho, M., Allione, A., Di Gregorio, A., Guarrera, S., Panico, S., Ricceri, F., Romanazzi, V., Sacerdote, C., Vineis, P., Barroso, I., Sandhu, M.S., Luben, R.N., Crawford, G.J., Jousilahti, P., Perola, M., Boehnke, M., Bonnycastle, L.L., Collins, F.S., Jackson, A.U., Mohlke, K.L., Stringham, H.M., Valle, T.T., Willer, C.J., Bergman, R.N., Morken, M.A., Döring, A., Gieger, C., Illig, T., Meitinger, T., Org, E., Pfeufer, A., Wichmann, H.E., Kathiresan, S., Marrugat, J., O'Donnell, C.J., Schwartz, S.M., Siscovick, D.S., Subirana, I., Freimer, N.B., Hartikainen, A.L., McCarthy, M.I., OReilly, P.F., Peltonen, L., Pouta, A., de Jong, P.E., Snieder, H., van Gilst, W.H., Clarke, R., Goel, A., Hamsten, A., Peden, J.F., Seedorf, U., Syv, C., Tognoni, G., Lakatta, E.G., Sanna, S., Scheet, P., Schlessinger, D., Scuteri, A., Dörr, M., Ernst, F., Felix, S.B., Homuth, G., Lorbeer, R., Reffelmann, T., Rettig, R., Völker, U., Galan, P., Gut, I.G., Hercberg, S., Lathrop, G.M., Zeleneka, D., Deloukas, P., Soranzo, N., Williams, F.M., Zhai, G., Salomaa, V., Laakso, M., Elosua, R., Forouhi, N.G., Völzke, H., Uiterwaal, C.S., van der Schouw, Y.T., Numans, M.E., Matullo, G., Navis, G., Berglund, G., Bingham, S.A., Kooner, J.S., Paterson, A.D., Connell, J.M., Bandinelli, S., Ferrucci, L., Watkins, H., Spector, T.D., Tuomilehto, J., Altshuler, D., Strachan, D.P., Laan, M., Meneton, P., Wareham, N.J., Uda, M., Jarvelin, M.R., Mooser, V., Melander, O., Loos, R.J., Elliott, P., Abecasis, G.R., Caulfield, M., Munroe, P.B., Attwood, T., Belz, S., Braund, P., Brocheton, J., Cambien, F., Cooper, J., Crisp-Hihn, A., Diemert, P., Eardman, J., Foad, N., Godefroy, T., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimer, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Liljedahl, U., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Montalescot, G., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Proust, C., Rankin, A., Rendon, A., Rice, C.M., Sager, H.B., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Schunkert, H., Stephens, J., Syvannen, A.C., and Tennstedt, S.
- Subjects
Male ,Linkage disequilibrium ,Methylenetetrahydrofolate Reductase (NADPH2)/genetics ,cardiovascular-disease ,population ,Genome-wide association study ,Genetic Loci ,Blood Pressure ,ANGIOTENSINOGEN ,030204 cardiovascular system & hematology ,Linkage Disequilibrium ,0302 clinical medicine ,Gene Frequency ,Receptors ,common variants ,Genetics(clinical) ,ESSENTIAL-HYPERTENSION ,Genetics (clinical) ,POPULATION ,Oligonucleotide Array Sequence Analysis ,Genetics ,0303 health sciences ,education.field_of_study ,Adult ,Aged ,Blood Pressure/genetics ,Case-Control Studies ,Female ,Gene Expression Profiling ,Genome-Wide Association Study ,Haplotypes ,Humans ,Hypertension/genetics ,Middle Aged ,Plasma Membrane Calcium-Transporting ATPases/genetics ,Polymorphism, Single Nucleotide ,Receptors, Atrial Natriuretic Factor/genetics ,Sequence Analysis, DNA ,COMMON VARIANTS ,Single Nucleotide ,3. Good health ,SNP genotyping ,CARDIOVASCULAR-DISEASE ,Hypertension ,Sequence Analysis ,Atrial Natriuretic Factor ,QUANTITATIVE-TRAIT LOCI ,metaanalysis ,essential-hypertension ,SUSCEPTIBILITY LOCI ,Population ,Single-nucleotide polymorphism ,Biology ,Article ,03 medical and health sciences ,Plasma Membrane Calcium-Transporting ATPases ,Polymorphism ,GENOME-WIDE ASSOCIATION ,education ,Genotyping ,Allele frequency ,METAANALYSIS ,Methylenetetrahydrofolate Reductase (NADPH2) ,030304 developmental biology ,quantitative-trait loci ,Haplotype ,Receptors, Atrial Natriuretic Factor ,DNA ,susceptibility loci ,angiotensinogen ,Hypertension/*genetics ,genome-wide association ,linkage disequilibrium - Abstract
Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 x 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery, and follow-up data identified SNPs significantly associated with BP at p < 8.56 x 10(-7) at four further loci (NPR3, FIFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. ispartof: American Journal of Human Genetics vol:89 issue:6 pages:688-700 ispartof: location:United States status: published
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- 2011
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20. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene.
- Author
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Davison LJ, Wallace C, Cooper JD, Cope NF, Wilson NK, Smyth DJ, Howson JM, Saleh N, Al-Jeffery A, Angus KL, Stevens HE, Nutland S, Duley S, Coulson RM, Walker NM, Burren OS, Rice CM, Cambien F, Zeller T, Munzel T, Lackner K, Blakenberg S, Fraser P, Gottgens B, Todd JA, Attwood T, Belz S, Braund P, Cambien F, Cooper J, Crisp-Hihn A, Diemert P, Deloukas P, Foad N, Erdmann J, Goodall AH, Gracey J, Gray E, Williams RG, Heimerl S, Hengstenberg C, Jolley J, Krishnan U, Lloyd-Jones H, Lugauer I, Lundmark P, Maouche S, Moore JS, Muir D, Murray E, Nelson CP, Neudert J, Niblett D, O'Leary K, Ouwehand WH, Pollard H, Rankin A, Rice CM, Sager H, Samani NJ, Sambrook J, Schmitz G, Scholz M, Schroeder L, Schunkert H, Syvannen AC, Tennstedt S, and Wallace C
- Subjects
- Chromosomes, Human, Pair 16, Humans, Monocytes metabolism, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Autoimmune Diseases genetics, DNA genetics, DNA-Binding Proteins genetics, Membrane Proteins genetics
- Abstract
The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes., (© The Author 2011. Published by Oxford University Press.)
- Published
- 2012
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