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Your search keyword '"Johnson, Kathleen [0000-0002-6823-3252]"' showing total 19 results
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19 results on '"Johnson, Kathleen [0000-0002-6823-3252]"'

1. Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

Author

Wang, Jun, Kotagiri, Prasanti, Lyons, Paul, Al-Lamki, Rafia, Mescia, Federica, Bergamaschi, Laura, Turner, Lorinda, Morgan, Michael D, Calero-Nieto, Fernando J, Bach, Karsten, Mende, Nicole, Wilson, Nicola K, Watts, Emily R, Cambridge Institute Of Therapeutic Immunology And Infectious Disease-National Institute Of Health Research (CITIID-NIHR) Covid BioResource Collaboration, Maxwell, Patrick, Chinnery, Patrick F, Kingston, Nathalie, Papadia, Sofia, Stirrups, Kathleen, Walker, Neil, Gupta, Ravindra, Menon, David, Allinson, Kieren, Aitken, Sarah, Toshner, Mark, Weekes, Michael, Nathan, James, Walmsley, Sarah R, Ouwehand, Willem H, Kasanicki, Mary, Gottgens, Berthold, Marioni, John, Smith, Kenneth, Pober, Jordan S, Bradley, John, Wang, Jun [0000-0003-3667-3760], Lyons, Paul [0000-0001-7035-8997], Mende, Nicole [0000-0002-5078-2333], Maxwell, Patrick [0000-0002-0338-2679], Kingston, Nathalie [0000-0002-9190-2231], Johnson, Kathleen [0000-0002-6823-3252], Gupta, Ravindra [0000-0001-9751-1808], Menon, David [0000-0002-3228-9692], Aitken, Sarah [0000-0002-1897-4140], Toshner, Mark [0000-0002-3969-6143], Weekes, Michael [0000-0003-3196-5545], Nathan, James [0000-0002-0248-1632], Gottgens, Berthold [0000-0001-6302-5705], Marioni, John [0000-0001-9092-0852], Smith, Kenneth [0000-0003-3829-4326], Bradley, John [0000-0002-7774-8805], Apollo - University of Cambridge Repository, and Stirrups, Kathleen [0000-0002-6823-3252]

Subjects
FOS: Clinical medicine, FOS: Biological sciences, education, Immunology, Omics, Transcriptomics, Microbiology
Abstract

Funder: Royal Australasian College of Physicians, Funder: NIHR, Funder: UKRI, Funder: Chief Scientist Office, Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

Published
2022

2. Development and validation of a universal blood donor genotyping platform: a multinational prospective study

Author

Gleadall, Nicholas S, Veldhuisen, Barbera, Gollub, Jeremy, Butterworth, Adam S, Ord, John, Penkett, Christopher J, Timmer, Tiffany C, Sauer, Carolin M, Van Der Bolt, Nieke, Brown, Colin, Brugger, Kim, Dilthey, Alexander T, Duarte, Daniel, Grimsley, Shane, Van Den Hurk, Katja, Jongerius, John M, Luken, Jessie, Megy, Karyn, Miflin, Gail, Nelson, Christopher S, Prinsze, Femmeke J, Sambrook, Jennifer, Simeoni, Ilenia, Sweeting, Michael, Thornton, Nicole, Trompeter, Sara, Tuna, Salih, Varma, Ram, Walker, Matthew R, NIHR BioResource, Danesh, John, Roberts, David J, Ouwehand, Willem H, Stirrups, Kathleen E, Rendon, Augusto, Westhoff, Connie M, Di Angelantonio, Emanuele, Van Der Schoot, C Ellen, Astle, William J, Watkins, Nicholas A, Lane, William J, Butterworth, Adam [0000-0002-6915-9015], Sauer, Carolin [0000-0003-2168-6630], Megy, Karyn [0000-0002-2826-3879], Danesh, John [0000-0003-1158-6791], Ouwehand, Willem [0000-0002-7744-1790], Johnson, Kathleen [0000-0002-6823-3252], Rendon Restrepo, Augusto [0000-0001-8994-0039], Di Angelantonio, Emanuele [0000-0001-8776-6719], Astle, William [0000-0001-8866-6672], and Apollo - University of Cambridge Repository

Subjects
Genotype, Isoantibodies, Humans, Blood Donors, Blood Transfusion, Prospective Studies
Abstract

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

Published
2020

3. Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Author

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

Subjects
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.

Published
2020

4. Germline mutations in the transcription factor IKZF5 cause thrombocytopenia

Author

Lentaigne, Claire, Greene, Daniel, Sivapalaratnam, Suthesh, Favier, Remi, Seyres, Denis, Thys, Chantal, Grassi, Luigi, Mangles, Sarah, Sibson, Keith, Stubbs, Matthew, Burden, Frances, Bordet, Jean-Claude, Armari-Alla, Corinne, Erber, Wendy, Farrow, Samantha, Gleadall, Nicholas, Gomez, Keith, Megy, Karyn, Papadia, Sofia, Penkett, Christopher J, Sims, Matthew C, Stefanucci, Luca, Stephens, Jonathan C, Read, Randy J, Stirrups, Kathleen E, Ouwehand, Willem H, Laffan, Michael A, NIHR BioResource, Frontini, Mattia, Freson, Kathleen, Turro, Ernest, Seyres, Denis [0000-0002-2066-6980], Megy, Karyn [0000-0002-2826-3879], Papadia, Sofia [0000-0002-9222-3812], Stefanucci, Luca [0000-0002-4352-1151], Stephens, Jonathan [0000-0003-2020-9330], Read, Randy [0000-0001-8273-0047], Johnson, Kathleen [0000-0002-6823-3252], Ouwehand, Willem [0000-0002-7744-1790], Frontini, Mattia [0000-0001-8074-6299], Turro Bassols, Ernest [0000-0002-1820-6563], and Apollo - University of Cambridge Repository

Subjects
Blood Platelets, Male, Genetic Diseases, Inborn, Mutation, Missense, Cytoplasmic Granules, Thrombocytopenia, Chromatin, Thrombopoiesis, Ikaros Transcription Factor, HEK293 Cells, Gene Expression Regulation, Humans, Female, Germ-Line Mutation
Abstract

To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

Published
2020
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5. Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants

Author

Daniel Duarte, Mariana Bonduel, Sri V V Deevi, Kathleen Stirrups, Paolo Gresele, David Allsup, Rutendo Mapeta, Jonathan Stephens, Tadbir K. Bariana, Kathleen Freson, Nihr BioResource, Ernest Turro, Kim Elliott, Nicola Curry, David Keeling, D. J. Perry, Kate Downes, Carolyn M. Millar, Luigi Grassi, Keith Gomez, Nora Butta, Ilenia Simeoni, Emanuela Falcinelli, Peter William Collins, Michele P. Lambert, Christopher J. Penkett, Loredana Bury, John K. Wu, Nick Gleadall, Karina Althaus, Daniel Greene, Bruce Furie, Willem H. Ouwehand, Rachel Linger, Sarah K Westbury, Karyn Megy, Sarah Mangles, Megy, Karyn [0000-0002-2826-3879], Stephens, Jonathan [0000-0003-2020-9330], Downes, Kate [0000-0003-0366-1579], Johnson, Kathleen [0000-0002-6823-3252], Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], Simeoni, Ilenia [0000-0001-5039-2194], and Apollo - University of Cambridge Repository

Subjects
Male, Variable severity, Fluorescent Antibody Technique, Gene Expression, high throughput next generation sequencing, Child, Genetics (clinical), Research Articles, 0303 health sciences, Kidney, 030305 genetics & heredity, Chromosome Mapping, High-Throughput Nucleotide Sequencing, Middle Aged, Macrothrombocytes, MYH9‐related disorders, ACMG guidelines, 3. Good health, Clinical Practice, medicine.anatomical_structure, Phenotype, clinical diagnosis, Child, Preschool, Female, ACMG Guidelines, Research Article, Adult, medicine.medical_specialty, Adolescent, Genotype, Platelet disorder, genomics, high throughput sequencing, MYH9-related disorders, variant classification, Biology, DNA sequencing, Evolution, Molecular, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, 030304 developmental biology, Aged, Myosin Heavy Chains, Genetic variants, Genetic Variation, Infant, medicine.disease, Bleeding diathesis, Mutation
Abstract

The heterogeneous manifestations of MYH9‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE‐BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9‐RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9‐RD in clinical practice., MYH9‐related disorder diagnosis is still challenging in clinical practice. We analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder and identified 50 patients with a rare variant in MYH9. In the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered.

Published
2020

6. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

Author

Karyn Megy, Nicholas Gleadall, Christopher E. French, Ricardo Garcia Branco, Marie Erwood, Topun Austin, Olga Shamardina, Willem H. Ouwehand, Helen Dolling, F Lucy Raymond, Alba Sanchis-Juan, Luca Stefanucci, Keren J. Carss, Jonathan Stephens, Eleanor Dewhurst, Trevor Cole, Christopher J. Penkett, Isabelle Delon, Detelina Grozeva, Kathleen Stirrups, Andrew R. Webster, Gavin Arno, Stephens, Jonathan [0000-0003-2020-9330], French, Courtney [0000-0001-7620-1544], Shamardina, Olga [0000-0003-4994-2157], Johnson, Kathleen [0000-0002-6823-3252], Dolling, Helen [0000-0001-6279-3622], Stefanucci, Luca [0000-0002-4352-1151], Austin, Topun [0000-0002-8428-8624], Ouwehand, Willem [0000-0002-7744-1790], Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Nanopore, Male, lcsh:QH426-470, Systems biology, CDKL5, lcsh:Medicine, Cell Cycle Proteins, Heterogeneous-Nuclear Ribonucleoprotein U, Biology, Protein Serine-Threonine Kinases, Genome sequencing, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Genetics, CEP78, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Genome, Human, Research, Breakpoint, lcsh:R, Complex structural variant, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Human genetics, ARID1B, DNA-Binding Proteins, lcsh:Genetics, 030104 developmental biology, HNRNPU, Genomic Structural Variation, Mutation, Next-generation sequencing, Molecular Medicine, Identification (biology), Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Background Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. Methods We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. Results We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Conclusions Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation. Electronic supplementary material The online version of this article (10.1186/s13073-018-0606-6) contains supplementary material, which is available to authorized users.

Published
2018

7. The genetic architecture of type 2 diabetes

Author

Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Published
2016

8. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Author

Lawless, D, Geier, CB, Farmer, JR, Lango Allen, H, Thwaites, D, Atschekzei, F, Brown, M, Buchbinder, D, Burns, SO, Butte, MJ, Csomos, K, Deevi, SVV, Egner, W, Ehl, S, Eibl, MM, Fadugba, O, Foldvari, Z, Green, DM, Henrickson, SE, Holland, SM, John, T, Klemann, C, Kuijpers, TW, Moreira, F, Piller, A, Rayner-Matthews, P, Romberg, ND, Sargur, R, Schmidt, RE, Schröder, C, Schuetz, C, Sharapova, SO, Smith, KGC, Sogkas, G, Speckmann, C, Stirrups, K, Thrasher, AJ, Wolf, HM, Notarangelo, LD, Anwar, R, Boyes, J, Ujhazi, B, NIHR BioResource - Rare Diseases Consortium, Thaventhiran, J, Walter, JE, Savic, S, Lango Allen, Hana [0000-0002-7803-8688], Smith, Kenneth [0000-0003-3829-4326], Johnson, Kathleen [0000-0002-6823-3252], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository

Subjects
Adult, DNA-Binding Proteins, Homeodomain Proteins, Immunologic Deficiency Syndromes, Prevalence, Humans, Nuclear Proteins
Published
2018
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9. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease (vol 374, pg 1134, 2016)

Author

Stitziel, Nathan O, Stirrups, Kathleen E, Masca, Nicholas GD, Erdmann, Jeanette, Ferrario, Paola G, Koenig, Inke R, Weeke, Peter E, Webb, Thomas R, Auer, Paul L, Schick, Ursula M, Lu, Yingchang, Zhang, He, Dube, Marie-Pierre, Goel, Anuj, Farrall, Martin, Peloso, Gina M, Won, Hong-Hee, Do, Ron, Van Iperen, Erik, Kanoni, Stavroula, Kruppa, Jochen, Mahajan, Anubha, Scott, Robert A, Willenborg, Christina, Braund, Peter S, Van Capelleveen, Julian C, Doney, Alex SF, Donnelly, Louise A, Asselta, Rosanna, Merlini, Piera A, Duga, Stefano, Marziliano, Nicola, Denny, Josh C, Shaffer, Christian M, El-Mokhtari, Nour Eddine, Franke, Andre, Gottesman, Omri, Heilmann, Stefanie, Hengstenberg, Christian, Hoffmann, Per, Holmen, Oddgeir L, Hveem, Kristian, Jansson, Jan-Hakan, Joeckel, Karl-Heinz, Kessler, Thorsten, Kriebel, Jennifer, Laugwitz, Karl L, Marouli, Eirini, Martinelli, Nicola, McCarthy, Mark I, Van Zuydam, Natalie R, Meisinger, Christa, Esko, Tonu, Mihailov, Evelin, Escher, Stefan A, Alver, Maris, Moebus, Susanne, Morris, Andrew D, Muller-Nurasyid, Martina, Nikpay, Majid, Olivieri, Oliviero, Perreault, Louis-Philippe Lemieux, AlQarawi, Alaa, Robertson, Neil R, Akinsanya, Karen O, Reilly, Dermot F, Vogt, Thomas F, Yin, Wu, Asselbergs, Folkert W, Kooperberg, Charles, Jackson, Rebecca D, Stahl, Eli, Strauch, Konstantin, Varga, Tibor V, Waldenberger, Melanie, Zeng, Lingyao, Kraja, Aldi T, Liu, Chunyu, Ehret, Georg B, Newton-Cheh, Christopher, Chasman, Daniel I, Chowdhury, Rajiv, Ferrario, Marco, Ford, Ian, Jukema, J Wouter, Kee, Frank, Kuulasmaa, Kari, Nordestgaard, Borge G, Perola, Markus, Saleheen, Danish, Sattar, Naveed, Surendran, Praveen, Tregouet, David, Young, Robin, Howson, Joanna MM, Butterworth, Adam S, Danesh, John, Ardissino, Diego, Bottinger, Erwin P, Erbel, Raimund, Franks, Paul W, Girelli, Domenico, Hall, Alistair S, Hovingh, G Kees, Kastrati, Adnan, Lieb, Wolfgang, Meitinger, Thomas, Kraus, William E, Shah, Svati H, McPherson, Ruth, Orho-Melander, Marju, Melander, Olle, Metspalu, Andres, Palmer, Colin NA, Peters, Annette, Rader, Daniel J, Reilly, Muredach P, Loos, Ruth JF, Reiner, Alex P, Roden, Dan M, Tardif, Jean-Claude, Thompson, John R, Wareham, Nicholas J, Watkins, Hugh, Willer, Cristen J, Kathiresan, Sekar, Deloukas, Panos, Samani, Nilesh J, Schunkert, Heribert, Other departments, Vascular Medicine, Johnson, Kathleen [0000-0002-6823-3252], Surendran, Praveen [0000-0002-4911-6077], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
03 medical and health sciences, 0302 clinical medicine, 030212 general & internal medicine, 030204 cardiovascular system & hematology
Abstract

BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10−10) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10−8), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10−4) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10−7). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.)

Published
2017
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10. Rare variants in $\textit{GP1BB}$ are responsible for autosomal dominant macrothrombocytopenia

Author

Sivapalaratnam, S, Westbury, SK, Stephens, JC, Greene, D, Downes, K, Kelly, AM, Lentaigne, C, Astle, WJ, Huizinga, EG, Nurden, P, Papadia, S, Peerlinck, K, Penkett, CJ, Perry, DJ, Roughley, C, Simeoni, I, Stirrups, K, Hart, DP, Tait, RC, Mumford, AD, NIHR BioResource, Laffan, MA, Freson, K, Ouwehand, WH, Kunishima, S, Turro, E, Stephens, Jonathan [0000-0003-2020-9330], Downes, Kate [0000-0003-0366-1579], Astle, William [0000-0001-8866-6672], Papadia, Sofia [0000-0002-9222-3812], Simeoni, Ilenia [0000-0001-5039-2194], Johnson, Kathleen [0000-0002-6823-3252], Ouwehand, Willem [0000-0002-7744-1790], Turro Bassols, Ernest [0000-0002-1820-6563], and Apollo - University of Cambridge Repository

Subjects
Blood Platelets, Male, Genome, Human, Platelet Count, Gene Expression, High-Throughput Nucleotide Sequencing, Hemorrhage, Thrombocytopenia, Pedigree, Platelet Glycoprotein GPIb-IX Complex, Case-Control Studies, Mutation, Humans, Female, Alleles, Genes, Dominant
Abstract

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, $\textit{GP1BBA}$, $\textit{GP1BB}$, and $\textit{GP9}$) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in $\textit{GP1BA}$ have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in $\textit{GP1BB}$ By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in $\textit{GP1BB}$ and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in $\textit{GP1BB}$.

Published
2017

11. Rare and low-frequency coding variants alter human adult height

Author

Stirrups, KE, Butterworth, AS, Chowdhury, R, Danesh, J, Di Angelantonio, E, Howson, JMM, Surendran, P, Young, R, Dennis, JG, Easton, DF, Thompson, DJ, Dunning, AM, Pirie, A, Tyrer, JP, Langenberg, C, Luan, J, Scott, RA, Wareham, NJ, Willems, SM, Zhao, JH, Sivapalaratnam, S, Johnson, Kathleen [0000-0002-6823-3252], Butterworth, Adam [0000-0002-6915-9015], Chowdhury, Rajiv [0000-0003-4881-5690], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], Howson, Joanna [0000-0001-7618-0050], Surendran, Praveen [0000-0002-4911-6077], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Thompson, Deborah [0000-0003-1465-5799], Dunning, Alison [0000-0001-6651-7166], Tyrer, Jonathan [0000-0003-3724-4757], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], and Apollo - University of Cambridge Repository

Subjects
genetic association study, development
Abstract

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome-wide association studies. Here, we report 83 new height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing variants of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Published
2017
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12. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Author

Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, Stitziel, Nathan O, Stirrups, Kathleen E, Masca, Nicholas GD, Erdmann, Jeanette, Ferrario, Paola G, König, Inke R, Weeke, Peter E, Webb, Thomas R, Auer, Paul L, Schick, Ursula M, Lu, Yingchang, Zhang, He, Dube, Marie-Pierre, Goel, Anuj, Farrall, Martin, Peloso, Gina M, Won, Hong-Hee, Do, Ron, van Iperen, Erik, Kanoni, Stavroula, Kruppa, Jochen, Mahajan, Anubha, Scott, Robert A, Willenberg, Christina, Braund, Peter S, van Capelleveen, Julian C, Doney, Alex SF, Donnelly, Louise A, Asselta, Rosanna, Merlini, Piera A, Duga, Stefano, Marziliano, Nicola, Denny, Josh C, Shaffer, Christian M, El-Mokhtari, Nour Eddine, Franke, Andre, Gottesman, Omri, Heilmann, Stefanie, Hengstenberg, Christian, Hoffman, Per, Holmen, Oddgeir L, Hveem, Kristian, Jansson, Jan-Håkan, Jöckel, Karl-Heinz, Kessler, Thorsten, Kriebel, Jennifer, Laugwitz, Karl L, Marouli, Eirini, Martinelli, Nicola, McCarthy, Mark I, Van Zuydam, Natalie R, Meisinger, Christa, Esko, Tõnu, Mihailov, Evelin, Escher, Stefan A, Alver, Maris, Moebus, Susanne, Morris, Andrew D, Müller-Nurasyid, Martina, Nikpay, Majid, Olivieri, Oliviero, Lemieux Perreault, Louis-Philippe, AlQarawi, Alaa, Robertson, Neil R, Akinsanya, Karen O, Reilly, Dermot F, Vogt, Thomas F, Yin, Wu, Asselbergs, Folkert W, Kooperberg, Charles, Jackson, Rebecca D, Stahl, Eli, Strauch, Konstantin, Varga, Tibor V, Waldenberger, Melanie, Zeng, Lingyao, Kraja, Aldi T, Liu, Chunyu, Ehret, George B, Newton-Cheh, Christopher, Chasman, Daniel I, Chowdhury, Rajiv, Ferrario, Marco, Ford, Ian, Jukema, J Wouter, Kee, Frank, Kuulasmaa, Kari, Nordestgaard, Børge G, Perola, Markus, Saleheen, Danish, Sattar, Naveed, Surendran, Praveen, Tregouet, David, Young, Robin, Howson, Joanna MM, Butterworth, Adam S, Danesh, John, Ardissino, Diego, Bottinger, Erwin P, Erbel, Raimund, Franks, Paul W, Girelli, Domenico, Hall, Alistair S, Hovingh, G Kees, Kastrati, Adnan, Lieb, Wolfgang, Meitinger, Thomas, Kraus, William E, Shah, Svati H, McPherson, Ruth, Orho-Melander, Marju, Melander, Olle, Metspalu, Andres, Palmer, Colin NA, Peters, Annette, Rader, Daniel, Reilly, Muredach P, Loos, Ruth JF, Reiner, Alex P, Roden, Dan M, Tardif, Jean-Claude, Thompson, John R, Wareham, Nicholas J, Watkins, Hugh, Willer, Cristen J, Kathiresan, Sekkar, Deloukas, Panos, Samani, Nilesh J, Schunkert, Heribert, Johnson, Kathleen [0000-0002-6823-3252], Chowdhury, Rajiv [0000-0003-4881-5690], Surendran, Praveen [0000-0002-4911-6077], Howson, Joanna [0000-0001-7618-0050], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Male, Genotyping Techniques, education, Mutation, Missense, Coronary Artery Disease, Sequence Analysis, DNA, Middle Aged, Lipoprotein Lipase, Risk Factors, Mutation, Angiopoietin-Like Protein 4, Humans, Female, Angiopoietins, Cell Adhesion Molecules, Triglycerides, Aged
Abstract

BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).

Published
2016

13. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author

Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract

To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.

Published
2016

14. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Author

Simon Stritt, Michael Laffan, Salih Tuna, Sylvia Richardson, David J. Perry, F. Lucy Raymond, Sjoert B. G. Jansen, Myrto Kostadima, Tadbir K. Bariana, Ilenia Simeoni, Steve Austin, Andrew D Mumford, Carolyn M. Millar, Christopher J. Penkett, Sandrine Marlin, Wendy N. Erber, Sol Schulman, William J. Astle, Keith Gomez, Bernhard Nieswandt, Rémi Favier, Sofia Papadia, Claire Lentaigne, Augusto Rendon, Sofie Ashford, Michele P. Lambert, Stephanie Maiwald, Tamam Bakchoul, Peter William Collins, Chris Van Geet, Ernest Turro, Paquita Nurden, Anne M. Kelly, Mary Mathias, Romina Petersen, Rutendo Mapeta, Jonathan Stephens, Daniel Greene, Sarah K Westbury, Chantal Thys, Kathleen Freson, Willem H. Ouwehand, Alan T. Nurden, Kathleen Stirrups, John Bradley, Turro Bassols, Ernest [0000-0002-1820-6563], Astle, William [0000-0001-8866-6672], Papadia, Sofia [0000-0002-9222-3812], Stephens, Jonathan [0000-0003-2020-9330], Tuna, Salih [0000-0003-3606-4367], Simeoni, Ilenia [0000-0001-5039-2194], Johnson, Kathleen [0000-0002-6823-3252], Rendon Restrepo, Augusto [0000-0001-8994-0039], Bradley, John [0000-0002-7774-8805], Raymond, Lucy [0000-0003-2652-3355], Richardson, Sylvia [0000-0003-1998-492X], Ouwehand, Willem [0000-0002-7744-1790], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and Medical Research Council

Subjects
0301 basic medicine, Male, Candidate gene, 030204 cardiovascular system & hematology, Biochemistry, 0302 clinical medicine, Inside BLOOD Commentary, Platelet, DIAPH1, Cytoskeleton, Child, Exome sequencing, Cells, Cultured, Genetics, Cardiovascular Medicine And Haematology, Hematology, Syndrome, Middle Aged, Cell biology, Pedigree, Formins, Sensorineural hearing loss, Female, Adult, Adolescent, Clinical Sciences, Immunology, Biology, Filamentous actin, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, medicine, Humans, Genetic Predisposition to Disease, Hearing Loss, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Aged, BRIDGE-BPD Consortium, Cell Biology, medicine.disease, Thrombocytopenia, 030104 developmental biology, HEK293 Cells, A549 Cells, Case-Control Studies, Mutation, biology.protein, Paediatrics And Reproductive Medicine
Abstract

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MK). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping and similarity regression. We describe two unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 p.R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was associated with reduced proplatelet formation from cultured MKs, cell clustering and abnormal cortical filamentous actin. Similarly, in platelets there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Over-expression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insights into the autoregulation of DIAPH1 activity.

Published
2015

15. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie-France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen-Torvik, Laura J, Grarup, Niels, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork-Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater-Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J., Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii-DerI, Cheng, Ching-Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abbas, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki-Eleni, Frånberg, Mattias, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, I T, Lee, Wen-Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, Malerba, Giovanni, Mamakou, Vasiliki, Marouli, Eirini, Maruthur, Nisa M, Matchan, Angela, McKean-Cowdin, Roberta, McLeod, Olga, Metcalf, Ginger A, Mohlke, Karen L, Muzny, Donna M, Ntalla, Ioanna, Palmer, Nicholette D, Pasko, Dorota, Peter, Andreas, Rayner, Nigel W, Renström, Frida, Rice, Ken, Sala, Cinzia F, Sennblad, Bengt, Serafetinidis, Ioannis, Smith, Jennifer A, Soranzo, Nicole, Speliotes, Elizabeth K, Stahl, Eli A, Stirrups, Kathleen, Tentolouris, Nikos, Thanopoulou, Anastasia, Torres, Mina, Traglia, Michela, Tsafantakis, Emmanouil, Javad, Sundas, Yanek, Lisa R, Zengini, Eleni, Becker, Diane M, Bis, Joshua C, Brown, James B, Adrienne Cupples, L, Hansen, Torben, Ingelsson, Erik, Karter, Andrew J, Lorenzo, Carlos, Mathias, Rasika A, Norris, Jill M, Peloso, Gina M, Sheu, Wayne H.-H., Toniolo, Daniela, Vaidya, Dhananjay, Varma, Rohit, Wagenknecht, Lynne E, Boeing, Heiner, Bottinger, Erwin P, Dedoussis, George, Deloukas, Panos, Ferrannini, Ele, Franco, Oscar H, Franks, Paul W, Gibbs, Richard A, Gudnason, Vilmundur, Hamsten, Anders, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, Hofman, Albert, Jansson, Jan-Håkan, Langenberg, Claudia, Launer, Lenore J, Levy, Daniel, Oostra, Ben A, O’Donnell, Christopher J, O’Rahilly, Stephen, Padmanabhan, Sandosh, Pankow, James S, Polasek, Ozren, Province, Michael A, Rich, Stephen S, Ridker, Paul M, Rudan, Igor, Schulze, Matthias B, Smith, Blair H, Uitterlinden, André G, Walker, Mark, Watkins, Hugh, Wong, Tien Y, Zeggini, Eleftheria, Sharp, Stephen J, Forouhi, Nita G, Kerrison, Nicola D, Lucarelli, Debora ME, Sims, Matt, Barroso, Inês, McCarthy, Mark I, Arriola, Larraitz, Balkau, Beverley, Barricarte, Aurelio, Gonzalez, Carlos, Grioni, Sara, Kaaks, Rudolf, Key, Timothy J, Navarro, Carmen, Nilsson, Peter M, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Sánchez, María–José, Slimani, Nadia, Tjonneland, Anne, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Riboli, Elio, Laakso, Markku, Borecki, Ingrid B, Chasman, Daniel I, Pedersen, Oluf, Psaty, Bruce M, Shyong Tai, E, van Duijn, Cornelia M, Wareham, Nicholas J, Waterworth, Dawn M, Boerwinkle, Eric, Linda Kao, W H, Florez, Jose C, Loos, Ruth J.F., Wilson, James G, Frayling, Timothy M, Siscovick, David S, Dupuis, Josée, Rotter, Jerome I, Meigs, James B, Scott, Robert A, Goodarzi, Mark O, Jennifer Wessel, Audrey Y. Chu, Sara M. Willems, Shuai Wang, Hanieh Yaghootkar, Jennifer A. Brody, Marco Dauriz, Marie France Hivert, Sridharan Raghavan, Leonard Lipovich, Bertha Hidalgo, Keolu Fox, Jennifer E. Huffman, Ping An, Yingchang Lu, Laura J. Rasmussen Torvik, Niels Grarup, Margaret G. Ehm, Li Li, Abigail S. Baldridge, Alena Stančáková, Ravinder Abrol, Céline Besse, Anne Boland, Jette Bork Jensen, Myriam Fornage, Daniel F. Freitag, Melissa E. Garcia, Xiuqing Guo, Kazuo Hara, Aaron Isaacs, Johanna Jakobsdottir, Leslie A. Lange, Jill C. Layton, Man Li, Jing Hua Zhao, Karina Meidtner, Alanna C. Morrison, Mike A. Nalls, Marjolein J. Peter, Maria Sabater Lleal, Claudia Schurmann, Angela Silveira, Albert V. Smith, Lorraine Southam, Marcus H. Stoiber, Rona J. Strawbridge, Kent D. Taylor, Tibor V. Varga, Kristine H. Allin, Najaf Amin, Jennifer L. Aponte, Tin, Aung, Barbieri, CATERINA MARIA, Nathan A. Bihlmeyer, Michael Boehnke, Cristina Bombieri, Donald W. Bowden, Sean M. Burns, Yuning Chen, Yii DerI Chen, Ching Yu Cheng, Adolfo Correa, Jacek Czajkowski, Abbas Dehghan, Georg B. Ehret, Gudny Eiriksdottir, Stefan A. Escher, Aliki Eleni Farmaki, Mattias Frånberg, Giovanni Gambaro, Franco Giulianini, William A. Goddard, Anuj Goel, Omri Gottesman, Megan L. Grove, Stefan Gustafsson, Yang Hai, Göran Hallmans, Jiyoung Heo, Per Hoffmann, Mohammad K. Ikram, Richard A. Jensen, Marit E. Jørgensen, Torben Jørgensen, Maria Karaleftheri, Chiea C. Khor, Andrea Kirkpatrick, Aldi T. Kraja, Johanna Kuusisto, Ethan M. Lange, I. T. Lee, Wen Jane Lee, Aaron Leong, Jiemin Liao, Chunyu Liu, Yongmei Liu, Cecilia M. Lindgren, Allan Linneberg, Giovanni Malerba, Vasiliki Mamakou, Eirini Marouli, Nisa M. Maruthur, Angela Matchan, Roberta McKean Cowdin, Olga McLeod, Ginger A. Metcalf, Karen L. Mohlke, Donna M. Muzny, Ioanna Ntalla, Nicholette D. Palmer, Dorota Pasko, Andreas Peter, Nigel W. Rayner, Frida Renström, Ken Rice, Cinzia F. Sala, Bengt Sennblad, Ioannis Serafetinidis, Jennifer A. Smith, Nicole Soranzo, Elizabeth K. Speliote, Eli A. Stahl, Kathleen Stirrup, Nikos Tentolouris, Anastasia Thanopoulou, Mina Torres, Michela Traglia, Emmanouil Tsafantakis, Sundas Javad, Lisa R. Yanek, Eleni Zengini, Diane M. Becker, Joshua C. Bi, James B. Brown, L. Adrienne Cupple, Torben Hansen, Erik Ingelsson, Andrew J. Karter, Carlos Lorenzo, Rasika A. Mathias, Jill M. Norri, Gina M. Peloso, Wayne H. H. Sheu, Daniela Toniolo, Dhananjay Vaidya, Rohit Varma, Lynne E. Wagenknecht, Heiner Boeing, Erwin P. Bottinger, George Dedoussis, Panos Delouka, Ele Ferrannini, Oscar H. Franco, Paul W. Franks, Richard A. Gibb, Vilmundur Gudnason, Anders Hamsten, Tamara B. Harris, Andrew T. Hattersley, Caroline Hayward, Albert Hofman, Jan Håkan Jansson, Claudia Langenberg, Lenore J. Launer, Daniel Levy, Ben A. Oostra, Christopher J. O’Donnell, Stephen O’Rahilly, Sandosh Padmanabhan, James S. Pankow, Ozren Polasek, Michael A. Province, Stephen S. Rich, Paul M. Ridker, Igor Rudan, Matthias B. Schulze, Blair H. Smith, André G. Uitterlinden, Mark Walker, Hugh Watkins, Tien Y. Wong, Eleftheria Zeggini, The EPIC InterAct Consortium, Markku Laakso, Ingrid B. Borecki, Daniel I. Chasman, Oluf Pedersen, Bruce M. Psaty, E. Shyong Tai, Cornelia M. van Duijn, Nicholas J. Wareham, Dawn M. Waterworth, Eric Boerwinkle, W. H. Linda Kao, Jose C. Florez, Ruth J. F. Loos, James G. Wilson, Timothy M. Frayling, David S. Siscovick, Josée Dupuis, Jerome I. Rotter, James B. Meigs, Robert A. Scott, Mark O., Goodarzi, Wessel, Jennifer, Chu, Audrey Y, Willems, Sara M, Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A, Dauriz, Marco, Hivert, Marie France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E, An, Ping, Lu, Yingchang, Rasmussen Torvik, Laura J, Grarup, Niel, Ehm, Margaret G, Li, Li, Baldridge, Abigail S, Stančáková, Alena, Abrol, Ravinder, Besse, Céline, Boland, Anne, Bork Jensen, Jette, Fornage, Myriam, Freitag, Daniel F, Garcia, Melissa E, Guo, Xiuqing, Hara, Kazuo, Isaacs, Aaron, Jakobsdottir, Johanna, Lange, Leslie A, Layton, Jill C, Li, Man, Hua Zhao, Jing, Meidtner, Karina, Morrison, Alanna C, Nalls, Mike A, Peters, Marjolein J, Sabater Lleal, Maria, Schurmann, Claudia, Silveira, Angela, Smith, Albert V, Southam, Lorraine, Stoiber, Marcus H, Strawbridge, Rona J, Taylor, Kent D, Varga, Tibor V, Allin, Kristine H, Amin, Najaf, Aponte, Jennifer L, Aung, Tin, Barbieri, Caterina, Bihlmeyer, Nathan A, Boehnke, Michael, Bombieri, Cristina, Bowden, Donald W, Burns, Sean M, Chen, Yuning, Chen, Yii DerI, Cheng, Ching Yu, Correa, Adolfo, Czajkowski, Jacek, Dehghan, Abba, Ehret, Georg B, Eiriksdottir, Gudny, Escher, Stefan A, Farmaki, Aliki Eleni, Frånberg, Mattia, Gambaro, Giovanni, Giulianini, Franco, Goddard, William A, Goel, Anuj, Gottesman, Omri, Grove, Megan L, Gustafsson, Stefan, Hai, Yang, Hallmans, Göran, Heo, Jiyoung, Hoffmann, Per, Ikram, Mohammad K, Jensen, Richard A, Jørgensen, Marit E, Jørgensen, Torben, Karaleftheri, Maria, Khor, Chiea C, Kirkpatrick, Andrea, Kraja, Aldi T, Kuusisto, Johanna, Lange, Ethan M, Lee, I. T, Lee, Wen Jane, Leong, Aaron, Liao, Jiemin, Liu, Chunyu, Liu, Yongmei, Lindgren, Cecilia M, Linneberg, Allan, Malerba, Giovanni, Mamakou, Vasiliki, Marouli, Eirini, Maruthur, Nisa M, Matchan, Angela, McKean Cowdin, Roberta, Mcleod, Olga, Metcalf, Ginger A, Mohlke, Karen L, Muzny, Donna M, Ntalla, Ioanna, Palmer, Nicholette D, Pasko, Dorota, Peter, Andrea, Rayner, Nigel W, Renström, Frida, Rice, Ken, Sala, Cinzia F, Sennblad, Bengt, Serafetinidis, Ioanni, Smith, Jennifer A, Soranzo, Nicole, Speliotes, Elizabeth K, Stahl, Eli A, Stirrups, Kathleen, Tentolouris, Niko, Thanopoulou, Anastasia, Torres, Mina, Traglia, Michela, Tsafantakis, Emmanouil, Javad, Sunda, Yanek, Lisa R, Zengini, Eleni, Becker, Diane M, Bis, Joshua C, Brown, James B, Cupples, L. Adrienne, Hansen, Torben, Ingelsson, Erik, Karter, Andrew J, Lorenzo, Carlo, Mathias, Rasika A, Norris, Jill M, Peloso, Gina M, Sheu, Wayne H. H, Toniolo, Daniela, Vaidya, Dhananjay, Varma, Rohit, Wagenknecht, Lynne E, Boeing, Heiner, Bottinger, Erwin P, Dedoussis, George, Deloukas, Pano, Ferrannini, Ele, Franco, Oscar H, Franks, Paul W, Gibbs, Richard A, Gudnason, Vilmundur, Hamsten, Ander, Harris, Tamara B, Hattersley, Andrew T, Hayward, Caroline, Hofman, Albert, Jansson, Jan Håkan, Langenberg, Claudia, Launer, Lenore J, Levy, Daniel, Oostra, Ben A, O'Donnell, Christopher J, O'Rahilly, Stephen, Padmanabhan, Sandosh, Pankow, James S, Polasek, Ozren, Province, Michael A, Rich, Stephen S, Ridker, Paul M, Rudan, Igor, Schulze, Matthias B, Smith, Blair H, Uitterlinden, André G, Walker, Mark, Watkins, Hugh, Wong, Tien Y, Zeggini, Eleftheria, Laakso, Markku, Borecki, Ingrid B, Chasman, Daniel I, Pedersen, Oluf, Psaty, Bruce M, Tai, E. Shyong, van Duijn, Cornelia M, Wareham, Nicholas J, Waterworth, Dawn M, Boerwinkle, Eric, Kao, W. H. Linda, Florez, Jose C, Loos, Ruth J. F, Wilson, James G, Frayling, Timothy M, Siscovick, David S, Dupuis, Josée, Rotter, Jerome I, Meigs, James B, Scott, Robert A, Goodarzi, Mark O., Panico, Salvatore, Soranzo, Nicole [0000-0003-1095-3852], Johnson, Kathleen [0000-0002-6823-3252], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Epidemiology, Surgery, Internal Medicine, Radiology & Nuclear Medicine, Clinical Genetics, Obstetrics & Gynecology, and Cell biology

Subjects
Blood Glucose, diabetes, exome chip, SEQUENCING DATA, European Continental Ancestry Group, Black People, Genetic Association Studie, Endocrinology and Diabetes, TRIGLYCERIDE LEVELS, Polymorphism, Single Nucleotide, Article, White People, Glucagon-Like Peptide-1 Receptor, Cohort Studies, SDG 3 - Good Health and Well-being, Mutation Rate, GLYCEMIC TRAITS, Humans, Settore MED/14 - NEFROLOGIA, Insulin, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genetic Association Studies, African Continental Ancestry Group, Oligonucleotide Array Sequence Analysis, PLASMA-GLUCOSE, INSULIN-RESISTANCE, epidemiology/genetics, Science & Technology, GLUCAGON-LIKE PEPTIDE-1, Diabetes, Genetic Variation, GERMLINE MUTATIONS, Fasting, epidemiology/genetics, Cohort Studies, Exome, diabetes, Multidisciplinary Sciences, RECEPTOR GENE, Diabetes Mellitus, Type 2, Genetic Loci, Endokrinologi och diabetes, CODING VARIATION, Glucose-6-Phosphatase, Science & Technology - Other Topics, exome chip, Human
Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility., Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.

Published
2015

16. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, de Geus, Eco JC, de Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, van Dijk, Suzanne C, van Schoor, Natasja M, Asselbergs, Folkert W, de Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, Loos, Ruth JF, Division of Statistical Genomics, Washington University School of Medicine, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Metabolic Science, MRC, Brown University, Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), King‘s College London, Groningen Bioinformatics Centre, GBB, University of Groningen [Groningen], University of Queensland [Brisbane], National Institut of Food Science and Technology, University of Agriculture, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of neurology, Leiden University Medical Center (LUMC), University of Washington [Seattle], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Limnology, Ecology, Department of Ecology and Evolutionary Biology, University of California, Core Genotyping Facility, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Chemical Engineering Taiwan (DCET - NTHU), National Tsing Hua University [Hsinchu] (NTHU), University of Oxford [Oxford], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Medical Sciences, Department of Educational Psychology and Counseling, National Taiwan Normal University (NTNU), Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE Genetics, deCODE genetics [Reykjavik], Interuniversity Cardiology Institute Netherlands, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], Medical Department III, Universität Leipzig [Leipzig], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], GNS Science, Blackett Laboratory, Imperial College London, Medstar Research Institute, University of Rochester [USA], MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Dept Biochem & Mol Biol, Pennsylvania State University (Penn State), Penn State System-Penn State System, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Epidemiology, University Medical Centre Groningen, Unit for Molecular Epidemiology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (KU), Faculty of Medicine, Institute of Public Health, Aalborg University [Denmark] (AAU), Department of Nutrition-Dietetics, Harokopio University of Athens, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College of London [London] (UCL), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Research Center for Prevention and Health, Glostrup Hospital, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Cambridge Institute of Public Health, University of Cambridge [UK] (CAM), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Queensland Institute of Medical Research, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Head of Medical Sequencing, Department of Biostatistics, University of Washington, Department of Chronic Disease Prevention, Molecular Epidemiology, Department of Genetics, Université Laval [Québec] (ULaval), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Université de Lausanne (UNIL), Carl Gustav Carus University Hospital, Loughborough University, Genomics and Bioinformatics Platform, Fondazione Filarete, Department of Medicine, Surgery, and Dentistry, University of Milano, Medizinische Klinik II, Universität zu Lübeck [Lübeck], Department of Genomic Medicine, University of Manchester [Manchester], The Wellcome Trust Centre for Human Genetics [Oxford], National Institutes of Health [Bethesda] (NIH), Department of Nephrology, University Medical Center, University of Groningen, Helmholtz-Zentrum München (HZM), Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Genetics and Pathology, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Franz-Volhard-Centrum für Klinische Forschung, ECRC, Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Finnish Institute of Occupational Health of Helsinki, Department of Clinical Chemistry, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Oncology, University of Tampere Medical School, University of Tampere, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, Department of Medicine, Montreal, Developmental Brain and Behaviour Unit, University of Southampton, Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Interdisciplinary Center for Psychiatric Epidemiology, Experimental Cardiology Laboratory, University Medical Center [Utrecht], Peter MacCallum Cancer Center, Faculty of Health Sciences, Aarhus University [Aarhus], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Department of Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Department of Epidemiology, University of Washington, Department of Medicine, University of Washington, Cardiovascular Health Research Unit, University of Washington, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital (TYKS), Erasmus Medical Centre, Cedars-Sinai Medical Center, Department of Pathological Biochemistry, Royal Infirmary, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Maastricht University [Maastricht], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Epidemiology & Biostatistics, Radboud University Medical Center [Nijmegen], Institute for Community Medicine, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), MRC epidemiology Unit, Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Department of Genetics and Biotechnology, Wellcome Trust, Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Department of Medical Genetics, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), P30 AG010161/AG/NIA NIH HHS/United States, Psychiatry, Epidemiology and Data Science, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, RS: CARIM - R3 - Vascular biology, MUMC+: DA BV AIOS Radiologie (9), Epidemiologie, Orthopedie, Institute for Molecular Medicine Finland, Helsinki Collegium for Advanced Studies, Behavioural Sciences, University of Helsinki, Transplantation Laboratory, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Marja-Liisa Lokki / Principal Investigator, Kardiologian yksikkö, Leif Groop Research Group, Quantitative Genetics, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Ehret, Georg Benedikt, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universiteit Leiden-Universiteit Leiden, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), University of California (UC), University of Oxford, Lund University [Lund], Universität Leipzig, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, University of Copenhagen = Københavns Universitet (UCPH), Université de Lausanne = University of Lausanne (UNIL), Universität zu Lübeck = University of Lübeck [Lübeck], Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Gothenburg (GU)-Institute of Medicine, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Luan, Jian'an [0000-0003-3137-6337], Tyrer, Jonathan [0000-0003-3724-4757], Forouhi, Nita [0000-0002-5041-248X], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Biochemistry, Surgery, Internal Medicine, Public Health, Medical Oncology, Pathology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Male, Cancer Research, endocrine system diseases, Biological pathways, QH426-470, Genome, Body Mass Index, Body Size, Genetics (clinical), ddc:616, Genetics & Heredity, Sex Characteristics, Loci, MAGIC Consortium, Mass index, Age Factors, Chromosome Mapping, Middle Aged, Genealogy, Self-reported height, Peripheral-blood, Scale (social sciences), ICBP Consortium, Female, Life Sciences & Biomedicine, Medical Genetics, Research Article, arcOGEN Consortium, musculoskeletal diseases, Adult, European Continental Ancestry Group, Natural menopause, Aged, Body Size/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Biology, Body size, DIAGRAM Consortium, Age and sex, White People, Fat distribution, GLGC Consortium, 03 medical and health sciences, Life-course, Genetics, Weight-gain, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0604 Genetics, Science & Technology, nutritional and metabolic diseases, Correction, 030104 developmental biology, GWAS meta-analysis, Global-BPGen Consortium, Common SNPS, CHARGE Consortium, 3111 Biomedicine, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR, Author Summary Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.

Published
2014

17. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

18. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author

Surendran, P., Drenos, F., Young, R., Warren, H., Cook, J.P., Manning, A.K., Grarup, N., Sim, X., Barnes, D.R., Witkowska, K., Staley, J.R., Tragante, V., Tukiainen, T., Yaghootkar, H., Masca, N., Freitag, D.F., Ferreira, T., Giannakopoulou, O., Tinker, A., Harakalova, M., Mihailov, E., Liu, C., Kraja, A.T., Nielsen, S.F., Rasheed, A., Samue, M., Zhao, W., Bonnycastle, L.L., Jackson, A.U., Narisu, N., Swift, A.J., Southam, L., Marten, J., Huyghe, J.R., Stancakova, A., Fava, C., Ohlsson, T., Matchan, A., Stirrups, K.E., Bork-Jensen, J., Gjesing, A.P., Kontto, J., Perola, M., Shaw-Hawkins, S., Havulinna, A.S., Zhang, H., Donnelly, L.A., Groves, C.J., Rayner, N.W., Neville, M.J., Robertson, N.R., Yiorkas, A.M., Herzig, K.H., Kajantie, E., Zhang, W., Willems, S.M., Lannfelt, L., Malerba, G., Soranzo, N., Trabetti, E., Verweij, N., Evangelou, E., Moayyeri, A., Vergnaud, A.C., Nelson, C.P., Poveda, A., Varga, T.V., Caslake, M., Craen, A.J.M. de, Trompet, S., Luan, J., Scott, R.A., Harris, S.E., Liewald, D.C.M., Marioni, R., Menni, C., Farmaki, A.E., Hallmans, G., Renstrom, F., Huffman, J.E., Hassinen, M., Burgess, S., Vasan, R.S., Felix, J.F., Uria-Nickelsen, M., Malarstign, A., Reilly, D.F., Hoek, M., Vogt, T.F., Lin, H.H., Lieb, W., Traylor, M., Markus, H.S., Highland, H.M., Justice, A.E., Marouli, E., Lindstrom, J., Uusitupa, M., Komulainen, P., Lakka, T.A., Rauramaa, R., Polasek, O., Rudan, I., Rolandsson, O., Franks, P.W., Dedoussis, G., Spector, T.D., Jousilahti, P., Mannisto, S., Deary, I.J., Starr, J.M., Langenberg, C., Wareham, N.J., Brown, M.J., Dominiczak, A.F., Connell, J.M., Jukema, J.W., Sattar, N., Ford, I., Packard, C.J., Esko, T., Magi, R., Metspalu, A., Boer, R.A. de, Meer, P. van der, Harst, P. van der, Gambaro, G., Ingelsson, E., Lind, L., Bakker, P.I.W. de, Numans, M.E., Brandslund, I., Christensen, C., Petersen, E.R.B., Korpi-Hyovalti, E., Oksa, H., Chambers, J.C., Kooner, J.S., Blakemore, A.I.F., Franks, S., Jarvelin, M.R., Husemoen, L.L., Linneberg, A., Skaaby, T., Thuesen, B., Karpe, F., Tuomilehto, J., Doney, A.S.F., Morris, A.D., Palmer, C.N.A., Holmen, O.L., Hveem, K., Willer, C.J., Tuomi, T., Groop, L., Karajamaki, A., Palotie, A., Ripatti, S., Salomaa, V., Alam, D.S., Majmnder, A.A.S., Angelantonio, E. di, Chowdhury, R., McCarthy, M.I., Poulter, N., Stanton, A.V., Sever, P., Amouyel, P., Arveiler, D., Blankenberg, S., Ferrieres, J., Kee, F., Kuulasmaa, K., Muller-Nurasyid, M., Veronesi, G., Virtamo, J., Deloukas, P., Elliott, P., Zeggini, E., Kathiresan, S., Melander, O., Kuusisto, J., Laakso, M., Padmanabhan, S., Porteous, D.J., Hayward, C., Scotland, G., Collins, F.S., Mohlke, K.L., Hansen, T., Pedersen, O., Boehnke, M., Stringham, H.M., Frossard, P., Newton-Cheh, C., Tobin, M.D., Nordestgaard, B.G., Caulfield, M.J., Mahajan, A., Morris, A.P., Tomaszewski, M., Samani, N.J., Saleheen, D., Asselbergs, F.W., Lindgren, C.M., Danesh, J., Wain, L.V., Butterworth, A.S., Howson, J.M.M., Munroe, P.B., CHARGE Heart Failure Consortiumm, EchoGen Consortiumm, Metastroke Consortiumm, Giant Consortiumm, EPIC-InterAct Consortium, Lifelines Cohort Study, Wellcome Trust Case Control Consor, Understanding Soc Sci Grp, EPIC-CVD Consortium, CHARGE Exome Chip Blood Pressure C, T2D-GENES Consortium, GoT2DGenes Consortium, ExomeBP Consortium, CHD Exome Consortium, Erasmus MC other, Epidemiology, Internal Medicine, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Surendran, Praveen [0000-0002-4911-6077], Barnes, Daniel [0000-0002-3781-7570], Marten, Jonathan [0000-0001-6916-2014], Johnson, Kathleen [0000-0002-6823-3252], Soranzo, Nicole [0000-0003-1095-3852], Luan, Jian'an [0000-0003-3137-6337], Burgess, Stephen [0000-0001-5365-8760], Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Di Angelantonio, Emanuele [0000-0001-8776-6719], Chowdhury, Rajiv [0000-0003-4881-5690], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Apollo - University of Cambridge Repository, British Heart Foundation, Home Office, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, and Action on Hearing Loss

Subjects
0301 basic medicine, EchoGen Consortium, Population genetics, LOCI, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, 0302 clinical medicine, Settore MED/14 - NEFROLOGIA, Missense mutation, GENE-CENTRIC ARRAY, GoT2DGenes Consortium, AGING RESEARCH, Genetics, education.field_of_study, CHD Exome+ Consortium, CHARGE-Heart Failure Consortium, 11 Medical And Health Sciences, 3. Good health, CARDIOVASCULAR-DISEASE, Hypertension, Medical genetics, HEART, Wellcome Trust Case Control Consortium, EPIC-InterAct Consortium, ExomeBP Consortium, CHARGE, Understanding Society Scientific Group, medicine.medical_specialty, Genotype, Population, Biology, CHARGE+ Exome Chip Blood Pressure Consortium, EPIC-CVD Consortium, Article, 03 medical and health sciences, Lifelines Cohort Study, genome-wide association studies, hypertension, population genetics, Genetic variation, GIANT Consortium, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, PLASMA-LEVELS, IDENTIFICATION, Genetic Variation, 06 Biological Sciences, medicine.disease, METASTROKE Consortium, T2D-GENES Consortium, 030104 developmental biology, Blood pressure, Pathophysiology of hypertension, RISK-FACTORS, Developmental Biology, Genome-Wide Association Study, blood pressure, gene
Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ~155,063 samples for independent replication. We identified 30 new blood pressure– or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention. N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure -lowering or lipid-lowering agents, or both, and consultancy fees. S.K. has received research grants from Merck, Bayer and Aegerion, is on the SAB of Catabasis, Regeneron Genetics Center, Merck and Celera, has equity in San Therapeutics and Catabasis, and performs consulting for Novartis, Aegerion, Bristol Myers Squibb, Sanofi, AstraZeneca and Alnylam. P. Sever has received research awards from Pfizer. A. Malarstig and M.U.-N. are full-time employees of Pfizer. D.F.R. and M. Hoek are full-time employees of Merck. M.J.C. is Chief Scientist for Genomics England, a UK government company. The authors declare no other competing financial interests.

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19. Systematic evaluation of pleiotropy identifies 6 further loci associated with coronary artery disease

Author

Webb, T, Erdmann, J, Stirrups, K, Stitziel, N, Masca, N, Jansen, H, Kanoni, S, Nelson, C, Ferrario, P, König, I, Eicher, J, Johnson, A, Hamby, S, Betsholtz, C, Ruusalepp, A, Franzén, O, Schadt, E, Björkegren, J, Weeke, P, Auer, P, Schick, U, Lu, Y, Zhang, H, Dube, M, Goel, A, Farrall, M, Peloso, G, Won, H, Do, R, van Iperen, E, Kruppa, J, Mahajan, A, Scott, R, Willenborg, C, Braund, P, van Capelleveen, J, Doney, A, Donnelly, L, Asselta, R, Merlini, P, Duga, S, Marziliano, N, Denny, J, Shaffer, C, El-Mokhtari, N, Franke, A, Heilmann, S, Hengstenberg, C, Hoffmann, P, Holmen, O, Hveem, K, Jansson, J, Jöckel, K, Kessler, T, Kriebel, J, Laugwitz, K, Marouli, E, Martinelli, N, McCarthy, M, Van Zuydam, N, Meisinger, C, Esko, T, Mihailov, E, Escher, S, Alver, M, Moebus, S, Morris, A, Virtamo, J, Nikpay, M, Olivieri, O, Provost, S, AlQarawi, A, Robertson, N, Akinsansya, K, Reilly, D, Vogt, T, Yin, W, Asselbergs, F, Kooperberg, C, Jackson, R, Stahl, E, Müller-Nurasyid, M, Strauch, K, Varga, T, Waldenberger, M, Consortium, Wellcome Trust Case Control, Zeng, L, Chowdhury, R, Salomaa, V, Ford, I, Jukema, J, Amouyel, P, Kontto, J, Investigators, MORGAM, Nordestgaard, B, Ferrières, J, Saleheen, D, Sattar, N, Surendran, P, Wagner, A, Young, R, Howson, J, Butterworth, A, Danesh, J, Ardissino, D, Bottinger, E, Erbel, R, Franks, P, Girelli, D, Hall, A, Hovingh, G, Kastrati, A, Lieb, W, Meitinger, T, Kraus, W, Shah, S, McPherson, R, Orho-Melander, M, Melander, O, Metspalu, A, Palmer, C, Peters, A, Rader, D, Reilly, M, Loos, R, Reiner, A, Roden, D, Tardif, J, Thompson, J, Wareham, N, Watkins, H, Willer, C, Samani, N, Schunkert, H, Deloukas, P, Kathiresan, S, Investigators, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, Johnson, Kathleen [0000-0002-6823-3252], Chowdhury, Rajiv [0000-0003-4881-5690], Surendran, Praveen [0000-0002-4911-6077], Howson, Joanna [0000-0001-7618-0050], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
expression quantitative trait loci, single nucleotide polymorphism, cholesteryl ester transfer protein, genome-wide association, genetics
Abstract

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

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