Author: "Fadista, J." - Searchworks@Jio Institute Digital Library Search Results

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1. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes

Author: Skotte, L, Fadista, J, Bybjerg-Grauholm, J, Appadurai, V, Hildebrand, MS, Hansen, TF, Banasik, K, Grove, J, Albinana, C, Geller, F, Bjurstrom, CF, Vilhjalmsson, BJ, Coleman, M, Damiano, JA, Burgess, R, Scheffer, IE, Pedersen, OBV, Erikstrup, C, Westergaard, D, Nielsen, KR, Sorensen, E, Bruun, MT, Liu, X, Hjalgrim, H, Pers, TH, Mortensen, PB, Mors, O, Nordentoft, M, Dreier, JW, Borglum, AD, Christensen, J, Hougaard, DM, Buil, A, Hviid, A, Melbye, M, Ullum, H, Berkovic, SF, Werge, T, Feenstra, B, Skotte, L, Fadista, J, Bybjerg-Grauholm, J, Appadurai, V, Hildebrand, MS, Hansen, TF, Banasik, K, Grove, J, Albinana, C, Geller, F, Bjurstrom, CF, Vilhjalmsson, BJ, Coleman, M, Damiano, JA, Burgess, R, Scheffer, IE, Pedersen, OBV, Erikstrup, C, Westergaard, D, Nielsen, KR, Sorensen, E, Bruun, MT, Liu, X, Hjalgrim, H, Pers, TH, Mortensen, PB, Mors, O, Nordentoft, M, Dreier, JW, Borglum, AD, Christensen, J, Hougaard, DM, Buil, A, Hviid, A, Melbye, M, Ullum, H, Berkovic, SF, Werge, T, and Feenstra, B
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
Published: 2022

2. The Genetic Landscape of Renal Complications in Type 1 Diabetes

Author: Sandholm, Niina, Van Zuydam, Natalie, Ahlqvist, Emma, Juliusdottir, Thorhildur, Deshmukh, Harshal A., Rayner, N. William, Di Camillo, Barbara, Forsblom, Carol, Fadista, Joao, Ziemek, Daniel, Salem, Rany M., Hiraki, Linda T., Pezzolesi, Marcus, Trégouët, David, Dahlström, Emma, Valo, Erkka, Oskolkov, Nikolay, Ladenvall, Claes, Marcovecchio, M. Loredana, Cooper, Jason, Sambo, Francesco, Malovini, Alberto, Manfrini, Marco, McKnight, Amy Jayne, Lajer, Maria, Harjutsalo, Valma, Gordin, Daniel, Parkkonen, Maija, Lyssenko, Valeriya, McKeigue, Paul M., Rich, Stephen S., Brosnan, Mary Julia, Fauman, Eric, Bellazzi, Riccardo, Rossing, Peter, Hadjadj, Samy, Krolewski, Andrzej, Paterson, Andrew D., Hirschhorn, Joel N., Maxwell, Alexander P., Cobelli, Claudio, Colhoun, Helen M., Groop, Leif, McCarthy, Mark I., Groop, Per-Henrik, Sandholm, N., Van Zuydam, N., Ahlqvist, E., Juliusdottir, T., Deshmukh, H.A., Di Camillo, B., Forsblom, C., Fadista, J., Ziemek, D., Salem, R.M., Hiraki, L.T., Pezzolesi, M., Trégouët, D., Dahlström, E., Valo, E., Oskolkov, N., Ladenvall, C., Marcovecchio, M.L., Cooper, J., Sambo, F., Malovini, A., Manfrini, M., McKnight, A. J., Lajer, M., V, Gordin, D., Parkkonen, M., Tuomilehto, J., V, McKeigue, P.M., Rich, S.S., Brosnan, M.J., Fauman, E., Bellazzi, R., Rossing, P., Hadjadj, S., Krolewski, A., Paterson, A.D., Florez, J.C., Hirschhorn, J.N., Maxwell, A.P., Dunger, D., Cobelli, C., Colhoun, H.M., Groop, L., McCarthy, M.I., and Groop, P.-H.
Published: 2017
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3. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability (Nature Communications, (2021), 12, 1, (24), 10.1038/s41467-020-19366-9)

Author: Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J.L. (Josine L.), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A.J. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), Geus, E.J.C. (Eco) de, Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), Duijn, C.M. (Cornelia) van, Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Matullo, G., Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth J. F.), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P. (Patricia), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Barroso, I.E. (Inês), Morris, A.P. (Andrew), Prokopenko, I. (Inga), Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J.L. (Josine L.), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A.J. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), Geus, E.J.C. (Eco) de, Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), Duijn, C.M. (Cornelia) van, Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Matullo, G., Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth J. F.), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P. (Patricia), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Barroso, I.E. (Inês), Morris, A.P. (Andrew), and Prokopenko, I. (Inga)
Abstract: The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.
Published: 2021
Full Text: View/download PDF

4. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J. (Josine), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah H.), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), de Geus, E.J.C.N. (Eco J. C. N.), Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard O.), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), van Duijn, C.M. (Cornelia M.), Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy L.), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Navis, G. (Gerjan), Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P.B. (Patricia B.), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Dupuis, J. (Josée), Barroso, I.E. (Inês), Morris, A.P. (Andrew P.), Prokopenko, I. (Inga), Lagou, V. (Vasiliki), Mägi, R. (Reedik), Hottenga, J.J. (Jouke Jan), Grallert, H. (Harald), Perry, J.R.B. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J. (Josine), Dimas, A.S. (Antigone), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gådin, J.R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amélie), Fadista, J. (João), Stathopoulou, M.G. (Maria G), Isaacs, A. (Aaron), Willems, S.M. (Sara), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A.U. (Anne U.), Montasser, M.E. (May E.), O’Connell, J.R. (Jeff R.), Bielak, L.F. (Lawrence F.), Webster, R.J. (Rebecca J.), Meitinger, T. (Thomas), Stafford, M., Pourcain, B.S. (Beate St), Timpson, N.J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y., Amin, N. (Najaf), Smith, A.V. (Albert), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P.C.D. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R.J. (Rona), Rasmussen-Torvik, L.J. (Laura), Esko, T. (Tõnu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R.M. (Ross), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M.E. (Marcus E.), Silbernagel, G. (Günther), Meyer, J. (Julia), Müller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P., Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian’an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N.W. (Nigel William), Nolte, I.M. (Ilja), Zemunik, T. (Tatijana), Iperen, E. (Erik van), Kovacs, P. (Peter), Hastie, N. (Nick), Wild, S.H. (Sarah H.), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O.D. (Olga), Egan, J. (Josephine), Kieß, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A.A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Kao, W.H.L. (Wen), Doney, A.S.F. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A.J. (Amanda J.), Groves, C.J. (Christopher J.), Herder, C. (Christian), Koistinen, H.A. (Heikki A.), Kinnunen, L. (Leena), Faire, U.D. (Ulf), Bakker, S.J.L. (Stephan), Uusitupa, M. (Matti), Palmer, C.N.A. (Colin N. A.), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E.A. (Eric), Palmer, C.N.A. (Colin), Magnusson, P.K. (Patrik), Krus, U. (Ulrika), Scapoli, C. (Chiara), de Geus, E.J.C.N. (Eco J. C. N.), Blüher, M. (Matthias), Wolffenbuttel, B.H.R. (Bruce), Province, M.A. (Michael A.), Abecasis, G.R. (Goncalo R.), Meigs, J.B. (James B.), Hovingh, G.K. (G. Kees), Lindström, J. (Jaana), Wilson, J.F. (James F.), Wright, A.F. (Alan F.), Dedoussis, G.V. (George), Bornstein, S.R. (Stefan), Schwarz, P.E.H. (Peter), Tönjes, A. (Anke), Winkelmann, B., Boehm, B.O. (Bernhard O.), März, W. (Winfried), Metspalu, A. (Andres), Price, J.F. (Jackie F.), Deloukas, P. (Panos), Körner, A. (Antje), Lakka, T.A. (Timo), Keinanen-Kiukaanniemi, S. (Sirkka), Saaristo, T. (Timo), Bergman, R.N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N.J. (Nick), Langenberg, C. (Claudia), Männistö, S. (Satu), Franks, P.W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), van Duijn, C.M. (Cornelia M.), Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N.L. (Nancy L.), Pramstaller, P.P. (Peter Paul), Boehnke, M. (Michael), Frayling, T.M. (Timothy M.), Shuldiner, A.R. (Alan R.), Peyser, P.A. (Patricia A.), Kardia, S.L.R. (Sharon L. R.), Palmer, L.J. (Lyle J.), Penninx, B.W.J.H. (Brenda), Meneton, P. (Pierre), Harris, T.B. (Tamara), Navis, G. (Gerjan), Harst, P. (Pim van der), Smith, G.D. (George Davey), Forouhi, N.G. (Nita), Loos, R.J.F. (Ruth), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D.I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P.B. (Patricia B.), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Watkins, H. (Hugh), Lecoeur, C. (Cécile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Zwart, J-A. (John-Anker), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Frants, R.R. (Rune), Lindgren, C.M. (Cecilia M.), McCarthy, M.I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M.A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R.M. (Richard), Ingelsson, E. (Erik), Sijbrands, E.J.G. (Eric), Dupuis, J. (Josée), Barroso, I.E. (Inês), Morris, A.P. (Andrew P.), and Prokopenko, I. (Inga)
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021
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5. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Lagou, V, Mägi, R, Hottenga, JJ, Grallert, H, Perry, JR, Bouatia-Naji, N, Marullo, L, Rybin, D, Jansen, R, Min, JL, Dimas, AS, Ulrich, A, Zudina, L, Gådin, JR, Jiang, L, Faggian, A, Bonnefond, A, Fadista, J, Stathopoulou, MG, Isaacs, Aaron, Willems, SM, Navarro, P, Tanaka, T, Jackson, AU, Montasser, ME, O’Connell, JR, Bielak, LF, Webster, RJ, Saxena, R, Stafford, JM, Pourcain, BS, Timpson, NJ, Salo, P, Shin, SY, Amin, Najaf, Smith, AV, Li, G, Verweij, N, Goel, A, Ford, I, Johnson, PCD, Johnson, T, Kapur, K, Thorleifsson, G, Strawbridge, RJ, Rasmussen-Torvik, LJ, Esko, T, Mihailov, E, Fall, T, Fraser, RM, Mahajan, A, Kanoni, S, Giedraitis, V, Kleber, ME, Silbernagel, G, Meyer, J, Müller-Nurasyid, M, Ganna, A, Sarin, AP, Yengo, L, Shungin, D, Luan, J, Horikoshi, M, An, P, Sanna, S, Boettcher, Y, Rayner, NW, Nolte, IM, Zemunik, T, van Iperen, E, Kovacs, P, Hastie, ND, Wild, SH, McLachlan, S, Campbell, S, Polasek, O, Carlson, O, Egan, J, Kiess, W, Willemsen, G, Kuusisto, J, Laakso, M, Dimitriou, M, Hicks, AA, Rauramaa, R, Bandinelli, S, Thorand, B, Liu, Y, Miljkovic, I, Lind, L, Doney, A, Perola, M, Hingorani, A, Kivimaki, M, Kumari, M, Bennett, AJ, Groves, CJ, Herder, C, Koistinen, HA, Kinnunen, L, de Faire, U, Bakker, SJ, Uusitupa, M, Palmer, CN, Jukema, JW, Sattar, N, Pouta, A, Snieder, H, Boerwinkle, E, Pankow, JS, Magnusson, PKE, Krus, U, Scapoli, C, de Geus, EJCN, Blüher, M, Wolffenbuttel, BH, Province, MA, Abecasis, GR, Meigs, JB, Hovingh, GK, Lindström, J, Wilson, JF, Wright, AF, Dedoussis, GVZ, Bornstein, SR, Schwarz, PEH, Tönjes, A, Winkelmann, BR, Boehm, BO, März, W, Metspalu, A, Price, JF, Deloukas, P, Körner, A, Lakka, TA, Keinanen-Kiukaanniemi, SM, Saaristo, TE, Bergman, RN, Tuomilehto, J, Wareham, NJ, Langenberg, C, Männistö, S, Franks, PW, Hayward, C, Vitart, V, Kaprio, J, Visvikis-Siest, S, Balkau, B, Altshuler, D, Rudan, I, Stumvoll, M, Campbell, H, Duijn, Cornelia, Gieger, C, Illig, T, Ferrucci, L, Pedersen, NL, Pramstaller, PP, Boehnke, M, Frayling, TM, Shuldiner, AR, Peyser, PA, Kardia, SL, Palmer, LJ, Penninx, BWJH, Meneton, P, Harris, TB, Navis, G, van der Harst, P, Smith, GD, Forouhi, NG, Loos, RJ, Salomaa, V, Soranzo, N, Boomsma, DI, Groop, L, Tuomi, T, Hofman, Bert, Munroe, PB, Gudnason, V, Siscovick, DS, Watkins, H, Lecoeur, C, Vollenweider, P, Franco-Cereceda, A, Eriksson, P, Jarvelin, M R R, Stefansson, K, Hamsten, A, Nicholson, G, Karpe, F, Dermitzakis, ET, Lindgren, CM, McCarthy, MI, Froguel, P, Kaakinen, MA, Lyssenko, V, Watanabe, RM, Ingelsson, E, Florez, JC, Dupuis, J, Barroso, I, Morris, AP, Prokopenko, I, Lagou, V, Mägi, R, Hottenga, JJ, Grallert, H, Perry, JR, Bouatia-Naji, N, Marullo, L, Rybin, D, Jansen, R, Min, JL, Dimas, AS, Ulrich, A, Zudina, L, Gådin, JR, Jiang, L, Faggian, A, Bonnefond, A, Fadista, J, Stathopoulou, MG, Isaacs, Aaron, Willems, SM, Navarro, P, Tanaka, T, Jackson, AU, Montasser, ME, O’Connell, JR, Bielak, LF, Webster, RJ, Saxena, R, Stafford, JM, Pourcain, BS, Timpson, NJ, Salo, P, Shin, SY, Amin, Najaf, Smith, AV, Li, G, Verweij, N, Goel, A, Ford, I, Johnson, PCD, Johnson, T, Kapur, K, Thorleifsson, G, Strawbridge, RJ, Rasmussen-Torvik, LJ, Esko, T, Mihailov, E, Fall, T, Fraser, RM, Mahajan, A, Kanoni, S, Giedraitis, V, Kleber, ME, Silbernagel, G, Meyer, J, Müller-Nurasyid, M, Ganna, A, Sarin, AP, Yengo, L, Shungin, D, Luan, J, Horikoshi, M, An, P, Sanna, S, Boettcher, Y, Rayner, NW, Nolte, IM, Zemunik, T, van Iperen, E, Kovacs, P, Hastie, ND, Wild, SH, McLachlan, S, Campbell, S, Polasek, O, Carlson, O, Egan, J, Kiess, W, Willemsen, G, Kuusisto, J, Laakso, M, Dimitriou, M, Hicks, AA, Rauramaa, R, Bandinelli, S, Thorand, B, Liu, Y, Miljkovic, I, Lind, L, Doney, A, Perola, M, Hingorani, A, Kivimaki, M, Kumari, M, Bennett, AJ, Groves, CJ, Herder, C, Koistinen, HA, Kinnunen, L, de Faire, U, Bakker, SJ, Uusitupa, M, Palmer, CN, Jukema, JW, Sattar, N, Pouta, A, Snieder, H, Boerwinkle, E, Pankow, JS, Magnusson, PKE, Krus, U, Scapoli, C, de Geus, EJCN, Blüher, M, Wolffenbuttel, BH, Province, MA, Abecasis, GR, Meigs, JB, Hovingh, GK, Lindström, J, Wilson, JF, Wright, AF, Dedoussis, GVZ, Bornstein, SR, Schwarz, PEH, Tönjes, A, Winkelmann, BR, Boehm, BO, März, W, Metspalu, A, Price, JF, Deloukas, P, Körner, A, Lakka, TA, Keinanen-Kiukaanniemi, SM, Saaristo, TE, Bergman, RN, Tuomilehto, J, Wareham, NJ, Langenberg, C, Männistö, S, Franks, PW, Hayward, C, Vitart, V, Kaprio, J, Visvikis-Siest, S, Balkau, B, Altshuler, D, Rudan, I, Stumvoll, M, Campbell, H, Duijn, Cornelia, Gieger, C, Illig, T, Ferrucci, L, Pedersen, NL, Pramstaller, PP, Boehnke, M, Frayling, TM, Shuldiner, AR, Peyser, PA, Kardia, SL, Palmer, LJ, Penninx, BWJH, Meneton, P, Harris, TB, Navis, G, van der Harst, P, Smith, GD, Forouhi, NG, Loos, RJ, Salomaa, V, Soranzo, N, Boomsma, DI, Groop, L, Tuomi, T, Hofman, Bert, Munroe, PB, Gudnason, V, Siscovick, DS, Watkins, H, Lecoeur, C, Vollenweider, P, Franco-Cereceda, A, Eriksson, P, Jarvelin, M R R, Stefansson, K, Hamsten, A, Nicholson, G, Karpe, F, Dermitzakis, ET, Lindgren, CM, McCarthy, MI, Froguel, P, Kaakinen, MA, Lyssenko, V, Watanabe, RM, Ingelsson, E, Florez, JC, Dupuis, J, Barroso, I, Morris, AP, and Prokopenko, I
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021

6. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author: Steinthorsdottir, V. (Valgerdur), McGinnis, R. (Ralph), Williams, N. O. (Nicholas O.), Stefansdottir, L. (Lilja), Thorleifsson, G. (Gudmar), Shooter, S. (Scott), Fadista, J. (Joao), Sigurdsson, J. K. (Jon K.), Auro, K. M. (Kirsi M.), Berezina, G. (Galina), Borges, M.-C. (Maria-Carolina), Bumpstead, S. (Suzannah), Bybjerg-Grauholm, J. (Jonas), Colgiu, I. (Irina), Dolby, V. A. (Vivien A.), Dudbridge, F. (Frank), Engel, S. M. (Stephanie M.), Franklin, C. S. (Christopher S.), Frigge, M. L. (Michael L.), Frisbaek, Y. (Yr), Geirsson, R. T. (Reynir T.), Geller, F. (Frank), Gretarsdottir, S. (Solveig), Gudbjartsson, D. F. (Daniel F.), Harmon, Q. (Quaker), Hougaard, D. M. (David Michael), Hegay, T. (Tatyana), Helgadottir, A. (Anna), Hjartardottir, S. (Sigrun), Jaeaeskelaeinen, T. (Tiina), Johannsdottir, H. (Hrefna), Jonsdottir, I. (Ingileif), Juliusdottir, T. (Thorhildur), Kalsheker, N. (Noor), Kasimov, A. (Abdumadjit), Kemp, J. P. (John P.), Kivinen, K. (Katja), Klungsoyr, K. (Kari), Lee, W. K. (Wai K.), Melbye, M. (Mads), Miedzybrodska, Z. (Zosia), Moffett, A. (Ashley), Najmutdinova, D. (Dilbar), Nishanova, F. (Firuza), Olafsdottir, T. (Thorunn), Perola, M. (Markus), Pipkin, F. B. (Fiona Broughton), Poston, L. (Lucilla), Prescott, G. (Gordon), Saevarsdottir, S. (Saedis), Salimbayeva, D. (Damilya), Scaife, P. J. (Paula Juliet), Skotte, L. (Line), Staines-Urias, E. (Eleonora), Stefansson, O. A. (Olafur A.), Sorensen, K. M. (Karina Meden), Thomsen, L. C. (Liv Cecilie Vestrheim), Tragante, V. (Vinicius), Trogstad, L. (Lill), Simpson, N. A. (Nigel A. B.), Laivuori, H. (Hannele), Morgan, L. (Linda), Aripova, T. (Tamara), Casas, J. P. (Juan P.), Dominiczak, A. F. (Anna F.), Walker, J. J. (James J.), Thorsteinsdottir, U. (Unnur), Iversen, A.-C. (Ann-Charlotte), Feenstra, B. (Bjarke), Lawlor, D. A. (Deborah A.), Boyd, H. A. (Heather Allison), Magnus, P. (Per), Zakhidova, N. (Nodira), Svyatova, G. (Gulnara), Stefansson, K. (Kari), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Pouta, A. (Anneli), Macphail, S. (Sheila), Kilby, M. (Mark), Habiba, M. (Marwan), Williamson, C. (Catherine), O'Shaughnessy, K. (Kevin), O'Brien, S. (Shaughn), Cameron, A. (Alan), Redman, C. W. (Christopher W. G.), Farrall, M. (Martin), and Caulfield, M. (Mark)
Subjects: embryonic structures, reproductive and urinary physiology, female genital diseases and pregnancy complications
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
Published: 2020

7. Genome-wide study identifies association between HLA-B∗55:01 and Self-Reported Penicillin Allergy

Author: Krebs, K., Bovijn, J., Zheng, N., Lepamets, M., Censin, J.C., Jürgenson, T., Särg, D., Abner, E., Laisk, T., Luo, Y., Skotte, L., Geller, F., Feenstra, B., Wang, W., Auton, A., Raychaudhuri, S., Esko, T., Metspalu, A., Laur, S., Roden, D.M., Wei, W-Q, Holmes, M.V., Lindgren, C.M., Phillips, E.J., Mägi, R., Milani, L., Fadista, J., Agee, M., Aslibekyan, S., Bell, R.K., Bryc, K., Clark, S.K., Elson, S.L., Fletez-Brant, K., Fontanillas, P., Furlotte, N.A., Gandhi, P.M., Heilbron, K., Hicks, B., Hinds, D.A., Huber, K.E., Jewett, E.M., Jiang, Y., Kleinman, A., Lin, K-H, Litterman, N.K., Luff, M.K., McCreight, J.C., McIntyre, M.H., McManus, K.F., Mountain, J.L., Mozaffari, S.V., Nandakumar, P., Noblin, E.S., Northover, C.A.M., O’Connell, J., Petrakovitz, A.A., Pitts, S.J., Poznik, G.D., Sathirapongsasuti, J.F., Shastri, A.J., Shelton, J.F., Shringarpure, S., Tian, C., Tung, J.Y., Tunney, R.J., Vacic, V., Wang, X., Zare, A.S., Krebs, K., Bovijn, J., Zheng, N., Lepamets, M., Censin, J.C., Jürgenson, T., Särg, D., Abner, E., Laisk, T., Luo, Y., Skotte, L., Geller, F., Feenstra, B., Wang, W., Auton, A., Raychaudhuri, S., Esko, T., Metspalu, A., Laur, S., Roden, D.M., Wei, W-Q, Holmes, M.V., Lindgren, C.M., Phillips, E.J., Mägi, R., Milani, L., Fadista, J., Agee, M., Aslibekyan, S., Bell, R.K., Bryc, K., Clark, S.K., Elson, S.L., Fletez-Brant, K., Fontanillas, P., Furlotte, N.A., Gandhi, P.M., Heilbron, K., Hicks, B., Hinds, D.A., Huber, K.E., Jewett, E.M., Jiang, Y., Kleinman, A., Lin, K-H, Litterman, N.K., Luff, M.K., McCreight, J.C., McIntyre, M.H., McManus, K.F., Mountain, J.L., Mozaffari, S.V., Nandakumar, P., Noblin, E.S., Northover, C.A.M., O’Connell, J., Petrakovitz, A.A., Pitts, S.J., Poznik, G.D., Sathirapongsasuti, J.F., Shastri, A.J., Shelton, J.F., Shringarpure, S., Tian, C., Tung, J.Y., Tunney, R.J., Vacic, V., Wang, X., and Zare, A.S.
Abstract: Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center’s BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe’s research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33–1.49, p value 2.04 × 10−31) and confirmed by independent replication in 23andMe’s research cohort (OR 1.30 95% CI 1.25–1.34, p value 1.00 × 10−47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.
Published: 2020

8. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects

Author: Middeldorp, CM, Mahajan, A, Horikoshi, M, Robertson, NR, Beaumont, RN, Bradfield, JP, Bustamante, M, Cousminer, DL, Day, FR, De Silva, NM, Guxens, M, Mook-Kanamori, DO, St Pourcain, B, Warrington, NM, Adair, LS, Ahlqvist, E, Ahluwalia, TS, Almgren, P, Ang, W, Atalay, M, Auvinen, J, Bartels, M, Beckmann, JS, Bilbao, JR, Bond, T, Borja, JB, Cavadino, A, Charoen, P, Chen, Z, Coin, L, Cooper, C, Curtin, JA, Custovic, A, Das, S, Davies, GE, Dedoussis, GV, Duijts, L, Eastwood, PR, Eliasen, AU, Elliott, P, Eriksson, JG, Estivill, X, Fadista, J, Fedko, IO, Frayling, TM, Gaillard, R, Gauderman, WJ, Geller, F, Gilliland, F, Gilsanz, V, Granell, R, Grarup, N, Groop, L, Hadley, D, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayes, MG, Hebebrand, J, Heinrich, J, Helgeland, O, Henders, AK, Henderson, J, Henriksen, TB, Hirschhorn, JN, Hivert, M-F, Hocher, B, Holloway, JW, Holt, P, Hottenga, J-J, Hypponen, E, Iniguez, C, Johansson, S, Jugessur, A, Kahonen, M, Kalkwarf, HJ, Kaprio, J, Karhunen, V, Kemp, JP, Kerkhof, M, Koppelman, GH, Korner, A, Kotecha, S, Kreiner-Moller, E, Kulohoma, B, Kumar, A, Kutalik, Z, Lahti, J, Lappe, JM, Larsson, H, Lehtimaki, T, Lewin, AM, Li, J, Lichtenstein, P, Lindgren, CM, Lindi, V, Linneberg, A, Liu, X, Liu, J, Lowe, WL, Lundstrom, S, Lyytikainen, L-P, Ma, RCW, Mace, A, Magi, R, Magnus, P, Mamun, AA, Mannikko, M, Martin, NG, Mbarek, H, McCarthy, NS, Medland, SE, Melbye, M, Melen, E, Mohlke, KL, Monnereau, C, Morgen, CS, Morris, AP, Murray, JC, Myhre, R, Najman, JM, Nivard, MG, Nohr, EA, Nolte, IM, Ntalla, I, O'Reilly, P, Oberfield, SE, Oken, E, Oldehinkel, AJ, Pahkala, K, Palviainen, T, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Pershagen, G, Pitkanen, N, Plomin, R, Power, C, Prasad, RB, Prokopenko, I, Pulkkinen, L, Raikkonen, K, Raitakari, OT, Reynolds, RM, Richmond, RC, Rivadeneira, F, Rodriguez, A, Rose, RJ, Salem, R, Santa-Marina, L, Saw, S-M, Schnurr, TM, Scott, JG, Selzam, S, Shepherd, JA, Simpson, A, Skotte, L, Sleiman, PMA, Snieder, H, Sorensen, TIA, Standl, M, Steegers, EAP, Strachan, DP, Straker, L, Strandberg, T, Taylor, M, Teo, Y-Y, Thiering, E, Torrent, M, Tyrrell, J, Uitterlinden, AG, van Beijsterveldt, T, van der Most, PJ, van Duijn, CM, Viikari, J, Vilor-Tejedor, N, Vogelezang, S, Vonk, JM, Vrijkotte, TGM, Vuoksimaa, E, Wang, CA, Watkins, WJ, Wichmann, H-E, Willemsen, G, Williams, GM, Wilson, JF, Wray, NR, Xu, S, Xu, C-J, Yaghootkar, H, Yi, L, Zafarmand, MH, Zeggini, E, Zemel, BS, Hinney, A, Lakka, TA, Whitehouse, AJO, Sunyer, J, Widen, EE, Feenstra, B, Sebert, S, Jacobsson, B, Njolstad, PR, Stoltenberg, C, Smith, GD, Lawlor, DA, Paternoster, L, Timpson, NJ, Ong, KK, Bisgaard, H, Bonnelykke, K, Jaddoe, VWV, Tiemeier, H, Jarvelin, M-R, Evans, DM, Perry, JRB, Grant, SFA, Boomsma, DI, Freathy, RM, McCarthy, MI, Felix, JF, Middeldorp, CM, Mahajan, A, Horikoshi, M, Robertson, NR, Beaumont, RN, Bradfield, JP, Bustamante, M, Cousminer, DL, Day, FR, De Silva, NM, Guxens, M, Mook-Kanamori, DO, St Pourcain, B, Warrington, NM, Adair, LS, Ahlqvist, E, Ahluwalia, TS, Almgren, P, Ang, W, Atalay, M, Auvinen, J, Bartels, M, Beckmann, JS, Bilbao, JR, Bond, T, Borja, JB, Cavadino, A, Charoen, P, Chen, Z, Coin, L, Cooper, C, Curtin, JA, Custovic, A, Das, S, Davies, GE, Dedoussis, GV, Duijts, L, Eastwood, PR, Eliasen, AU, Elliott, P, Eriksson, JG, Estivill, X, Fadista, J, Fedko, IO, Frayling, TM, Gaillard, R, Gauderman, WJ, Geller, F, Gilliland, F, Gilsanz, V, Granell, R, Grarup, N, Groop, L, Hadley, D, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayes, MG, Hebebrand, J, Heinrich, J, Helgeland, O, Henders, AK, Henderson, J, Henriksen, TB, Hirschhorn, JN, Hivert, M-F, Hocher, B, Holloway, JW, Holt, P, Hottenga, J-J, Hypponen, E, Iniguez, C, Johansson, S, Jugessur, A, Kahonen, M, Kalkwarf, HJ, Kaprio, J, Karhunen, V, Kemp, JP, Kerkhof, M, Koppelman, GH, Korner, A, Kotecha, S, Kreiner-Moller, E, Kulohoma, B, Kumar, A, Kutalik, Z, Lahti, J, Lappe, JM, Larsson, H, Lehtimaki, T, Lewin, AM, Li, J, Lichtenstein, P, Lindgren, CM, Lindi, V, Linneberg, A, Liu, X, Liu, J, Lowe, WL, Lundstrom, S, Lyytikainen, L-P, Ma, RCW, Mace, A, Magi, R, Magnus, P, Mamun, AA, Mannikko, M, Martin, NG, Mbarek, H, McCarthy, NS, Medland, SE, Melbye, M, Melen, E, Mohlke, KL, Monnereau, C, Morgen, CS, Morris, AP, Murray, JC, Myhre, R, Najman, JM, Nivard, MG, Nohr, EA, Nolte, IM, Ntalla, I, O'Reilly, P, Oberfield, SE, Oken, E, Oldehinkel, AJ, Pahkala, K, Palviainen, T, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Pershagen, G, Pitkanen, N, Plomin, R, Power, C, Prasad, RB, Prokopenko, I, Pulkkinen, L, Raikkonen, K, Raitakari, OT, Reynolds, RM, Richmond, RC, Rivadeneira, F, Rodriguez, A, Rose, RJ, Salem, R, Santa-Marina, L, Saw, S-M, Schnurr, TM, Scott, JG, Selzam, S, Shepherd, JA, Simpson, A, Skotte, L, Sleiman, PMA, Snieder, H, Sorensen, TIA, Standl, M, Steegers, EAP, Strachan, DP, Straker, L, Strandberg, T, Taylor, M, Teo, Y-Y, Thiering, E, Torrent, M, Tyrrell, J, Uitterlinden, AG, van Beijsterveldt, T, van der Most, PJ, van Duijn, CM, Viikari, J, Vilor-Tejedor, N, Vogelezang, S, Vonk, JM, Vrijkotte, TGM, Vuoksimaa, E, Wang, CA, Watkins, WJ, Wichmann, H-E, Willemsen, G, Williams, GM, Wilson, JF, Wray, NR, Xu, S, Xu, C-J, Yaghootkar, H, Yi, L, Zafarmand, MH, Zeggini, E, Zemel, BS, Hinney, A, Lakka, TA, Whitehouse, AJO, Sunyer, J, Widen, EE, Feenstra, B, Sebert, S, Jacobsson, B, Njolstad, PR, Stoltenberg, C, Smith, GD, Lawlor, DA, Paternoster, L, Timpson, NJ, Ong, KK, Bisgaard, H, Bonnelykke, K, Jaddoe, VWV, Tiemeier, H, Jarvelin, M-R, Evans, DM, Perry, JRB, Grant, SFA, Boomsma, DI, Freathy, RM, McCarthy, MI, and Felix, JF
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019

9. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author: Liu, X. (Xueping), Helenius, D. (Dorte), Skotte, L. (Line), Beaumont, R. N. (Robin N.), Wielscher, M. (Matthias), Geller, F. (Frank), Juodakis, J. (Julius), Mahajan, A. (Anubha), Bradfield, J. P. (Jonathan P.), Lin, F. T. (Frederick Tj), Vogelezang, S. (Suzanne), Bustamante, M. (Mariona), Ahluwalia, T. S. (Tarunveer S.), Pitkanen, N. (Niina), Wang, C. A. (Carol A.), Bacelis, J. (Jonas), Borges, M. C. (Maria C.), Zhang, G. (Ge), Bedell, B. A. (Bruce A.), Rossi, R. M. (Robert M.), Skogstrand, K. (Kristin), Peng, S. (Shouneng), Thompson, W. K. (Wesley K.), Appadurai, V. (Vivek), Lawlor, D. A. (Debbie A.), Kalliala, I. (Ilkka), Power, C. (Christine), McCarthy, M. I. (Mark, I), Boyd, H. A. (Heather A.), Marazita, M. L. (Mary L.), Hakonarson, H. (Hakon), Hayes, M. G. (M. Geoffrey), Scholtens, D. M. (Denise M.), Rivadeneira, F. (Fernando), Jaddoe, V. W. (Vincent W. V.), Vinding, R. K. (Rebecca K.), Bisgaard, H. (Hans), Knight, B. A. (Bridget A.), Pahkala, K. (Katja), Raitakari, O. (Olli), Helgeland, O. (Oyvind), Johansson, S. (Stefan), Njolstad, P. R. (Pal R.), Fadista, J. (Joao), Schork, A. J. (Andrew J.), Nudel, R. (Ron), Miller, D. E. (Daniel E.), Chen, X. (Xiaoting), Weirauch, M. T. (Matthew T.), Mortensen, P. B. (Preben Bo), Borglum, A. D. (Anders D.), Nordentoft, M. (Merete), Mors, O. (Ole), Hao, K. (Ke), Ryckman, K. K. (Kelli K.), Hougaard, D. M. (David M.), Kottyan, L. C. (Leah C.), Pennell, C. E. (Craig E.), Lyytikainen, L.-P. (Leo-Pekka), Bonnelykke, K. (Klaus), Vrijheid, M. (Martine), Felix, J. F. (Janine F.), Lowe, W. L. (William L., Jr.), Grant, S. F. (Struan Fa), Hypponen, E. (Elina), Jacobsson, B. (Bo), Järvelin, M.-R. (Marjo-Riitta), Muglia, L. J. (Louis J.), Murray, J. C. (Jeffrey C.), Freathy, R. M. (Rachel M.), Werge, T. M. (Thomas M.), Melbye, M. (Mads), Buil, A. (Alfonso), Feenstra, B. (Bjarke), Liu, X. (Xueping), Helenius, D. (Dorte), Skotte, L. (Line), Beaumont, R. N. (Robin N.), Wielscher, M. (Matthias), Geller, F. (Frank), Juodakis, J. (Julius), Mahajan, A. (Anubha), Bradfield, J. P. (Jonathan P.), Lin, F. T. (Frederick Tj), Vogelezang, S. (Suzanne), Bustamante, M. (Mariona), Ahluwalia, T. S. (Tarunveer S.), Pitkanen, N. (Niina), Wang, C. A. (Carol A.), Bacelis, J. (Jonas), Borges, M. C. (Maria C.), Zhang, G. (Ge), Bedell, B. A. (Bruce A.), Rossi, R. M. (Robert M.), Skogstrand, K. (Kristin), Peng, S. (Shouneng), Thompson, W. K. (Wesley K.), Appadurai, V. (Vivek), Lawlor, D. A. (Debbie A.), Kalliala, I. (Ilkka), Power, C. (Christine), McCarthy, M. I. (Mark, I), Boyd, H. A. (Heather A.), Marazita, M. L. (Mary L.), Hakonarson, H. (Hakon), Hayes, M. G. (M. Geoffrey), Scholtens, D. M. (Denise M.), Rivadeneira, F. (Fernando), Jaddoe, V. W. (Vincent W. V.), Vinding, R. K. (Rebecca K.), Bisgaard, H. (Hans), Knight, B. A. (Bridget A.), Pahkala, K. (Katja), Raitakari, O. (Olli), Helgeland, O. (Oyvind), Johansson, S. (Stefan), Njolstad, P. R. (Pal R.), Fadista, J. (Joao), Schork, A. J. (Andrew J.), Nudel, R. (Ron), Miller, D. E. (Daniel E.), Chen, X. (Xiaoting), Weirauch, M. T. (Matthew T.), Mortensen, P. B. (Preben Bo), Borglum, A. D. (Anders D.), Nordentoft, M. (Merete), Mors, O. (Ole), Hao, K. (Ke), Ryckman, K. K. (Kelli K.), Hougaard, D. M. (David M.), Kottyan, L. C. (Leah C.), Pennell, C. E. (Craig E.), Lyytikainen, L.-P. (Leo-Pekka), Bonnelykke, K. (Klaus), Vrijheid, M. (Martine), Felix, J. F. (Janine F.), Lowe, W. L. (William L., Jr.), Grant, S. F. (Struan Fa), Hypponen, E. (Elina), Jacobsson, B. (Bo), Järvelin, M.-R. (Marjo-Riitta), Muglia, L. J. (Louis J.), Murray, J. C. (Jeffrey C.), Freathy, R. M. (Rachel M.), Werge, T. M. (Thomas M.), Melbye, M. (Mads), Buil, A. (Alfonso), and Feenstra, B. (Bjarke)
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Published: 2019

10. TCF7L2 is a master regulator of insulin production and processing

Author: Zhou, Y., primary, Park, S.-Y., additional, Su, J., additional, Bailey, K., additional, Ottosson-Laakso, E., additional, Shcerbina, L., additional, Oskolkov, N., additional, Zhang, E., additional, Thevenin, T., additional, Fadista, J., additional, Bennet, H., additional, Vikman, P., additional, Wierup, N., additional, Fex, M., additional, Rung, J., additional, Wollheim, C., additional, Nobrega, M., additional, Renström, E., additional, Groop, L., additional, and Hansson, O., additional
Published: 2014
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11. Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

Author: Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, van de Bunt, M, Pearson, RD, Kumar, A, Mueller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, de Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RCW, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, McCarthy, MI, Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, van de Bunt, M, Pearson, RD, Kumar, A, Mueller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, de Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RCW, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, and McCarthy, MI
Abstract: This corrects the article DOI: 10.1038/sdata.2017.179.
Published: 2018

12. Data Descriptor: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

Author: Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, De Bunt, MV, Pearson, RD, Kumar, A, Muller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, De Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RC, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, McCarthy, MI, Flannick, J, Fuchsberger, C, Mahajan, A, Teslovich, TM, Agarwala, V, Gaulton, KJ, Caulkins, L, Koesterer, R, Ma, C, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, De Bunt, MV, Pearson, RD, Kumar, A, Muller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Stitzel, ML, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancakova, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Karajamaki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, De Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, PM, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvanen, A-C, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JC, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RC, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, DeFronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Magi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, J-Y, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, E, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Scott, LJ, Morris, AP, Kang, HM, Altshuler, D, Burtt, NP, Florez, JC, Boehnke, M, and McCarthy, MI
Abstract: To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
Published: 2017

13. In vivo efficacy of HD0471953: A novel GPR119 agonist for the treatment of type 2 diabetes mellitus

Author: 'T Hart, L. M., Fritsche, A., Nijpels, G., Van Leeuwen, N., Donnelly, L. A., Dekker, J. M., Alssema, M., Fadista, J., Carlotti, F., Gjesing, A. P., Palmer, C. N., Van Haeften, T. W., Herzberg-Schäfer, S. A., Simonis-Bik, A. M., Houwing-Duistermaat, J. J., Helmer, Q., Deelen, J., Guigas, B., Hansen, T., MacHicao, F., Willemsen, G., Heine, R. J., Kramer, M. H., Holst, J. J., De Koning, E. J., Häring, H. U., Pedersen, O., Groop, L., De Geus, E. J., Slagboom, P. E., Boomsma, D. I., Eekhoff, E. M., Pearson, E. R., Diamant, M., Epidemiology and Data Science, General practice, EMGO - Lifestyle, overweight and diabetes, Dermatology, CCA - Immuno-pathogenesis, Internal medicine, ICaR - Circulation and metabolism, ICaR - Ischemia and repair, and MOVE Research Institute
Published: 2015

14. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, K. (Kyle), Ferreira, T. (Teresa), Lee, Y. (Yeji), Raimondo, A. (Anne), Mägi, R. (Reedik), Reschen, M.E. (Michael E.), Mahajan, A. (Anubha), Locke, A. (Adam), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Scott, R.A. (Robert), Prokopenko, I. (Inga), Scott, L.J. (Laura), Green, T. (Todd), Sparsø, T. (Thomas), Thuillier, D. (Dorothee), Yengo, L. (Loic), Grallert, H. (Harald), Wahl, S. (Simone), Frånberg, M. (Mattias), Strawbridge, R.J. (Rona), Kestler, H. (Hans), Chheda, H. (Himanshu), Eisele, L. (Lewin), Gustafsson, S. (Stefan), Steinthorsdottir, V. (Valgerdur), Thorleifsson, G. (Gudmar), Qi, L. (Lu), Karssen, L.C. (Lennart), Leeuwen, E.M. (Elisa) van, Willems, S.M. (Sara), Li, M. (Man), Chen, H. (Han), Fuchsberger, C. (Christian), Kwan, P. (Phoenix), Ma, C. (Clement), Linderman, M. (Michael), Lu, Y. (Yingchang), Thomsen, S.K. (Soren K.), Rundle, J.K. (Jana K.), Beer, N.L. (Nicola L.), Bunt, M. (Martijn) van de, Chalisey, A. (Anil), Kang, H.M. (Hyun Min), Voight, B.F. (Benjamin), Abecasis, G.R. (Gonçalo), Almgren, P. (Peter), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Blüher, M. (Matthias), Boeing, H. (Heiner), Bonnycastle, L.L. (Lori), Bottinger, E.P. (Erwin P.), Burtt, N.P. (Noël), Carey, J. (Jason), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David J.), Crenshaw, A. (Andrew), Dam, R.M. (Rob) van, Doney, A.S.F. (Alex), Dorkhan, M. (Mozhgan), Edkins, T. (Ted), Eriksson, J.G. (Johan G.), Esko, T. (Tõnu), Eury, E. (Elodie), Fadista, J. (João), Flannick, J. (Jason), Fontanillas, P. (Pierre), Fox, C.S. (Caroline), Franks, P.W. (Paul W.), Gertow, K. (Karl), Gieger, C. (Christian), Gigante, B. (Bruna), Gottesman, R.F. (Rebecca), Grant, G.B. (George), Grarup, N. (Niels), Groves, C.J. (Christopher J.), Hassinen, M. (Maija), Have, C.T. (Christian T.), Herder, C. (Christian), Holmen, O.L. (Oddgeir), Hreidarsson, A.B. (Astradur), Humphries, S.E. (Steve E.), Hunter, D.J. (David J.), Jackson, A.U. (Anne), Jonsson, A. (Anna), Jørgensen, M.E. (Marit E.), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Kerrison, N.D. (Nicola D.), Kinnunen, L. (Leena), Klopp, N. (Norman), Kong, A. (Augustine), Kovacs, P. (Peter), Kraft, P. (Peter), Kravic, J. (Jasmina), Langford, C. (Cordelia), Leander, K. (Karin), Liang, L. (Liming), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia M.), Lindholm, B. (Bengt), Linneberg, A. (Allan), Liu, C.-T. (Ching-Ti), Lobbens, S. (Stéphane), Luan, J. (Jian'fan), Lyssenko, V. (Valeriya), Männistö, S. (Satu), McLeod, O. (Olga), Meyer, J. (Jobst), Mihailov, E. (Evelin), Mirza, G. (Ghazala), Mühleisen, T.W. (Thomas), Müller-Nurasyid, M. (Martina), Navarro, C. (Carmen), Nöthen, M.M. (Markus), Oskolkov, N.N. (Nikolay N.), Owen, K.R. (Katharine), Palli, D. (Domenico), Pechlivanis, S. (Sonali), Peltonen, L. (Leena Johanna), Perry, J.R.B. (John), Platou, C.P. (Carl), Roden, M. (Michael), Ruderfer, D. (Douglas), Rybin, D. (Denis), Van Der Schouw, Y.T. (Yvonne T.), Sennblad, B. (Bengt), Sigurosson, G. (Gunnar), Stancáková, A. (Alena), Steinbach, D., Storm, P. (Petter), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Sun, Q., Thorand, B. (Barbara), Tikkanen, E. (Emmi), Tönjes, A. (Anke), Trakalo, J. (Joseph), Tremoli, E. (Elena), Tuomi, T. (Tiinamaija), Wennauer, R. (Roman), Wiltshire, S. (Steven), Wood, A.R. (Andrew), Zeggini, E. (Eleftheria), Dunham, I. (Ian), Birney, E. (Ewan), Pasquali, L. (Lorenzo), Ferrer, J. (Jorge), Loos, R.J.F. (Ruth), Dupuis, J. (Josée), Florez, J.C. (Jose), Boerwinkle, E.A. (Eric), Pankow, J.S. (James), Duijn, C.M. (Cornelia) van, Sijbrands, E.J.G. (Eric), Meigs, J.B. (James B.), Hu, F.B. (Frank), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Lakka, T.A. (Timo), Rauramaa, R. (Rainer), Stumvoll, M. (Michael), Pedersen, N.L. (Nancy L.), Lind, L. (Lars), Keinanen-Kiukaanniemi, S. (Sirkka), Korpi-Hyövälti, E. (Eeva), Saaristo, T. (Timo), Saltevo, J. (Juha), Kuusisto, J. (Johanna), Laakso, M. (Markku), Metspalu, A. (Andres), Erbel, R. (Raimund), Jöckel, K.-H. (Karl-Heinz), Moebus, S. (Susanne), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Ingelsson, E. (Erik), Boehm, B.O. (Bernhard), Bergman, R.N. (Richard N.), Collins, F.S. (Francis S.), Mohlke, K.L. (Karen L.), Koistinen, H. (Heikki), Tuomilehto, J. (Jaakko), Hveem, K. (Kristian), Njølstad, I. (Inger), Deloukas, P. (Panagiotis), Donnelly, P.J. (Peter J.), Frayling, T.M. (Timothy), Hattersley, A.T. (Andrew), Faire, U. (Ulf) de, Hamsten, A. (Anders), Illig, T. (Thomas), Peters, A. (Annette), Cauchi, S. (Stephane), Sladek, R. (Rob), Froguel, P. (Philippe), Hansen, T. (Torben), Pedersen, O. (Oluf), Morris, A.D. (Andrew), Palmer, C.N.A. (Collin N. A.), Kathiresan, S. (Sekar), Melander, O. (Olle), Nilsson, P.M. (Peter M.), Groop, L. (Leif), Barroso, I.E. (Inês), Langenberg, C. (Claudia), Wareham, N.J. (Nicholas J.), O'Callaghan, C.A. (Christopher A.), Gloyn, A.L. (Anna), Altshuler, D. (David), Boehnke, M. (Michael), Teslovich, T.M. (Tanya M.), McCarthy, M.I. (Mark), Morris, A.P. (Andrew), Gaulton, K. (Kyle), Ferreira, T. (Teresa), Lee, Y. (Yeji), Raimondo, A. (Anne), Mägi, R. (Reedik), Reschen, M.E. (Michael E.), Mahajan, A. (Anubha), Locke, A. (Adam), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Scott, R.A. (Robert), Prokopenko, I. (Inga), Scott, L.J. (Laura), Green, T. (Todd), Sparsø, T. (Thomas), Thuillier, D. (Dorothee), Yengo, L. (Loic), Grallert, H. (Harald), Wahl, S. (Simone), Frånberg, M. (Mattias), Strawbridge, R.J. (Rona), Kestler, H. (Hans), Chheda, H. (Himanshu), Eisele, L. (Lewin), Gustafsson, S. (Stefan), Steinthorsdottir, V. (Valgerdur), Thorleifsson, G. (Gudmar), Qi, L. (Lu), Karssen, L.C. (Lennart), Leeuwen, E.M. (Elisa) van, Willems, S.M. (Sara), Li, M. (Man), Chen, H. (Han), Fuchsberger, C. (Christian), Kwan, P. (Phoenix), Ma, C. (Clement), Linderman, M. (Michael), Lu, Y. (Yingchang), Thomsen, S.K. (Soren K.), Rundle, J.K. (Jana K.), Beer, N.L. (Nicola L.), Bunt, M. (Martijn) van de, Chalisey, A. (Anil), Kang, H.M. (Hyun Min), Voight, B.F. (Benjamin), Abecasis, G.R. (Gonçalo), Almgren, P. (Peter), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Blüher, M. (Matthias), Boeing, H. (Heiner), Bonnycastle, L.L. (Lori), Bottinger, E.P. (Erwin P.), Burtt, N.P. (Noël), Carey, J. (Jason), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David J.), Crenshaw, A. (Andrew), Dam, R.M. (Rob) van, Doney, A.S.F. (Alex), Dorkhan, M. (Mozhgan), Edkins, T. (Ted), Eriksson, J.G. (Johan G.), Esko, T. (Tõnu), Eury, E. (Elodie), Fadista, J. (João), Flannick, J. (Jason), Fontanillas, P. (Pierre), Fox, C.S. (Caroline), Franks, P.W. (Paul W.), Gertow, K. (Karl), Gieger, C. (Christian), Gigante, B. (Bruna), Gottesman, R.F. (Rebecca), Grant, G.B. (George), Grarup, N. (Niels), Groves, C.J. (Christopher J.), Hassinen, M. (Maija), Have, C.T. (Christian T.), Herder, C. (Christian), Holmen, O.L. (Oddgeir), Hreidarsson, A.B. (Astradur), Humphries, S.E. (Steve E.), Hunter, D.J. (David J.), Jackson, A.U. (Anne), Jonsson, A. (Anna), Jørgensen, M.E. (Marit E.), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Kerrison, N.D. (Nicola D.), Kinnunen, L. (Leena), Klopp, N. (Norman), Kong, A. (Augustine), Kovacs, P. (Peter), Kraft, P. (Peter), Kravic, J. (Jasmina), Langford, C. (Cordelia), Leander, K. (Karin), Liang, L. (Liming), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia M.), Lindholm, B. (Bengt), Linneberg, A. (Allan), Liu, C.-T. (Ching-Ti), Lobbens, S. (Stéphane), Luan, J. (Jian'fan), Lyssenko, V. (Valeriya), Männistö, S. (Satu), McLeod, O. (Olga), Meyer, J. (Jobst), Mihailov, E. (Evelin), Mirza, G. (Ghazala), Mühleisen, T.W. (Thomas), Müller-Nurasyid, M. (Martina), Navarro, C. (Carmen), Nöthen, M.M. (Markus), Oskolkov, N.N. (Nikolay N.), Owen, K.R. (Katharine), Palli, D. (Domenico), Pechlivanis, S. (Sonali), Peltonen, L. (Leena Johanna), Perry, J.R.B. (John), Platou, C.P. (Carl), Roden, M. (Michael), Ruderfer, D. (Douglas), Rybin, D. (Denis), Van Der Schouw, Y.T. (Yvonne T.), Sennblad, B. (Bengt), Sigurosson, G. (Gunnar), Stancáková, A. (Alena), Steinbach, D., Storm, P. (Petter), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Sun, Q., Thorand, B. (Barbara), Tikkanen, E. (Emmi), Tönjes, A. (Anke), Trakalo, J. (Joseph), Tremoli, E. (Elena), Tuomi, T. (Tiinamaija), Wennauer, R. (Roman), Wiltshire, S. (Steven), Wood, A.R. (Andrew), Zeggini, E. (Eleftheria), Dunham, I. (Ian), Birney, E. (Ewan), Pasquali, L. (Lorenzo), Ferrer, J. (Jorge), Loos, R.J.F. (Ruth), Dupuis, J. (Josée), Florez, J.C. (Jose), Boerwinkle, E.A. (Eric), Pankow, J.S. (James), Duijn, C.M. (Cornelia) van, Sijbrands, E.J.G. (Eric), Meigs, J.B. (James B.), Hu, F.B. (Frank), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Lakka, T.A. (Timo), Rauramaa, R. (Rainer), Stumvoll, M. (Michael), Pedersen, N.L. (Nancy L.), Lind, L. (Lars), Keinanen-Kiukaanniemi, S. (Sirkka), Korpi-Hyövälti, E. (Eeva), Saaristo, T. (Timo), Saltevo, J. (Juha), Kuusisto, J. (Johanna), Laakso, M. (Markku), Metspalu, A. (Andres), Erbel, R. (Raimund), Jöckel, K.-H. (Karl-Heinz), Moebus, S. (Susanne), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Ingelsson, E. (Erik), Boehm, B.O. (Bernhard), Bergman, R.N. (Richard N.), Collins, F.S. (Francis S.), Mohlke, K.L. (Karen L.), Koistinen, H. (Heikki), Tuomilehto, J. (Jaakko), Hveem, K. (Kristian), Njølstad, I. (Inger), Deloukas, P. (Panagiotis), Donnelly, P.J. (Peter J.), Frayling, T.M. (Timothy), Hattersley, A.T. (Andrew), Faire, U. (Ulf) de, Hamsten, A. (Anders), Illig, T. (Thomas), Peters, A. (Annette), Cauchi, S. (Stephane), Sladek, R. (Rob), Froguel, P. (Philippe), Hansen, T. (Torben), Pedersen, O. (Oluf), Morris, A.D. (Andrew), Palmer, C.N.A. (Collin N. A.), Kathiresan, S. (Sekar), Melander, O. (Olle), Nilsson, P.M. (Peter M.), Groop, L. (Leif), Barroso, I.E. (Inês), Langenberg, C. (Claudia), Wareham, N.J. (Nicholas J.), O'Callaghan, C.A. (Christopher A.), Gloyn, A.L. (Anna), Altshuler, D. (David), Boehnke, M. (Michael), Teslovich, T.M. (Tanya M.), McCarthy, M.I. (Mark), and Morris, A.P. (Andrew)
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015
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15. In vivo efficacy of HD0471953:A novel GPR119 agonist for the treatment of type 2 diabetes mellitus

Author: 'T Hart, L. M., Fritsche, A., Nijpels, G., Van Leeuwen, N., Donnelly, L. A., Dekker, J. M., Alssema, M., Fadista, J., Carlotti, F., Gjesing, A. P., Palmer, C. N., Van Haeften, T. W., Herzberg-Schäfer, S. A., Simonis-Bik, A. M., Houwing-Duistermaat, J. J., Helmer, Q., Deelen, J., Guigas, B., Hansen, T., MacHicao, F., Willemsen, G., Heine, R. J., Kramer, M. H., Holst, J. J., De Koning, E. J., Häring, H. U., Pedersen, O., Groop, L., De Geus, E. J., Slagboom, P. E., Boomsma, D. I., Eekhoff, E. M., Pearson, E. R., Diamant, M., 'T Hart, L. M., Fritsche, A., Nijpels, G., Van Leeuwen, N., Donnelly, L. A., Dekker, J. M., Alssema, M., Fadista, J., Carlotti, F., Gjesing, A. P., Palmer, C. N., Van Haeften, T. W., Herzberg-Schäfer, S. A., Simonis-Bik, A. M., Houwing-Duistermaat, J. J., Helmer, Q., Deelen, J., Guigas, B., Hansen, T., MacHicao, F., Willemsen, G., Heine, R. J., Kramer, M. H., Holst, J. J., De Koning, E. J., Häring, H. U., Pedersen, O., Groop, L., De Geus, E. J., Slagboom, P. E., Boomsma, D. I., Eekhoff, E. M., Pearson, E. R., and Diamant, M.
Published: 2015

16. Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity

Author: Keildson, S., Fadista, J., Ladenvall, C., Hedman, A. K., Elgzyri, T., Small, K. S., Grundberg, E., Nica, A. C., Glass, D., Richards, J. B., Barrett, A., Nisbet, J., Zheng, H. -F, Rönn, T., Ström, Kristoffer, Eriksson, K. -F, Prokopenko, I., Spector, T. D., Dermitzakis, E. T., Deloukas, P., McCarthy, M. I., Rung, J., Groop, L., Franks, P. W., Lindgren, C. M., Hansson, O., Keildson, S., Fadista, J., Ladenvall, C., Hedman, A. K., Elgzyri, T., Small, K. S., Grundberg, E., Nica, A. C., Glass, D., Richards, J. B., Barrett, A., Nisbet, J., Zheng, H. -F, Rönn, T., Ström, Kristoffer, Eriksson, K. -F, Prokopenko, I., Spector, T. D., Dermitzakis, E. T., Deloukas, P., McCarthy, M. I., Rung, J., Groop, L., Franks, P. W., Lindgren, C. M., and Hansson, O.
Abstract: Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96×1025) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR <5%; P = 1.34×1024). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 1026) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016-0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r 2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7×1023). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity. © 2014 by the American Diabetes Association.., Language of Original Document: English
Published: 2014
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17. Assessing porcine structural variation with array-CGH and massively parallel sequencing

Author: Santos Fadista, J P, Holm, L E, Thomsen, B, and Bendixen, C
Published: 2009

18. The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

Author: t Hart, L.M., Fritsche, A., Nijpels, G., van Leeuwen, N., Donnelly, L.A., Dekker, J.M., Alssema, M., Fadista, J., Carlotti, F., Gjesing, A.P., Palmer, C.N., van Haeften, T.W., Herzberg-Schafer, S.A., Simonis-Bik, A.M., Houwing-Duistermaat, J.J., Helmer, Q., Deelen, J., Guigas, B., Hansen, T., Machicao, F., Willemsen, G., Heine, R.J., Kramer, M.H., Holst, J.J., de Koning, E.J., Haring, H.U., Pedersen, O., Groop, L., de Geus, E.J., Slagboom, P.E., Boomsma, D.I., Eekhoff, E.M., Pearson, E.R., Diamant, M., t Hart, L.M., Fritsche, A., Nijpels, G., van Leeuwen, N., Donnelly, L.A., Dekker, J.M., Alssema, M., Fadista, J., Carlotti, F., Gjesing, A.P., Palmer, C.N., van Haeften, T.W., Herzberg-Schafer, S.A., Simonis-Bik, A.M., Houwing-Duistermaat, J.J., Helmer, Q., Deelen, J., Guigas, B., Hansen, T., Machicao, F., Willemsen, G., Heine, R.J., Kramer, M.H., Holst, J.J., de Koning, E.J., Haring, H.U., Pedersen, O., Groop, L., de Geus, E.J., Slagboom, P.E., Boomsma, D.I., Eekhoff, E.M., Pearson, E.R., and Diamant, M.
Abstract: The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P, The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P
Published: 2013

19. Analyses of pig genomes provide insight into porcine demography and evolution

Author: Groenen, M. A., Archibald, A. L., Uenishi, H., Tuggle, C. K., Takeuchi, Y., Rothschild, M. F., Rogel-Gaillard, C., Park, C., Milan, D., Megens, H. J., Li, S., Larkin, D. M., Kim, H., Frantz, L. A., Caccamo, M., Ahn, H., Aken, B. L., Anselmo, A., Anthon, C., Auvil, L., Badaoui, B., Beattie, C. W., Bendixen, C., Berman, D., Blecha, F., Blomberg, Jonas, Bolund, L., Bosse, M., Botti, S., Bujie, Z., Byström, M., Capitanu, B., Carvalho-Silva, D., Chardon, P., Chen, C., Cheng, R., Choi, S. H., Chow, W., Clark, R. C., Clee, C., Crooijmans, R. P., Dawson, H. D., Dehais, P., De Sapio, F., Dibbits, B., Drou, N., Du, Z. Q., Eversole, K., Fadista, J., Fairley, S., Faraut, T., Faulkner, G. J., Fowler, K. E., Fredholm, M., Fritz, E., Gilbert, J. G., Giuffra, E., Gorodkin, J., Griffin, D. K., Harrow, J. L., Hayward, Alexander, Howe, K., Hu, Z. L., Humphray, S. J., Hunt, T., Hornshoj, H., Jeon, J. T., Jern, Patric, Jones, M., Jurka, J., Kanamori, H., Kapetanovic, R., Kim, J., Kim, J. H., Kim, K. W., Kim, T. H., Larson, G., Lee, K., Lee, K. T., Leggett, R., Lewin, H. A., Li, Y., Liu, W., Loveland, J. E., Lu, Y., Lunney, J. K., Ma, J., Madsen, O., Mann, K., Matthews, L., McLaren, S., Morozumi, T., Murtaugh, M. P., Narayan, J., Nguyen, D. T., Ni, P., Oh, S. J., Onteru, S., Panitz, F., Park, E. W., Park, H. S., Pascal, G., Paudel, Y., Perez-Enciso, M., Ramirez-Gonzalez, R., Reecy, J. M., Rodriguez-Zas, S., Rohrer, G. A., Rund, L., Sang, Y., Schachtschneider, K., Schraiber, J. G., Schwartz, J., Scobie, L., Scott, C., Searle, S., Servin, B., Southey, B. R., Sperber, Göran, Stadler, P., Sweedler, J. V., Tafer, H., Thomsen, B., Wali, R., Wang, J., White, S., Xu, X., Yerle, M., Zhang, G., Zhang, J., Zhao, S., Rogers, J., Churcher, C., Schook, L. B., Groenen, M. A., Archibald, A. L., Uenishi, H., Tuggle, C. K., Takeuchi, Y., Rothschild, M. F., Rogel-Gaillard, C., Park, C., Milan, D., Megens, H. J., Li, S., Larkin, D. M., Kim, H., Frantz, L. A., Caccamo, M., Ahn, H., Aken, B. L., Anselmo, A., Anthon, C., Auvil, L., Badaoui, B., Beattie, C. W., Bendixen, C., Berman, D., Blecha, F., Blomberg, Jonas, Bolund, L., Bosse, M., Botti, S., Bujie, Z., Byström, M., Capitanu, B., Carvalho-Silva, D., Chardon, P., Chen, C., Cheng, R., Choi, S. H., Chow, W., Clark, R. C., Clee, C., Crooijmans, R. P., Dawson, H. D., Dehais, P., De Sapio, F., Dibbits, B., Drou, N., Du, Z. Q., Eversole, K., Fadista, J., Fairley, S., Faraut, T., Faulkner, G. J., Fowler, K. E., Fredholm, M., Fritz, E., Gilbert, J. G., Giuffra, E., Gorodkin, J., Griffin, D. K., Harrow, J. L., Hayward, Alexander, Howe, K., Hu, Z. L., Humphray, S. J., Hunt, T., Hornshoj, H., Jeon, J. T., Jern, Patric, Jones, M., Jurka, J., Kanamori, H., Kapetanovic, R., Kim, J., Kim, J. H., Kim, K. W., Kim, T. H., Larson, G., Lee, K., Lee, K. T., Leggett, R., Lewin, H. A., Li, Y., Liu, W., Loveland, J. E., Lu, Y., Lunney, J. K., Ma, J., Madsen, O., Mann, K., Matthews, L., McLaren, S., Morozumi, T., Murtaugh, M. P., Narayan, J., Nguyen, D. T., Ni, P., Oh, S. J., Onteru, S., Panitz, F., Park, E. W., Park, H. S., Pascal, G., Paudel, Y., Perez-Enciso, M., Ramirez-Gonzalez, R., Reecy, J. M., Rodriguez-Zas, S., Rohrer, G. A., Rund, L., Sang, Y., Schachtschneider, K., Schraiber, J. G., Schwartz, J., Scobie, L., Scott, C., Searle, S., Servin, B., Southey, B. R., Sperber, Göran, Stadler, P., Sweedler, J. V., Tafer, H., Thomsen, B., Wali, R., Wang, J., White, S., Xu, X., Yerle, M., Zhang, G., Zhang, J., Zhao, S., Rogers, J., Churcher, C., and Schook, L. B.
Abstract: For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
Published: 2012
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20. Analyses of pig genomes provide insight into porcine demography and evolution

Author: Groenen, MAM, Archibald, AL, Uenishi, H, Tuggle, CK, Takeuchi, Y, Rothschild, MF, Rogel-Gaillard, C, Park, C, Milan, D, Megens, H-J, Li, S, Larkin, DM, Kim, H, Frantz, LAF, Caccamo, M, Ahn, H, Aken, BL, Anselmo, A, Anthon, C, Auvil, L, Badaoui, B, Beattie, CW, Bendixen, C, Berman, D, Blecha, F, Blomberg, J, Bolund, L, Bosse, M, Botti, S, Zhan, B, Bystrom, M, Capitanu, B, Carvalho-Silva, D, Chardon, P, Chen, C, Cheng, R, Choi, S-H, Chow, W, Clark, RC, Clee, C, Crooijmans, RPMA, Dawson, HD, Dehais, P, De Sapio, F, Dibbits, B, Drou, N, Du, Z-Q, Eversole, K, Fadista, J, Fairley, S, Faraut, T, Faulkner, GJ, Fowler, KE, Fredholm, M, Fritz, E, Gilbert, JGR, Giuffra, E, Gorodkin, J, Griffin, DK, Harrow, JL, Hayward, A, Howe, K, Hu, Z-L, Humphray, SJ, Hunt, T, Hornshoj, H, Jeon, J-T, Jern, P, Jones, M, Jurka, J, Kanamori, H, Kapetanovic, R, Kim, J, Kim, J-H, Kim, K-W, Kim, T-H, Larson, G, Lee, K, Lee, K-T, Leggett, R, Lewin, HA, Li, Y, Liu, W, Loveland, JE, Lu, Y, Lunney, JK, Ma, J, Madsen, O, Mann, K, Matthews, L, McLaren, S, Morozumi, T, Murtaugh, MP, Narayan, J, Dinh, TN, Ni, P, Oh, S-J, Onteru, S, Panitz, F, Park, E-W, Park, H-S, Pascal, G, Paudel, Y, Perez-Enciso, M, Ramirez-Gonzalez, R, Reecy, JM, Rodriguez-Zas, S, Rohrer, GA, Rund, L, Sang, Y, Schachtschneider, K, Schraiber, JG, Schwartz, J, Scobie, L, Scott, C, Searle, S, Servin, B, Southey, BR, Sperber, G, Stadler, P, Sweedler, JV, Tafer, H, Thomsen, B, Wali, R, Wang, J, White, S, Xu, X, Yerle, M, Zhang, G, Zhang, J, Zhao, S, Rogers, J, Churcher, C, Schook, LB, Groenen, MAM, Archibald, AL, Uenishi, H, Tuggle, CK, Takeuchi, Y, Rothschild, MF, Rogel-Gaillard, C, Park, C, Milan, D, Megens, H-J, Li, S, Larkin, DM, Kim, H, Frantz, LAF, Caccamo, M, Ahn, H, Aken, BL, Anselmo, A, Anthon, C, Auvil, L, Badaoui, B, Beattie, CW, Bendixen, C, Berman, D, Blecha, F, Blomberg, J, Bolund, L, Bosse, M, Botti, S, Zhan, B, Bystrom, M, Capitanu, B, Carvalho-Silva, D, Chardon, P, Chen, C, Cheng, R, Choi, S-H, Chow, W, Clark, RC, Clee, C, Crooijmans, RPMA, Dawson, HD, Dehais, P, De Sapio, F, Dibbits, B, Drou, N, Du, Z-Q, Eversole, K, Fadista, J, Fairley, S, Faraut, T, Faulkner, GJ, Fowler, KE, Fredholm, M, Fritz, E, Gilbert, JGR, Giuffra, E, Gorodkin, J, Griffin, DK, Harrow, JL, Hayward, A, Howe, K, Hu, Z-L, Humphray, SJ, Hunt, T, Hornshoj, H, Jeon, J-T, Jern, P, Jones, M, Jurka, J, Kanamori, H, Kapetanovic, R, Kim, J, Kim, J-H, Kim, K-W, Kim, T-H, Larson, G, Lee, K, Lee, K-T, Leggett, R, Lewin, HA, Li, Y, Liu, W, Loveland, JE, Lu, Y, Lunney, JK, Ma, J, Madsen, O, Mann, K, Matthews, L, McLaren, S, Morozumi, T, Murtaugh, MP, Narayan, J, Dinh, TN, Ni, P, Oh, S-J, Onteru, S, Panitz, F, Park, E-W, Park, H-S, Pascal, G, Paudel, Y, Perez-Enciso, M, Ramirez-Gonzalez, R, Reecy, JM, Rodriguez-Zas, S, Rohrer, GA, Rund, L, Sang, Y, Schachtschneider, K, Schraiber, JG, Schwartz, J, Scobie, L, Scott, C, Searle, S, Servin, B, Southey, BR, Sperber, G, Stadler, P, Sweedler, JV, Tafer, H, Thomsen, B, Wali, R, Wang, J, White, S, Xu, X, Yerle, M, Zhang, G, Zhang, J, Zhao, S, Rogers, J, Churcher, C, and Schook, LB
Abstract: For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars ∼1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
Published: 2012

21. The CTRB1/CTRB2/BCAR1 locus is associated with GLP-1 stimulated insulin secretion and DPP-4 inhibitor treatment response

Author: Hart, L.M. 't, Fritsche, A., Leeuwen, N. van, Nijpels, G., Donnelly, L.A., Dekker, J.M., Fadista, J., Groop, L., Carlotti, F., Koning, E.J.P. de, Boomsma, D.I., Geus, E.J.C. de, Eekhoff, E.M.W., Pearson, E.R., and Diamant, M.

22. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

Author: van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, Mckeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia H T, Luk, Andrea O Y, Lee, Heung Man, Lim, Cadmon K P, Szeto, Cheuk Chun, Wing Yee, So, Chan, Juliana C N, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, Mcknight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, Ac, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kr, Riihelä, M, Ryysy, L, Laukkanen, Kh, Nyländen, P, Sademies, A, Anderson, S, Asplund, B, Byskata, U, Liedes, P, Kuusela, M, Virkkala, T, Nikkola, A, Ritola, E, Niska, Tm, Saarinen, H, Oukko-Ruponen, Se, Virtanen, T, Lyytinen, Va, Kari, Ph, Simonen, T, Kaprio, Sa, Kärkkäinen, J, Rantaeskola, B, Kääriäinen, Tp, Haaga, J, Pietiläinen, Al, Klemetti, S, Nyandoto, T, Rontu, E, Satuli-Autere, S, Toivonen, Kr, Lansimaki, Hv, Ahonen, R, Ivaska-Suomela, M, Jauhiainen, A, Laine, Mm, Pellonpää, T, Puranen, R, Airas, Ma, Laakso, J, Rautavaara, K, Erola, Rm, Jatkola, E, Lönnblad, Tr, Malm, A, Mäkelä, J, Rautamo, E, Hentunen, P, Lagerstam, J, Feodoroff, M, Gordin, D, Heikkilä, O, Hietala, K, Fagerudd, J, Korolainen, M, Kyllönen, L, Kytö, J, Lindh, S, Pettersson-Fernholm, K, Rosengård-Bärlund, M, Sandelin, A, Thorn, L, Tuomikangas, J, Vesisenaho, T, Wadén, J, Sipilä, V, Kalliomäki, Ft, Koskelainen, J, Nikkanen, R, Savolainen, N, Sulonen, H, Valtonen, E, Norvio, L, Hämäläinen, A, Toivanen, E, Parta, Ja, Pirttiniemi, I, Aranko, S, Ervasti, S, Kauppinen-Mäkelin, R, Kuusisto, A, Leppälä, T, Nikkilä, K, Pekkonen, L, Jokelainen, Ks, Kananen, K, Karjalainen, M, Kemppainen, P, Mankinen, Am, Reponen, A, Sankari, M, Suominen, P, Lappalainen, A, Liimatainen, M, Santaholma, J, Aimolahti, A, Huovinen, E, Ilkka, V, Lehtimäki, M, Pälikkö-Kontinen, E, Vanhanen, A, Koskinen, E, Siitonen, T, Huttunen, E, Ikäheimo, R, Karhapää, P, Kekäläinen, P, Laakso, M, Lakka, T, Lampainen, E, Moilanen, L, Tanskanen, S, Niskanen, L, Tuovinen, U, Vauhkonen, I, Voutilainen, E, Rcw, Ma, Chan, Jcn, Huang, Y, Lan, Hy, Lok, S, Tomlinson, B, Tsui, Skw, Yu, W, Yip, Kyl, Chan, Tf, Fan, X, So, Wy, Szeto, Cc, Tang, N, Luk, Ao, Tian, X, Jiang, G, Tam, Cht, Lee, Hm, Lim, Ckp, Chan, Kkh, Xie, F, Acw, Ng, Cheung, Gpy, Yeung, Mw, Mai, S, Zhang, S, Yu, P, Weng, M, Maxwell, Ap, Mcknight, Aj, Savage, Da, Walker, J, Thomas, S, Viberti, Gc, Boulton, Ajm, Marshall, S, Demaine, Ag, Millward, Ba, Bain, Sc, Sandholm, N, Forsblom, C, Harjutsalo, V, Mäkinen, Vp, Ahola, Aj, Dahlström, E, Lehto, M, Lithovius, R, Panduru, Nm, Parkkonen, M, Saraheimo, M, Söderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, Lm, Tolonen, N, Groop, Ph, Mckay, Gj, Salem, Rm, Isakova, T, Palmer, C, Guiducci, C, Taylor, A, Mirel, Db, Williams, Ww, Hirschhorn, Jn, Florez, Jc, Brennan, Ep, Sadlier, Dm, Martin, F, Godson, C, Mayer, L, Gubitosi-Klug, R, Bourne, P, Schutta, M, Lackaye, Me, Gregory, Ns, Kruger, D, Jones, Jk, Bhan, A, Golden, E, Aiello, L, Larkin, M, Nathan, D, Ziegler, G, Caulder, S, Pittman, C, Luttrell, L, Lopes-Virella, M, Johnson, M, Gunyou, K, Bergenstal, R, Vittetoe, B, Sivitz, W, Flaherty, N, Bantle, J, Hitt, S, Goldstein, D, Hainsworth, D, Cimino, L, Orchard, T, Wigley, C, Dagogo-Jack, S, Strowig, S, Raskin, P, Barnie, A, Zinman, B, Fahlstrom, R, Palmer, J, Harth, J, Driscoll, M, Mcdonald, C, Lipps Hagan, J, May, M, Levandoski, L, White, N, Gatcomb, P, Tamborlane, W, Adelman, D, Colson, S, Molitch, M, Lorenzi, G, Mudaliar, S, Johnsonbaugh, S, Miller, R, Canady, J, Schade, D, Bernal, Ml, Malone, J, Morrison, A, Martin, C, Herman, W, Pop-Busui, R, Cowie, C, Leschek, E, Cleary, P, Lachin, J, Braffett, B, Steffes, M, Arends, V, Blodi, B, Danis, R, Lawrence, D, Wabers, H, Soliman, E, Zhang, Zm, Campbell, C, Hensley, S, Keasler, L, Mark, M, Albertini, M, Boustany, C, Ehlgen, A, Gerl, M, Huber, J, Schölch, C, Zimdahl-Gelling, H, Groop, L, Agardh, E, Ahlqvist, E, Ajanki, T, Al Maghrabi, N, Almgren, P, Apelqvist, J, Bengtsson, E, Berglund, L, Björckbacka, H, Blom-Nilsson, U, Borell, M, Burström, A, Cilio, C, Cinthio, M, Dreja, K, Dunér, P, Engelbertsen, D, Fadista, J, Gomez, M, Goncalves, I, Hedblad, B, Hultgårdh, A, Johansson, Me, Kennbäck, C, Kravic, J, Ladenvall, C, Lernmark, Å, Lindholm, E, Ling, C, Luthman, H, Melander, O, Neptin, M, Nilsson, J, Nilsson, P, Nilsson, T, Nordin, G, Orho-Melander, M, Ottoson-Laakso, E, Persson, A, Persson, M, Persson, Må, Postma, J, Pranter, E, Rattik, S, Sterner, G, Tindberg, L, Wigren, M, Zetterqvist, A, Åkerlund, M, Ostling, G, Kanninen, T, Ahonen-Bishopp, A, Eliasson, A, Herrala, T, Tikka-Kleemola, P, Hamsten, A, Betsholtz, C, Björkholm, A, Foroogh, F, Genové, G, Gertow, K, Gigante, B, He, B, Leander, K, Mcleod, O, Nastase-Mannila, M, Patrakka, J, Silveira, A, Strawbridge, R, Tryggvason, K, Vikström, M, Ohrvik, J, Österholm, Am, Thorand, B, Gieger, C, Grallert, H, Ludwig, T, Nitz, B, Schneider, A, Wang-Sattler, R, Zierer, A, Remuzzi, G, Benigni, A, Donadelli, R, Lesti, Md, Noris, M, Perico, N, Perna, A, Piras, R, Ruggenenti, P, Rurali, E, Dunger, D, Chassin, L, Dalton, N, Deanfield, J, Horsford, J, Rice, C, Rudd, J, Walker, N, Whitehead, K, Wong, M, Colhoun, H, Adams, F, Akbar, T, Belch, J, Deshmukh, H, Dove, F, Ellingford, A, Farran, B, Ferguson, M, Henderson, G, Houston, G, Khan, F, Leese, G, Liu, Y, Livingstone, S, Looker, H, Mccann, M, Mcgurnaghan, S, Morris, A, Newton, D, Pearson, E, Reekie, G, Smith, N, Shore, A, Aizawa, K, Ball, C, Bellenger, N, Casanova, F, Frayling, T, Gates, P, Gooding, K, Hattersley, A, Ling, R, Mawson, D, Shandas, R, Strain, D, Thorn, C, Smith, U, Hammarstedt, A, Häring, H, Pedersen, O, Sesti, G, Fagerholm, E, Toppila, I, Valo, E, Salomaa, V, Havulinna, A, Kristiansson, K, Okamo, P, Peltola, T, Perola, M, Pietilä, A, Ripatti, S, Taimi, M, Ylä-Herttuala, S, Babu, M, Dijkstra, M, Gurzeler, E, Huusko, J, Kholová, I, Merentie, M, Poikolainen, M, Mccarthy, M, Groves, C, Juliusdottir, T, Karpe, F, Lagou, V, Rayner, W, Robertson, N, van Zuydam, N, Cobelli, C, Di Camillo, B, Finotello, F, Sambo, F, Toffolo, G, Trifoglio, E, Bellazzi, R, Barbarini, N, Bucalo, M, Larizza, C, Magni, P, Malovini, A, Marini, S, Mulas, F, Quaglini, S, Sacchi, L, Vitali, F, Ferrannini, E, Boldrini, B, Kozakova, M, Mari, A, Morizzo, C, Mota, L, Natali, A, Palombo, C, Venturi, E, Walker, M, Patrono, C, Pagliaccia, F, Rocca, B, Nuutila, P, Haukkala, J, Knuuti, J, Roivainen, A, Saraste, A, Mckeague, P, Colombo, M, Steckel-Hamann, B, Bokvist, K, Shankar, S, Thomas, M, Gan, Lm, Heinonen, S, Jönsson-Rylander, Ac, Momo, R, Schnecke, V, Unwin, R, Walentinsson, A, Whatling, C, Nogoceke, E, Pacheco, Gd, Formentini, I, Schindler, T, Tortoli, P, Bassi, L, Boni, E, Dallai, A, Guidi, F, Lenge, M, Matera, R, Ramalli, A, Ricci, S, Viti, J, Jablonka, B, Crowther, D, Gassenhuber, J, Hess, S, Hubschle, T, Juretschke, Hp, Rutten, H, Sadowski, T, Wohlfart, P, Brosnan, J, Clerin, V, Fauman, E, Hyde, C, Malarstig, A, Pullen, N, Tilley, M, Tuthill, T, Vangjeli, C, Linda T, Ziemek D., Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ronald C W, Ma, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin N A, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, Mccarthy, Mark, I, Palombo, Carlo, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Nefrologian yksikkö, Department of Medicine, Institute for Molecular Medicine Finland, Tiinamaija Tuomi Research Group, Endokrinologian yksikkö, Per Henrik Groop / Principal Investigator, Leif Groop Research Group, HUS Abdominal Center, HUS Internal Medicine and Rehabilitation, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: 0301 basic medicine, Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Type 2 diabetes, Bioinformatics, Kidney Failure, 0302 clinical medicine, Genome-wide analysis, 80 and over, Diabetic Nephropathies, Renal Insufficiency, Chronic, Genome-wide analysis, Type 2 Diabetes, Aged, 80 and over, RISK, INSULIN-RESISTANCE, diabetes, Diabetes, STAGE RENAL-DISEASE, Single Nucleotide, Middle Aged, Type 2 Diabetes, SUSCEPTIBILITY GENES, Adult, Aged, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, OBESITY, BIOLOGICAL PATHWAYS, nephropathy, Medical genetics, Type 2, kidney, medicine.medical_specialty, Diabetic Nephropathies/epidemiology, Settore BIO/14 - FARMACOLOGIA, Renal Insufficiency, Chronic/complications, NEPHROPATHY, SNP, 030209 endocrinology & metabolism, Nephropathy, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Journal Article, Diabetes Mellitus, Internal Medicine, medicine, Medicine [Science], Polymorphism, Diabetic Kidney Disease, METAANALYSIS, Genetic heterogeneity, business.industry, Diabetes Mellitus, Type 2/complications, association, Case-control study, nutritional and metabolic diseases, Kidney Failure, Chronic/complications, FAT DISTRIBUTION, medicine.disease, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Microalbuminuria, genetic, business
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore)

23. RCAN1 is critical for ß-cell mitochondrial function and is overexpressed in human Type 2 diabetes

Author: Peiris, H., Duffield, M., Claire Jessup, Kashmir, V., Fadista, J., Genders, A., Mcgee, S., Ryan, M., Laybutt, D. R., Coates, P. T., Pritchard, M. A., Groop, L., and Damien Keating

24. Comparative analysis of the human pancreatic islet transcriptome from non-diabetic and diabetic donors

Author: Fadista, J, primary
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25. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

Author: Beaumont RN, Flatley C, Vaudel M, Wu X, Chen J, Moen GH, Skotte L, Helgeland Ø, Solé-Navais P, Banasik K, Albiñana C, Ronkainen J, Fadista J, Stinson SE, Trajanoska K, Wang CA, Westergaard D, Srinivasan S, Sánchez-Soriano C, Bilbao JR, Allard C, Groleau M, Kuulasmaa T, Leirer DJ, White F, Jacques PÉ, Cheng H, Hao K, Andreassen OA, Åsvold BO, Atalay M, Bhatta L, Bouchard L, Brumpton BM, Brunak S, Bybjerg-Grauholm J, Ebbing C, Elliott P, Engelbrechtsen L, Erikstrup C, Estarlich M, Franks S, Gaillard R, Geller F, Grove J, Hougaard DM, Kajantie E, Morgen CS, Nohr EA, Nyegaard M, Palmer CNA, Pedersen OB, Rivadeneira F, Sebert S, Shields BM, Stoltenberg C, Surakka I, Thørner LW, Ullum H, Vaarasmaki M, Vilhjalmsson BJ, Willer CJ, Lakka TA, Gybel-Brask D, Bustamante M, Hansen T, Pearson ER, Reynolds RM, Ostrowski SR, Pennell CE, Jaddoe VWV, Felix JF, Hattersley AT, Melbye M, Lawlor DA, Hveem K, Werge T, Nielsen HS, Magnus P, Evans DM, Jacobsson B, Järvelin MR, Zhang G, Hivert MF, Johansson S, Freathy RM, Feenstra B, and Njølstad PR
Subjects: Female, Humans, Pregnancy, Birth Weight genetics, Fetal Development genetics, Insulin, Male, Genome-Wide Association Study, Placenta metabolism
Abstract: A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth., (© 2023. The Author(s).)
Published: 2023
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26. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Author: Budu-Aggrey A, Kilanowski A, Sobczyk MK, Shringarpure SS, Mitchell R, Reis K, Reigo A, Mägi R, Nelis M, Tanaka N, Brumpton BM, Thomas LF, Sole-Navais P, Flatley C, Espuela-Ortiz A, Herrera-Luis E, Lominchar JVT, Bork-Jensen J, Marenholz I, Arnau-Soler A, Jeong A, Fawcett KA, Baurecht H, Rodriguez E, Alves AC, Kumar A, Sleiman PM, Chang X, Medina-Gomez C, Hu C, Xu CJ, Qi C, El-Heis S, Titcombe P, Antoun E, Fadista J, Wang CA, Thiering E, Wu B, Kress S, Kothalawala DM, Kadalayil L, Duan J, Zhang H, Hadebe S, Hoffmann T, Jorgenson E, Choquet H, Risch N, Njølstad P, Andreassen OA, Johansson S, Almqvist C, Gong T, Ullemar V, Karlsson R, Magnusson PKE, Szwajda A, Burchard EG, Thyssen JP, Hansen T, Kårhus LL, Dantoft TM, Jeanrenaud ACSN, Ghauri A, Arnold A, Homuth G, Lau S, Nöthen MM, Hübner N, Imboden M, Visconti A, Falchi M, Bataille V, Hysi P, Ballardini N, Boomsma DI, Hottenga JJ, Müller-Nurasyid M, Ahluwalia TS, Stokholm J, Chawes B, Schoos AM, Esplugues A, Bustamante M, Raby B, Arshad S, German C, Esko T, Milani LA, Metspalu A, Terao C, Abuabara K, Løset M, Hveem K, Jacobsson B, Pino-Yanes M, Strachan DP, Grarup N, Linneberg A, Lee YA, Probst-Hensch N, Weidinger S, Jarvelin MR, Melén E, Hakonarson H, Irvine AD, Jarvis D, Nijsten T, Duijts L, Vonk JM, Koppelmann GH, Godfrey KM, Barton SJ, Feenstra B, Pennell CE, Sly PD, Holt PG, Williams LK, Bisgaard H, Bønnelykke K, Curtin J, Simpson A, Murray C, Schikowski T, Bunyavanich S, Weiss ST, Holloway JW, Min JL, Brown SJ, Standl M, and Paternoster L
Subjects: Humans, Genetic Predisposition to Disease genetics, Hispanic or Latino genetics, Black People, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Dermatitis, Atopic genetics
Abstract: Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities., (© 2023. Springer Nature Limited.)
Published: 2023
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27. Comprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci.

Author: Fadista J, Skotte L, Karjalainen J, Abner E, Sørensen E, Ullum H, Werge T, Esko T, Milani L, Palotie A, Daly M, Melbye M, Feenstra B, and Geller F
Subjects: Collagen metabolism, Follow-Up Studies, Genome-Wide Association Study, Humans, Hernia, Inguinal genetics, Hernia, Inguinal surgery
Abstract: Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology., (© 2022. The Author(s).)
Published: 2022
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28. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Author: Skotte L, Fadista J, Bybjerg-Grauholm J, Appadurai V, Hildebrand MS, Hansen TF, Banasik K, Grove J, Albiñana C, Geller F, Bjurström CF, Vilhjálmsson BJ, Coleman M, Damiano JA, Burgess R, Scheffer IE, Pedersen OBV, Erikstrup C, Westergaard D, Nielsen KR, Sørensen E, Bruun MT, Liu X, Hjalgrim H, Pers TH, Mortensen PB, Mors O, Nordentoft M, Dreier JW, Børglum AD, Christensen J, Hougaard DM, Buil A, Hviid A, Melbye M, Ullum H, Berkovic SF, Werge T, and Feenstra B
Subjects: Anoctamins genetics, Child, Child, Preschool, Fever complications, Fever genetics, Genome-Wide Association Study, Humans, NAV1.1 Voltage-Gated Sodium Channel genetics, Epilepsy genetics, Seizures, Febrile genetics
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Published: 2022
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29. Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.

Author: Fadista J, Yakimov V, Võsa U, Hansen CS, Kasela S, Skotte L, Geller F, Courraud J, Esko T, Kukuškina V, Buil A, Melbye M, Werge TM, Hougaard DM, Milani L, Bybjerg-Grauholm J, Cohen AS, and Feenstra B
Subjects: Adult, Gene Expression Regulation, Neoplastic, Humans, Infant, Newborn, Neoplasms etiology, Neoplasms metabolism, Phenotype, Polyamine Oxidase, Gene Expression Regulation, Enzymologic, Genetic Predisposition to Disease, Mendelian Randomization Analysis methods, Neoplasms pathology, Oxidoreductases Acting on CH-NH Group Donors genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract: Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10 -49 ) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10 -28 ) and adults (P = 2.748 × 10 -8 ) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention., (© 2021. The Author(s).)
Published: 2021
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30. Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity.

Author: Fadista J, Kraven LM, Karjalainen J, Andrews SJ, Geller F, Baillie JK, Wain LV, Jenkins RG, and Feenstra B
Subjects: COVID-19 genetics, Genome-Wide Association Study, Humans, Idiopathic Pulmonary Fibrosis genetics, Lung pathology, Mucin-5B genetics, Polymorphism, Single Nucleotide genetics, Risk, SARS-CoV-2, Severity of Illness Index, COVID-19 pathology, Genetic Predisposition to Disease genetics, Idiopathic Pulmonary Fibrosis pathology
Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity., Methods: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10 -8 ) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls)., Findings: We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10 -3 ). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10 -2 ) ., Interpretation: The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors., Funding: Novo Nordisk Foundation and Oak Foundation., Competing Interests: Declaration of Competing Interest JF works for Novo Nordisk A/S since January 2021. LVW receives funding from GSK and Orion, outside of the submitted work. RGJ Jenkins reports personal fees and other from Biogen, personal fees from Galapagos, other from Galecto, personal fees and other from GlaxoSmithKline, personal fees from Heptares, personal fees and other from MedImmune, personal fees from Boehringer Ingelheim, personal fees from Pliant, personal fees from Roche/InterMune, personal fees from MedImmune, personal fees from PharmAkea, personal fees from Bristol Myers Squibb, personal fees from Chiesi, personal fees from Roche/Promedior, other from RedX, other from NuMedii, other from Nordic Biosciences, outside the submitted work; and RGJ is supported by a National Institute of Health Research Professorship (NIHR ref: RP-2017-08-ST2-014). RGJ is a trustee for Action for Pulmonary Fibrosis., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2021
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31. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Author: Lagou V, Mägi R, Hottenga JJ, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, Dimas AS, Ulrich A, Zudina L, Gådin JR, Jiang L, Faggian A, Bonnefond A, Fadista J, Stathopoulou MG, Isaacs A, Willems SM, Navarro P, Tanaka T, Jackson AU, Montasser ME, O'Connell JR, Bielak LF, Webster RJ, Saxena R, Stafford JM, Pourcain BS, Timpson NJ, Salo P, Shin SY, Amin N, Smith AV, Li G, Verweij N, Goel A, Ford I, Johnson PCD, Johnson T, Kapur K, Thorleifsson G, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Müller-Nurasyid M, Ganna A, Sarin AP, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire U, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blüher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindström J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Tönjes A, Winkelmann BR, Boehm BO, März W, Metspalu A, Price JF, Deloukas P, Körner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Männistö S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PV, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N, Boomsma DI, Groop L, Tuomi T, Hofman A, Munroe PB, Gudnason V, Siscovick DS, Watkins H, Lecoeur C, Vollenweider P, Franco-Cereceda A, Eriksson P, Jarvelin MR, Stefansson K, Hamsten A, Nicholson G, Karpe F, Dermitzakis ET, Lindgren CM, McCarthy MI, Froguel P, Kaakinen MA, Lyssenko V, Watanabe RM, Ingelsson E, Florez JC, Dupuis J, Barroso I, Morris AP, and Prokopenko I
Published: 2021
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32. Integrating genetics with newborn metabolomics in infantile hypertrophic pyloric stenosis.

Author: Fadista J, Skotte L, Courraud J, Geller F, Gørtz S, Wohlfahrt J, Melbye M, Cohen AS, and Feenstra B
Subjects: Case-Control Studies, Chromatography, Liquid, Computational Biology, Denmark, Feeding Behavior, Female, Genetic Association Studies, Genetic Variation, Humans, Infant, Newborn, Male, Mass Spectrometry, Polymorphism, Single Nucleotide, Pyloric Stenosis, Hypertrophic diagnosis, Biomarkers, Genetic Predisposition to Disease, Metabolome, Metabolomics methods, Pyloric Stenosis, Hypertrophic genetics, Pyloric Stenosis, Hypertrophic metabolism
Abstract: Introduction: Infantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle., Objectives: Since previous reports have implicated lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns., Methods: We used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case-control design., Results: The phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (P = 4.68 × 10 -8 ) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case-control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (P = 6.15 × 10 -3 ). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS., Conclusions: We detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.
Published: 2021
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33. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Author: Lagou V, Mägi R, Hottenga JJ, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, Dimas AS, Ulrich A, Zudina L, Gådin JR, Jiang L, Faggian A, Bonnefond A, Fadista J, Stathopoulou MG, Isaacs A, Willems SM, Navarro P, Tanaka T, Jackson AU, Montasser ME, O'Connell JR, Bielak LF, Webster RJ, Saxena R, Stafford JM, Pourcain BS, Timpson NJ, Salo P, Shin SY, Amin N, Smith AV, Li G, Verweij N, Goel A, Ford I, Johnson PCD, Johnson T, Kapur K, Thorleifsson G, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Müller-Nurasyid M, Ganna A, Sarin AP, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire U, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blüher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindström J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Tönjes A, Winkelmann BR, Boehm BO, März W, Metspalu A, Price JF, Deloukas P, Körner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Männistö S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PV, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N, Boomsma DI, Groop L, Tuomi T, Hofman A, Munroe PB, Gudnason V, Siscovick DS, Watkins H, Lecoeur C, Vollenweider P, Franco-Cereceda A, Eriksson P, Jarvelin MR, Stefansson K, Hamsten A, Nicholson G, Karpe F, Dermitzakis ET, Lindgren CM, McCarthy MI, Froguel P, Kaakinen MA, Lyssenko V, Watanabe RM, Ingelsson E, Florez JC, Dupuis J, Barroso I, Morris AP, and Prokopenko I
Subjects: Adult, Anorexia Nervosa blood, Anorexia Nervosa ethnology, Anorexia Nervosa physiopathology, Fasting blood, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance blood, Glucose Intolerance ethnology, Glucose Intolerance physiopathology, Humans, Insulin Receptor Substrate Proteins blood, Kruppel-Like Transcription Factors blood, Male, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, White People, Anorexia Nervosa genetics, Blood Glucose metabolism, Glucose Intolerance genetics, Insulin blood, Insulin Receptor Substrate Proteins genetics, Insulin Resistance genetics, Kruppel-Like Transcription Factors genetics
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021
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34. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Author: Steinthorsdottir V, McGinnis R, Williams NO, Stefansdottir L, Thorleifsson G, Shooter S, Fadista J, Sigurdsson JK, Auro KM, Berezina G, Borges MC, Bumpstead S, Bybjerg-Grauholm J, Colgiu I, Dolby VA, Dudbridge F, Engel SM, Franklin CS, Frigge ML, Frisbaek Y, Geirsson RT, Geller F, Gretarsdottir S, Gudbjartsson DF, Harmon Q, Hougaard DM, Hegay T, Helgadottir A, Hjartardottir S, Jääskeläinen T, Johannsdottir H, Jonsdottir I, Juliusdottir T, Kalsheker N, Kasimov A, Kemp JP, Kivinen K, Klungsøyr K, Lee WK, Melbye M, Miedzybrodska Z, Moffett A, Najmutdinova D, Nishanova F, Olafsdottir T, Perola M, Pipkin FB, Poston L, Prescott G, Saevarsdottir S, Salimbayeva D, Scaife PJ, Skotte L, Staines-Urias E, Stefansson OA, Sørensen KM, Thomsen LCV, Tragante V, Trogstad L, Simpson NAB, Aripova T, Casas JP, Dominiczak AF, Walker JJ, Thorsteinsdottir U, Iversen AC, Feenstra B, Lawlor DA, Boyd HA, Magnus P, Laivuori H, Zakhidova N, Svyatova G, Stefansson K, and Morgan L
Subjects: Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Asia, Central epidemiology, Blood Pressure genetics, Case-Control Studies, Datasets as Topic, Europe epidemiology, Female, Fibroblast Growth Factor 5 genetics, Genetic Loci genetics, Genome-Wide Association Study, Humans, Hypertension, Pregnancy-Induced epidemiology, MDS1 and EVI1 Complex Locus Protein genetics, Middle Aged, Pre-Eclampsia epidemiology, Pregnancy, Prospective Studies, Genetic Predisposition to Disease, Hypertension, Pregnancy-Induced genetics, Multifactorial Inheritance, Pre-Eclampsia genetics
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
Published: 2020
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35. Genome-wide Study Identifies Association between HLA-B ∗ 55:01 and Self-Reported Penicillin Allergy.

Author: Krebs K, Bovijn J, Zheng N, Lepamets M, Censin JC, Jürgenson T, Särg D, Abner E, Laisk T, Luo Y, Skotte L, Geller F, Feenstra B, Wang W, Auton A, Raychaudhuri S, Esko T, Metspalu A, Laur S, Roden DM, Wei WQ, Holmes MV, Lindgren CM, Phillips EJ, Mägi R, Milani L, and Fadista J
Subjects: Adult, Alleles, Arthritis, Rheumatoid complications, Arthritis, Rheumatoid immunology, Chromosomes, Human, Pair 6 chemistry, Drug Hypersensitivity complications, Drug Hypersensitivity etiology, Drug Hypersensitivity immunology, Electronic Health Records, Europe, Female, Gene Expression, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, HLA-B Antigens immunology, Histocompatibility Testing, Humans, Male, Penicillins adverse effects, Protein Tyrosine Phosphatase, Non-Receptor Type 22 immunology, Psoriasis complications, Psoriasis immunology, Self Report, T-Lymphocytes immunology, T-Lymphocytes pathology, United States, Arthritis, Rheumatoid genetics, Drug Hypersensitivity genetics, HLA-B Antigens genetics, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Psoriasis genetics
Abstract: Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B ∗ 55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10 -31 ) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10 -47 ). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B ∗ 55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2020
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36. Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D.

Author: Viñuela A, Varshney A, van de Bunt M, Prasad RB, Asplund O, Bennett A, Boehnke M, Brown AA, Erdos MR, Fadista J, Hansson O, Hatem G, Howald C, Iyengar AK, Johnson P, Krus U, MacDonald PE, Mahajan A, Manning Fox JE, Narisu N, Nylander V, Orchard P, Oskolkov N, Panousis NI, Payne A, Stitzel ML, Vadlamudi S, Welch R, Collins FS, Mohlke KL, Gloyn AL, Scott LJ, Dermitzakis ET, Groop L, Parker SCJ, and McCarthy MI
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Animals, Blood Glucose metabolism, Cell Line, Tumor, Cohort Studies, Diabetes Mellitus, Type 2 blood, Diacylglycerol Kinase genetics, Diacylglycerol Kinase metabolism, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, RNA-Seq, Sequence Analysis, DNA, Transcription Factor 7-Like 2 Protein genetics, Transcription Factor 7-Like 2 Protein metabolism, Young Adult, Blood Glucose genetics, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease, Islets of Langerhans metabolism, Quantitative Trait Loci
Abstract: Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.
Published: 2020
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37. Glucocorticoid induces human beta cell dysfunction by involving riborepressor GAS5 LincRNA.

Author: Esguerra JLS, Ofori JK, Nagao M, Shuto Y, Karagiannopoulos A, Fadista J, Sugihara H, Groop L, and Eliasson L
Subjects: Animals, Apoptosis drug effects, Cells, Cultured, Dexamethasone pharmacology, Dose-Response Relationship, Drug, Humans, Insulin-Secreting Cells metabolism, Male, Rats, Rats, Wistar, Glucocorticoids pharmacology, Insulin-Secreting Cells drug effects, RNA, Long Noncoding metabolism
Abstract: Objective: A widely recognized metabolic side effect of glucocorticoid (GC) therapy is steroid-induced diabetes mellitus (DM). However, studies on the molecular basis of GC-induced pancreatic beta cell dysfunction in human beta cells are lacking. The significance of non-coding RNAs in various cellular processes is emerging. In this study, we aimed to show the direct negative impact of GC on beta cell function and elucidate the role of riborepressor GAS5 lincRNA in the GC signaling pathway in human pancreatic beta cells., Methods: Patients undergoing two weeks of high-dose prednisolone therapy were monitored for C-peptide levels. Human pancreatic islets and the human beta cell line EndoC-βH1 were incubated in pharmacological concentrations of dexamethasone. The GAS5 level was modulated using anti-sense LNA gapmeR or short oligonucleotides with GAS5 HREM (hormone response element motif). Immunoblotting and/or real-time PCR were used to assess changes in protein and RNA expression, respectively. Functional characterization included glucose-stimulated insulin secretion and apoptosis assays. Correlation analysis was performed on RNAseq data of human pancreatic islets., Results: We found reduced C-peptide levels in patients undergoing high-dose GC therapy. Human islets and the human beta cell line EndoC-βH1 exposed to GC exhibited reduced insulin secretion and increased apoptosis. Concomitantly, reduced expression of important beta cell transcription factors, PDX1 and NKX6-1, as well as exocytotic protein SYT13 were observed. The expression of the glucocorticoid receptor was decreased, while that of serum and glucocorticoid-regulated kinase 1 (SGK1) was elevated. The expression of these genes was found to significantly correlate with GAS5 in human islet transcriptomics data. Increasing GAS5 levels using GAS5 HREM alleviated the inhibitory effects of dexamethasone on insulin secretion., Conclusions: The direct adverse effect of glucocorticoid in human beta cell function is mediated via important beta cell proteins and components of the GC signaling pathway in an intricate interplay with GAS5 lincRNA, a potentially novel therapeutic target to counter GC-mediated beta cell dysfunction., (Copyright © 2019 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Published: 2020
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38. GNAS gene is an important regulator of insulin secretory capacity in pancreatic β-cells.

Author: Taneera J, Dhaiban S, Mohammed AK, Mukhopadhyay D, Aljaibeji H, Sulaiman N, Fadista J, and Salehi A
Subjects: Aged, Animals, Cell Line, Chromogranins genetics, Cyclic AMP genetics, Cyclic AMP metabolism, Female, GTP-Binding Protein alpha Subunits, Gs genetics, Humans, Insulin-Secreting Cells cytology, Male, Middle Aged, Organ Specificity, Peptide Elongation Factor 1 genetics, Peptide Elongation Factor 1 metabolism, Rats, Chromogranins biosynthesis, GTP-Binding Protein alpha Subunits, Gs biosynthesis, Gene Expression Regulation, Insulin Secretion, Insulin-Secreting Cells metabolism
Abstract: Background: Type 2 diabetes (T2D) is a complex polygenic disease with unclear mechanism. In an attempt to identify novel genes involved in β-cell function, we harness a bioinformatics method called Loss-of-function tool (LoFtool) gene score., Methods: RNA-sequencing data from human islets were used to cross-reference genes within the 1st quartile of most intolerant LoFtool score with the 100th most expressed genes in human islets. Out of these genes, GNAS and EEF1A1 genes were selected for further investigation in diabetic islets, metabolic tissues along with their correlation with diabetic phenotypes. The influence of GNAS and EEF1A1 on insulin secretion and β-cell function were validated in INS-1 cells., Results: A comparatively higher expression level of GNAS and EEF1A1 was observed in human islets than fat, liver and muscle tissues. Furthermore, diabetic islets displayed a reduced expression of GNAS, but not of EEF1A, compared to non-diabetic islets. The expression of GNAS was positively correlated with insulin secretory index, GLP1R, GIPR and inversely correlated with HbA 1c . Diabetic human islets displayed a reduced cAMP generation and insulin secretory capacity in response to glucose. Moreover, siRNA silencing of GNAS in INS-1 cells reduced insulin secretion, insulin content, and cAMP production. In addition, the expression of Insulin, PDX1, and MAFA was significantly down-regulated in GNAS-silenced cells. However, cell viability and apoptosis rate were unaffected., Conclusion: LoFtool is a powerful tool to identify genes associated with pancreatic islets dysfunction. GNAS is a crucial gene for the β-cell insulin secretory capacity., (Copyright © 2019 Elsevier B.V. All rights reserved.)
Published: 2019
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39. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

Author: Liu X, Helenius D, Skotte L, Beaumont RN, Wielscher M, Geller F, Juodakis J, Mahajan A, Bradfield JP, Lin FTJ, Vogelezang S, Bustamante M, Ahluwalia TS, Pitkänen N, Wang CA, Bacelis J, Borges MC, Zhang G, Bedell BA, Rossi RM, Skogstrand K, Peng S, Thompson WK, Appadurai V, Lawlor DA, Kalliala I, Power C, McCarthy MI, Boyd HA, Marazita ML, Hakonarson H, Hayes MG, Scholtens DM, Rivadeneira F, Jaddoe VWV, Vinding RK, Bisgaard H, Knight BA, Pahkala K, Raitakari O, Helgeland Ø, Johansson S, Njølstad PR, Fadista J, Schork AJ, Nudel R, Miller DE, Chen X, Weirauch MT, Mortensen PB, Børglum AD, Nordentoft M, Mors O, Hao K, Ryckman KK, Hougaard DM, Kottyan LC, Pennell CE, Lyytikainen LP, Bønnelykke K, Vrijheid M, Felix JF, Lowe WL Jr, Grant SFA, Hyppönen E, Jacobsson B, Jarvelin MR, Muglia LJ, Murray JC, Freathy RM, Werge TM, Melbye M, Buil A, and Feenstra B
Subjects: Female, Genome-Wide Association Study, Gestational Age, Humans, Infant, Newborn, Pregnancy, Premature Birth genetics, Chromosomes, Human, Pair 2 genetics, Cytokines genetics, Fetus metabolism, Genome, Human genetics, Polymorphism, Single Nucleotide
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10 -14 ). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Published: 2019
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40. Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis.

Author: Fadista J, Skotte L, Geller F, Bybjerg-Grauholm J, Gørtz S, Romitti PA, Caggana M, Kay DM, Matsson H, Boyd HA, Hougaard DM, Nordenskjöld A, Mills JL, Melbye M, and Feenstra B
Subjects: Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Polymorphism, Single Nucleotide, Cell Cycle Proteins genetics, Homeodomain Proteins genetics, Microtubule-Associated Proteins genetics, Neoplasm Proteins genetics, Pyloric Stenosis, Hypertrophic genetics, Serine Endopeptidases genetics, Transcription Factors genetics
Abstract: Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.
Published: 2019
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41. Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes.

Author: Sharma A, Halu A, Decano JL, Padi M, Liu YY, Prasad RB, Fadista J, Santolini M, Menche J, Weiss ST, Vidal M, Silverman EK, Aikawa M, Barabási AL, Groop L, and Loscalzo J
Abstract: Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS p -values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study. We identified variants regulating gene expression (expression quantitative loci, eQTL) of HiCc pathway genes in islet samples. These eQTL genes showed higher levels of differential expression compared to non-eQTL genes in low, medium, and high glucose concentrations in rat islets. Among genes with highly significant eQTL evidence, NFATC4 belonged to four HiCc pathways. We asked if the expressions of T2D-associated candidate genes from GWAS and literature are regulated by Nfatc4 in rat islets. Extensive in vitro silencing of Nfatc4 in rat islet cells displayed reduced expression of 16, and increased expression of four putative downstream T2D genes. Overall, our approach uncovers the mechanistic connection of NFATC4 with downstream targets including a previously unknown one, TCF7L2, and establishes the HiCc pathways' relationship to T2D., Competing Interests: In the past three years, E.K.S. received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria and travel support from Novartis. J.L. discloses a relevant conflict for his founder’s role with Scipher, Inc. (a network medicine company).
Published: 2018
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42. Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.

Author: Fadista J, Lund M, Skotte L, Geller F, Nandakumar P, Chatterjee S, Matsson H, Granström AL, Wester T, Salo P, Virtanen V, Carstensen L, Bybjerg-Grauholm J, Hougaard DM, Pakarinen M, Perola M, Nordenskjöld A, Chakravarti A, Melbye M, and Feenstra B
Subjects: Haplotypes, Humans, Hirschsprung Disease genetics, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-ret genetics
Abstract: Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10 -10 ; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.
Published: 2018
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43. Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

Author: Flannick J, Fuchsberger C, Mahajan A, Teslovich TM, Agarwala V, Gaulton KJ, Caulkins L, Koesterer R, Ma C, Moutsianas L, McCarthy DJ, Rivas MA, Perry JRB, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SCJ, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MCY, Palmer ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JMM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VKL, Park KS, Saleheen D, So WY, Tam CHT, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA, Thameem F, Wilson G, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney ASF, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM, Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, DePristo M, de Angelis MH, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J, Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang L, Peters A, Huth C, O'Rahilly SP, Palmer CNA, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvänen AC, Bergman RN, Bharadwaj D, Bottinger EP, Cho YS, Chandak GR, Chan JCN, Chia KS, Daly MJ, Ebrahim SB, Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RCW, Pollin TI, Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJF, Small KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ, Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G, Trakalo J, Buck D, Prokopenko I, Mägi R, Lind L, Farjoun Y, Owen KR, Gloyn AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD, Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD, Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G, Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R, Lander ES, Gabriel S, Mohlke KL, Meitinger T, Groop L, Abecasis G, Scott LJ, Morris AP, Kang HM, Altshuler D, Burtt NP, Florez JC, Boehnke M, and McCarthy MI
Abstract: This corrects the article DOI: 10.1038/sdata.2017.179.
Published: 2018
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44. Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

Author: Flannick J, Fuchsberger C, Mahajan A, Teslovich TM, Agarwala V, Gaulton KJ, Caulkins L, Koesterer R, Ma C, Moutsianas L, McCarthy DJ, Rivas MA, Perry JRB, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SCJ, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MCY, Palmer ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JMM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VKL, Park KS, Saleheen D, So WY, Tam CHT, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA, Thameem F, Wilson G, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney ASF, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM, Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, DePristo M, de Angelis MH, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J, Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang L, Peters A, Huth C, O'Rahilly SP, Palmer CNA, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvänen AC, Bergman RN, Bharadwaj D, Bottinger EP, Cho YS, Chandak GR, Chan JC, Chia KS, Daly MJ, Ebrahim SB, Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RCW, Pollin TI, Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJF, Small KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ, Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G, Trakalo J, Buck D, Prokopenko I, Mägi R, Lind L, Farjoun Y, Owen KR, Gloyn AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD, Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD, Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G, Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R, Lander ES, Gabriel S, Mohlke KL, Meitinger T, Groop L, Abecasis G, Scott LJ, Morris AP, Kang HM, Altshuler D, Burtt NP, Florez JC, Boehnke M, and McCarthy MI
Subjects: Humans, White People, Diabetes Mellitus, Type 2 genetics, Genetic Variation
Abstract: To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
Published: 2017
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45. Glucose-Induced Changes in Gene Expression in Human Pancreatic Islets: Causes or Consequences of Chronic Hyperglycemia.

Author: Ottosson-Laakso E, Krus U, Storm P, Prasad RB, Oskolkov N, Ahlqvist E, Fadista J, Hansson O, Groop L, and Vikman P
Subjects: Chronic Disease, Diabetes Mellitus, Type 2 metabolism, Gene Expression, Genome-Wide Association Study, Humans, Hyperglycemia complications, Insulin metabolism, Insulin Secretion, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Hyperglycemia metabolism, Islets of Langerhans metabolism
Abstract: Dysregulation of gene expression in islets from patients with type 2 diabetes (T2D) might be causally involved in the development of hyperglycemia, or it could develop as a consequence of hyperglycemia (i.e., glucotoxicity). To separate the genes that could be causally involved in pathogenesis from those likely to be secondary to hyperglycemia, we exposed islets from human donors to normal or high glucose concentrations for 24 h and analyzed gene expression. We compared these findings with gene expression in islets from donors with normal glucose tolerance and hyperglycemia (including T2D). The genes whose expression changed in the same direction after short-term glucose exposure, as in T2D, were considered most likely to be a consequence of hyperglycemia. Genes whose expression changed in hyperglycemia but not after short-term glucose exposure, particularly those that also correlated with insulin secretion, were considered the strongest candidates for causal involvement in T2D. For example, ERO1LB , DOCK10 , IGSF11 , and PRR14L were downregulated in donors with hyperglycemia and correlated positively with insulin secretion, suggesting a protective role, whereas TMEM132C was upregulated in hyperglycemia and correlated negatively with insulin secretion, suggesting a potential pathogenic role. This study provides a catalog of gene expression changes in human pancreatic islets after exposure to glucose., (© 2017 by the American Diabetes Association.)
Published: 2017
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46. A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Author: Manning A, Highland HM, Gasser J, Sim X, Tukiainen T, Fontanillas P, Grarup N, Rivas MA, Mahajan A, Locke AE, Cingolani P, Pers TH, Viñuela A, Brown AA, Wu Y, Flannick J, Fuchsberger C, Gamazon ER, Gaulton KJ, Im HK, Teslovich TM, Blackwell TW, Bork-Jensen J, Burtt NP, Chen Y, Green T, Hartl C, Kang HM, Kumar A, Ladenvall C, Ma C, Moutsianas L, Pearson RD, Perry JRB, Rayner NW, Robertson NR, Scott LJ, van de Bunt M, Eriksson JG, Jula A, Koskinen S, Lehtimäki T, Palotie A, Raitakari OT, Jacobs SBR, Wessel J, Chu AY, Scott RA, Goodarzi MO, Blancher C, Buck G, Buck D, Chines PS, Gabriel S, Gjesing AP, Groves CJ, Hollensted M, Huyghe JR, Jackson AU, Jun G, Justesen JM, Mangino M, Murphy J, Neville M, Onofrio R, Small KS, Stringham HM, Trakalo J, Banks E, Carey J, Carneiro MO, DePristo M, Farjoun Y, Fennell T, Goldstein JI, Grant G, Hrabé de Angelis M, Maguire J, Neale BM, Poplin R, Purcell S, Schwarzmayr T, Shakir K, Smith JD, Strom TM, Wieland T, Lindstrom J, Brandslund I, Christensen C, Surdulescu GL, Lakka TA, Doney ASF, Nilsson P, Wareham NJ, Langenberg C, Varga TV, Franks PW, Rolandsson O, Rosengren AH, Farook VS, Thameem F, Puppala S, Kumar S, Lehman DM, Jenkinson CP, Curran JE, Hale DE, Fowler SP, Arya R, DeFronzo RA, Abboud HE, Syvänen AC, Hicks PJ, Palmer ND, Ng MCY, Bowden DW, Freedman BI, Esko T, Mägi R, Milani L, Mihailov E, Metspalu A, Narisu N, Kinnunen L, Bonnycastle LL, Swift A, Pasko D, Wood AR, Fadista J, Pollin TI, Barzilai N, Atzmon G, Glaser B, Thorand B, Strauch K, Peters A, Roden M, Müller-Nurasyid M, Liang L, Kriebel J, Illig T, Grallert H, Gieger C, Meisinger C, Lannfelt L, Musani SK, Griswold M, Taylor HA Jr, Wilson G Sr, Correa A, Oksa H, Scott WR, Afzal U, Tan ST, Loh M, Chambers JC, Sehmi J, Kooner JS, Lehne B, Cho YS, Lee JY, Han BG, Käräjämäki A, Qi Q, Qi L, Huang J, Hu FB, Melander O, Orho-Melander M, Below JE, Aguilar D, Wong TY, Liu J, Khor CC, Chia KS, Lim WY, Cheng CY, Chan E, Tai ES, Aung T, Linneberg A, Isomaa B, Meitinger T, Tuomi T, Hakaste L, Kravic J, Jørgensen ME, Lauritzen T, Deloukas P, Stirrups KE, Owen KR, Farmer AJ, Frayling TM, O'Rahilly SP, Walker M, Levy JC, Hodgkiss D, Hattersley AT, Kuulasmaa T, Stančáková A, Barroso I, Bharadwaj D, Chan J, Chandak GR, Daly MJ, Donnelly PJ, Ebrahim SB, Elliott P, Fingerlin T, Froguel P, Hu C, Jia W, Ma RCW, McVean G, Park T, Prabhakaran D, Sandhu M, Scott J, Sladek R, Tandon N, Teo YY, Zeggini E, Watanabe RM, Koistinen HA, Kesaniemi YA, Uusitupa M, Spector TD, Salomaa V, Rauramaa R, Palmer CNA, Prokopenko I, Morris AD, Bergman RN, Collins FS, Lind L, Ingelsson E, Tuomilehto J, Karpe F, Groop L, Jørgensen T, Hansen T, Pedersen O, Kuusisto J, Abecasis G, Bell GI, Blangero J, Cox NJ, Duggirala R, Seielstad M, Wilson JG, Dupuis J, Ripatti S, Hanis CL, Florez JC, Mohlke KL, Meigs JB, Laakso M, Morris AP, Boehnke M, Altshuler D, McCarthy MI, Gloyn AL, and Lindgren CM
Subjects: Black or African American genetics, Alleles, Asian People genetics, Case-Control Studies, Diabetes Mellitus, Type 2 metabolism, Finland, Gene Frequency, Genetic Predisposition to Disease, Genotype, Hispanic or Latino genetics, Humans, Odds Ratio, Diabetes Mellitus, Type 2 genetics, Fasting metabolism, Insulin metabolism, Insulin Resistance genetics, Proto-Oncogene Proteins c-akt genetics, White People genetics
Abstract: To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2 ., (© 2017 by the American Diabetes Association.)
Published: 2017
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47. LoFtool: a gene intolerance score based on loss-of-function variants in 60 706 individuals.

Author: Fadista J, Oskolkov N, Hansson O, and Groop L
Subjects: Brain, Humans, Genetic Diseases, Inborn genetics, Genome, Human, Genomics methods, Loss of Function Mutation, Software
Abstract: Motivation: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease., Results: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P -value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression., Availability and Implementation: The LoFtool gene scores are available in the Supplementary data ., Contact: joaofadista@gmail.com., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)
Published: 2017
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48. CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion.

Author: Abels M, Riva M, Bennet H, Ahlqvist E, Dyachok O, Nagaraj V, Shcherbina L, Fred RG, Poon W, Sörhede-Winzell M, Fadista J, Lindqvist A, Kask L, Sathanoori R, Dekker-Nitert M, Kuhar MJ, Ahrén B, Wollheim CB, Hansson O, Tengholm A, Fex M, Renström E, Groop L, Lyssenko V, and Wierup N
Subjects: Animals, Blotting, Western, Calcium Signaling physiology, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Type 2 blood, Electrophysiology, Exocytosis genetics, Exocytosis physiology, Female, Glucagon-Secreting Cells metabolism, Glucose metabolism, Homeostasis, Humans, Immunohistochemistry, In Situ Hybridization, Insulin Secretion, Insulin-Secreting Cells metabolism, Islets of Langerhans metabolism, Male, Mice, Mice, Inbred C57BL, Middle Aged, Nerve Tissue Proteins genetics, Real-Time Polymerase Chain Reaction, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 physiopathology, Glucagon metabolism, Insulin metabolism, Nerve Tissue Proteins metabolism
Abstract: Aims/hypothesis: Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart (-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice., Methods: CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca(2+) oscillation patterns and exocytosis were studied in mouse islets., Results: We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca(2+) signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis., Conclusions/interpretation: We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.
Published: 2016
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49. The genetic architecture of type 2 diabetes.

Author: Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ, Rivas MA, Perry JRB, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SCJ, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MCY, Palmer ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JMM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VKL, Park KS, Saleheen D, So WY, Tam CHT, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, van der Schouw YT, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA Jr, Thameem F, Wilson G Sr, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney ASF, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM, Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, DePristo M, de Angelis MH, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J, Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang L, Peters A, Huth C, O'Rahilly SP, Palmer CNA, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvänen AC, Bergman RN, Bharadwaj D, Bottinger EP, Cho YS, Chandak GR, Chan JCN, Chia KS, Daly MJ, Ebrahim SB, Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RCW, Pollin TI, Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJF, Small KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ, Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G, Trakalo J, Buck D, Prokopenko I, Mägi R, Lind L, Farjoun Y, Owen KR, Gloyn AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD, Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD, Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G, Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R, Lander ES, Gabriel S, Burtt NP, Mohlke KL, Meitinger T, Groop L, Abecasis G, Florez JC, Scott LJ, Morris AP, Kang HM, Boehnke M, Altshuler D, and McCarthy MI
Subjects: Alleles, DNA Mutational Analysis, Europe ethnology, Exome, Genome-Wide Association Study, Genotyping Techniques, Humans, Sample Size, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics
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
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50. The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants.

Author: Fadista J, Manning AK, Florez JC, and Groop L
Subjects: Alleles, Diabetes Mellitus, Type 2 genetics, Exome, Genetic Heterogeneity, Genome-Wide Association Study methods, Humans, Genome-Wide Association Study standards, Linkage Disequilibrium, Mutation Rate
Abstract: Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 × 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome- and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity.
Published: 2016
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