91 results on '"Szelinger S"'
Search Results
2. De Novo Splice Site Mutation in CASK Causes FG Syndrome-4 and Congenital Nystagmus
- Author
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Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., Russell, M., Courtright, A. L., Belnap, N., Rangasamy, S., Ramsey, K., Opitz, J. M., Craig, D. W., Narayanan, V., Huentelman, M. J., and Schrauwen, I.
- Published
- 2017
- Full Text
- View/download PDF
3. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants
- Author
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Gamazon, E R, Badner, J A, Cheng, L, Zhang, C, Zhang, D, Cox, N J, Gershon, E S, Kelsoe, J R, Greenwood, T A, Nievergelt, C M, Chen, C, McKinney, R, Shilling, P D, Schork, N J, Smith, E N, Bloss, C S, Nurnberger, J I, Edenberg, H J, Foroud, T, Koller, D L, Scheftner, W A, Coryell, W, Rice, J, Lawson, W B, Nwulia, E A, Hipolito, M, Byerley, W, McMahon, F J, Schulze, T G, Berrettini, W H, Potash, J B, Zandi, P P, Mahon, P B, McInnis, M G, Zöllner, S, Zhang, P, Craig, D W, Szelinger, S, Barrett, T B, and Liu, C
- Published
- 2013
- Full Text
- View/download PDF
4. Singleton deletions throughout the genome increase risk of bipolar disorder
- Author
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Zhang, D, Cheng, L, Qian, Y, Alliey-Rodriguez, N, Kelsoe, J R, Greenwood, T, Nievergelt, C, Barrett, T B, McKinney, R, Schork, N, Smith, E N, Bloss, C, Nurnberger, J, Edenberg, H J, Foroud, T, Sheftner, W, Lawson, W B, Nwulia, E A, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, F, Schulze, T G, Berrettini, W, Potash, J B, Belmonte, P L, Zandi, P P, McInnis, M G, Zöllner, S, Craig, D, Szelinger, S, Koller, D, Christian, S L, Liu, C, and Gershon, E S
- Published
- 2009
- Full Text
- View/download PDF
5. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders
- Author
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Andlauer, T.F.M. (Till F. M.), Guzman-Parra, J. (Jose), Streit, F. (Fabian), Strohmaier, J. (Jana), González, M.J. (Maria José), Gil Flores, S. (Susana), Cabaleiro Fabeiro, F.J. (Francisco J.), del Río Noriega, F. (Francisco), Perez, F.P. (Fermin Perez), Haro González, J. (Jesus), Orozco Diaz, G. (Guillermo), Diego, Y. (Yolanda) de, Moreno-Küstner, B. (Berta), Auburger, G. (Georg), Degenhardt, F. (Franziska), Heilmann-Heimbach, S. (Stefanie), Herms, S. (Stefan), Hoffmann, P. (Per), Frank, J. (Josef), Foo, J.C. (Jerome C.), Treutlein, J. (Jens), Witt, S.H. (Stephanie H), Cichon, S. (Sven), Kogevinas, M. (Manolis), Stahl, E.A. (Eli A), Breen, G. (Gerome), Forstner, A.J. (Andreas J), McQuillin, A. (Andrew), Ripke, S. (Stephan), Trubetskoy, V. (Vassily), Mattheisen, M. (Manuel), Wang, Y. (Yunpeng), Coleman, J.R.I. (Jonathan R I), Gaspar, H.A. (Héléna A), Leeuw, C. (Christiaan) de, Steinberg, S. (Stacy), Pavlides, J.M.W. (Jennifer M Whitehead), Trzaskowski, M. (Maciej), Pers, T.H. (Tune H), Holmans, P.A. (Peter A.), Abbott, L. (Liam), Agerbo, E. (Esben), Akil, H. (Huda), Albani, D. (Diego), Alliey-Rodriguez, N. (Ney), Als, T.D. (Thomas D), Anjorin, A. (Adebayo), Antilla, V. (Verneri), Awasthi, S. (Swapnil), Badner, J.A. (Judith A), Bækvad-Hansen, M. (Marie), Barchas, J.D. (Jack D), Bass, N. (Nicholas), Bauer, M. (Michael), Belliveau, R.A. (Richard A.), Bergen, S.E. (Sarah), Pedersen, C.B. (C.), Bøen, E. (Erlend), Boks, M.P.M. (Marco), Boocock, J. (James), Budde, M. (Monika), Bunney, W.E. (William E), Burmeister, M., Bybjerg-Grauholm, J. (Jonas), Byerley, W.F. (William F), Casas, M. (Miquel), Cerrato, F. (Felecia), Cervantes, P. (Pablo), Chambert, K. (Kimberly), Charney, A.W. (Alexander W), Chen, D. (Danfeng), Churchhouse, C. (Claire), Clarke, T.-K. (Toni-Kim), Coryell, W.H. (William H), Craig, D.W. (David W), Cruceanu, C. (Cristiana), Czerski, P.M., Dale, A.M. (Anders), de Jong, S. (Simone), Del-Favero, J. (Jurgen), DePaulo, J.R. (J Raymond), Djurovic, S. (Srdjan), Dobbyn, A.L. (Amanda L), Dumont, A. (Ashley), Elvsåshagen, T. (Torbjørn), Escott-Price, V. (Valentina), Fan, C.C. (Chun Chieh), Fischer, S.B. (Sascha B), Flickinger, M. (Matthew), Foroud, T.M. (Tatiana M), Forty, L. (Liz), Fraser, C. (Christine), Luben, R.N. (Robert), Frisén, L. (Louise), Gade, K. (Katrin), Gage, D. (Diane), Garnham, J. (Julie), Giambartolomei, C. (Claudia), Pedersen, M.G. (Marianne Giørtz), Goldstein, J.I. (Jacqueline), Gordon, S.D. (Scott D), Gordon-Smith, K. (Katherine), Green, E.K. (Elaine K), Green, M.J. (Melissa J), Greenwood, T.A. (Tiffany A), Grove, J. (Jakob), Guan, W. (Weihua), Parra, J.G. (José Guzman), Hamshere, M.L. (Marian), Hautzinger, M. (Martin), Heilbronner, U. (Urs), Hipolito, M. (Maria), Holland, D. (Dominic), Huckins, L. (Laura), Jamain, S. (Stéphane), Johnson, J.S. (Jessica S), Juréus, A. (Anders), Kandaswamy, R. (Radhika), Karlsson, R. (Robert), Kennedy, J.L. (James L), Kittel-Schneider, S. (Sarah), Knowles, J.A. (James A), Koller, A.C. (Anna C), Kupka, R.W. (Ralph ), Lavebratt, C. (Catharina), Lawrence, J. (Jacob), Lawson, W.B. (William B), Leber, I. (Isabelle), Lee, P.H. (Phil H), Levy, S.E. (Shawn E), Li, J.Z. (Jun Z), Liu, C. (Chunyu), Lucae, S. (Susanne), Maaser, A. (Anna), Macintyre, D.J. (Donald J), Mahon, P.B. (Pamela B), Maier, W. (Wolfgang), Martinsson, L. (Lina), McCarroll, S.A. (Steve), McGuffin, P. (Peter), Mcinnis, M.G. (Melvin G), McKay, J.D. (James D), Medeiros, H. (Helena), Medland, S.E. (Sarah E), Meng, F. (Fan), Milani, L. (Lili), Montgomery, G.W. (Grant W), Morris, D.W. (Derek W), Mühleisen, T.W. (Thomas W), Mullins, N. (Niamh), Nguyen, H. (Hoang), Nievergelt, C.M. (Caroline M), Adolfsson, A.N. (Annelie Nordin), Nwulia, E.A. (Evaristus A), O’Donovan, C. (Claire), Loohuis, L.M.O. (Loes M Olde), Ori, A.P.S. (Anil P S), Oruc, L. (Lilijana), Ösby, U. (Urban), Perlis, R.H. (Roy H), Perry, A. (Amy), Pfennig, A. (Andrea), Potash, J.B. (James B), Purcell, S.M. (Shaun M), Regeer, E.J. (Eline Janet), Reif, A. (Andreas), Reinbold, C.S. (Céline S), Rice, J.P. (John), Richards, A. (Alex), Rivas, F. (Fabio), Rivera, M. (Margarita), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Ryu, J. (Julie), Sánchez-Mora, C. (Cristina), Schatzberg, A.F. (Alan F), Scheftner, W.A. (William A), Schork, N.J. (Nicholas), Weickert, C.S. (Cynthia Shannon), Shehktman, T. (Tatyana), Shilling, P.D. (Paul D), Sigurdsson, E. (Engilbert), Slaney, C. (Claire), Smeland, O.B. (Olav B), Sobell, J.L. (Janet L), Hansen, C.S. (Christine Søholm), Spijker, A.T. (Anne T), Clair, D.S., Steffens, M. (Michael), Strauss, J.S. (John S), Szelinger, S. (Szabolcs), Thompson, R.C. (Robert C), EThorgeirsson, T. (Thorgeir), Vedde, H. (Helmut), Wang, W. (Weiqing), Watson, S.J. (Stanley J), Weickert, T.W. (Thomas W), Xi, S. (Simon), Xu, W. (Wei), Young, A.H. (Allan H), Zandi, P.P. (Peter P), Zhang, P. (Ping), Zöllner, S. (Sebastian), Adolfsson, R., Agartz, I. (Ingrid), Alda, M. (Martin), Backlund, L. (Lena), Baune, B.T. (Bernhard T), Bellivier, F. (Frank), Berrettini, W. (Wade), Biernacka, J.M. (Joanna M), Blackwood, D.H.R. (Douglas), Boehnke, M. (Michael), Børglum, A.D. (Anders D), Corvin, A. (Aiden), Craddock, N. (Nicholas), Daly, M.J. (Mark), Dannlowski, U. (Udo), Esko, T. (Tõnu), Etain, B. (Bruno), Frye, M.A. (Mark A), Fullerton, J.M. (Janice M), Gershon, E.S. (Elliot S), Gill, M. (Michael), Goes, F. (Fernando), Grigoroiu-Serbanescu, M. (Maria), Hauser, J. (J.), Hougaard, D.M. (David M), Hultman, C.M. (Christina), Jones, I. (Ian), Jones, L.A. (Lisa A), Kahn, R. (René), Kirov, G. (George), Landén, M. (Mikael), Leboyer, M. (Marion), Lewis, C.M. (Cathryn), Li, Q.S. (Qingqin S), Lissowska, J. (Jolanta), Martin, N.G. (Nicholas), Mayoral, F. (Fermin), McElroy, S.L. (Susan L), McIntosh, A.M. (Andrew), Mcmahon, F.J. (Francis J), Melle, I. (Ingrid), Metspalu, A. (Andres), Mitchell, P.B. (Philip B), Morken, G. (Gunnar), Mors, O. (Ole), Mortensen, P.B. (Preben Bo), Müller-Myhsok, B. (Bertram), Myers, R.H. (Richard), Neale, B.M. (Benjamin), Nimgaonkar, V. (Vishwajit), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O’Donovan, M.C. (Michael C), Oedegaard, K.J. (Ketil J), Owen, M.J. (Michael J), Paciga, S.A. (Sara A), Pato, C. (Carlos), Posthuma, D. (Danielle), Ramos-Quiroga, J.A. (Josep Antoni), Ribasés, M. (Marta), Rietschel, M. (Marcella), Rouleau, G.A. (Guy A), Schalling, M. (Martin), Schofield, P.R. (Peter R), Schulze, T.G. (Thomas G), Serretti, A. (Alessandro), Smoller, J.W., Stefansson, H. (Hreinn), Zwart, J-A. (John-Anker), Stordal, E. (Eystein), Sullivan, P.F. (Patrick F), Turecki, G. (Gustavo), Vaaler, A.E. (Arne E), Vieta, E. (Eduard), Vincent, J.B. (John B), Werge, T.M. (Thomas), Nurnberger, J.I. (John I), Wray, N.R. (Naomi), Florio, A.D. (Arianna Di), Edenberg, H.J. (Howard), Ophoff, R.A. (Roel), Scott, L.J. (Laura J), Andreassen, O.A. (Ole), Kelsoe, J.R. (John), Sklar, P. (Pamela), Wray, N.R. (Naomi R), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J), Air, T.M. (Tracy M), Bacanu, S.A. (Silviu), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B), Binder, E.B. (Elisabeth), Bryois, J. (Julien), Buttenschøn, H.N. (Henriette N), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Colodro-Conde, L. (Lucía), Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E), Davies, G. (Gail), Deary, I.J. (Ian J), Degenhardt, F., Derks, E.M. (Eske M), Direk, N. (Nese), Dolan, C.V. (Conor), Dunn, E.C. (Erin C.), Eley, T.C. (T.), Kiadeh, F.F.H. (Farnush Farhadi Hassan), Finucane, H.K. (Hilary K), Foo, J.C. (Jerome C), Goes, F.S. (Fernando S), Gordon, S.D. (Scott D.), Hall, L.S. (Lynsey S), Hansen, T.F. (Thomas F), Hickie, I.B. (Ian), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David), Howard, D.M. (David M), Ising, M. (Marcus), Jansen, R. (Rick), Jones, I., Jones, L. (Louisa), Jorgenson, E. (Eric), Kohane, I.S. (Isaac S), Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Kutalik, Z. (Zoltán), Li, Y. (Yihan), Lind, P.A. (Penelope), MacIntyre, D.J. (Donald J), MacKinnon, D.F. (Dean F), Maier, R.M. (Robert M), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), Mcguffin, P. (Peter), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel M), Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Mondimore, F.M. (Francis M), Montgomery, G.W. (Grant), Mostafavi, S. (Sara), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O’Reilly, P.F. (Paul F), Oskarsson, H. (Hogni), Owen, M.J. (Michael), Painter, J.N. (Jodie N.), Pedersen, C.B. (Carsten Bøcker), Peterson, R.E. (Roseann E), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Quiroz, J.A. (Jorge A), Qvist, P. (Per), Rice, J.P. (John P), Riley, B.P. (Brien P.), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C), Shen, L. (Li), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Sinnamon, G.C.B. (Grant C B), Smith, A.V. (Davey), Smith, D.J. (Daniel J), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A), Thorgeirsson, T.E. (Thorgeir E), Traylor, M. (Matthew), Uitterlinden, A.G. (André), Umbricht, D. (Daniel), Van der Auwera, S. (Sandra), van Hemert, A.M. (Albert M), Viktorin, A. (Alexander), Visscher, P.M. (Peter M), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Wu, Y. (Yang), Xi, H.S. (Hualin S), Yang, J. (Joanna), Zhang, F. (Futao), Arolt, V. (Volker), Baune, B.T., Berger, K. (Klaus), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Domenici, E. (Enrico), Domschke, K. (Katharina), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Lewis, G., Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Martin, N.G. (Nicholas G), McIntosh, A.M. (Andrew M), Mors, O., Müller-Myhsok, B. (B.), Nöthen, M.M. (Markus M), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Porteous, D.J. (David J.), Preisig, M. (Martin), Schaefer, C. (Catherine), Smoller, J.W. (Jordan W), Stefansson, K. (Kari), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Völzke, H. (Henry), Weissman, M.M., Werge, T. (Thomas), Lewis, C.M. (Cathryn M), Levinson, D.F. (Douglas F.), Borglum, A.D. (Anders), Sullivan, P.F. (Patrick), Mayoral, F. (Fermín), Muller-Myhsok, B. (B.), Forstner, A.J. (Andreas J.), Nöthen, M.M. (Markus M.), Andlauer, T.F.M. (Till F. M.), Guzman-Parra, J. (Jose), Streit, F. (Fabian), Strohmaier, J. (Jana), González, M.J. (Maria José), Gil Flores, S. (Susana), Cabaleiro Fabeiro, F.J. (Francisco J.), del Río Noriega, F. (Francisco), Perez, F.P. (Fermin Perez), Haro González, J. (Jesus), Orozco Diaz, G. (Guillermo), Diego, Y. (Yolanda) de, Moreno-Küstner, B. (Berta), Auburger, G. (Georg), Degenhardt, F. (Franziska), Heilmann-Heimbach, S. (Stefanie), Herms, S. (Stefan), Hoffmann, P. (Per), Frank, J. (Josef), Foo, J.C. (Jerome C.), Treutlein, J. (Jens), Witt, S.H. (Stephanie H), Cichon, S. (Sven), Kogevinas, M. (Manolis), Stahl, E.A. (Eli A), Breen, G. (Gerome), Forstner, A.J. (Andreas J), McQuillin, A. (Andrew), Ripke, S. (Stephan), Trubetskoy, V. (Vassily), Mattheisen, M. (Manuel), Wang, Y. (Yunpeng), Coleman, J.R.I. (Jonathan R I), Gaspar, H.A. (Héléna A), Leeuw, C. (Christiaan) de, Steinberg, S. (Stacy), Pavlides, J.M.W. (Jennifer M Whitehead), Trzaskowski, M. (Maciej), Pers, T.H. (Tune H), Holmans, P.A. (Peter A.), Abbott, L. (Liam), Agerbo, E. (Esben), Akil, H. (Huda), Albani, D. (Diego), Alliey-Rodriguez, N. (Ney), Als, T.D. (Thomas D), Anjorin, A. (Adebayo), Antilla, V. (Verneri), Awasthi, S. (Swapnil), Badner, J.A. (Judith A), Bækvad-Hansen, M. (Marie), Barchas, J.D. (Jack D), Bass, N. (Nicholas), Bauer, M. (Michael), Belliveau, R.A. (Richard A.), Bergen, S.E. (Sarah), Pedersen, C.B. (C.), Bøen, E. (Erlend), Boks, M.P.M. (Marco), Boocock, J. (James), Budde, M. (Monika), Bunney, W.E. (William E), Burmeister, M., Bybjerg-Grauholm, J. (Jonas), Byerley, W.F. (William F), Casas, M. (Miquel), Cerrato, F. (Felecia), Cervantes, P. (Pablo), Chambert, K. (Kimberly), Charney, A.W. (Alexander W), Chen, D. (Danfeng), Churchhouse, C. (Claire), Clarke, T.-K. (Toni-Kim), Coryell, W.H. (William H), Craig, D.W. (David W), Cruceanu, C. (Cristiana), Czerski, P.M., Dale, A.M. (Anders), de Jong, S. (Simone), Del-Favero, J. (Jurgen), DePaulo, J.R. (J Raymond), Djurovic, S. (Srdjan), Dobbyn, A.L. (Amanda L), Dumont, A. (Ashley), Elvsåshagen, T. (Torbjørn), Escott-Price, V. (Valentina), Fan, C.C. (Chun Chieh), Fischer, S.B. (Sascha B), Flickinger, M. (Matthew), Foroud, T.M. (Tatiana M), Forty, L. (Liz), Fraser, C. (Christine), Luben, R.N. (Robert), Frisén, L. (Louise), Gade, K. (Katrin), Gage, D. (Diane), Garnham, J. (Julie), Giambartolomei, C. (Claudia), Pedersen, M.G. (Marianne Giørtz), Goldstein, J.I. (Jacqueline), Gordon, S.D. (Scott D), Gordon-Smith, K. (Katherine), Green, E.K. (Elaine K), Green, M.J. (Melissa J), Greenwood, T.A. (Tiffany A), Grove, J. (Jakob), Guan, W. (Weihua), Parra, J.G. (José Guzman), Hamshere, M.L. (Marian), Hautzinger, M. (Martin), Heilbronner, U. (Urs), Hipolito, M. (Maria), Holland, D. (Dominic), Huckins, L. (Laura), Jamain, S. (Stéphane), Johnson, J.S. (Jessica S), Juréus, A. (Anders), Kandaswamy, R. (Radhika), Karlsson, R. (Robert), Kennedy, J.L. (James L), Kittel-Schneider, S. (Sarah), Knowles, J.A. (James A), Koller, A.C. (Anna C), Kupka, R.W. (Ralph ), Lavebratt, C. (Catharina), Lawrence, J. (Jacob), Lawson, W.B. (William B), Leber, I. (Isabelle), Lee, P.H. (Phil H), Levy, S.E. (Shawn E), Li, J.Z. (Jun Z), Liu, C. (Chunyu), Lucae, S. (Susanne), Maaser, A. (Anna), Macintyre, D.J. (Donald J), Mahon, P.B. (Pamela B), Maier, W. (Wolfgang), Martinsson, L. (Lina), McCarroll, S.A. (Steve), McGuffin, P. (Peter), Mcinnis, M.G. (Melvin G), McKay, J.D. (James D), Medeiros, H. (Helena), Medland, S.E. (Sarah E), Meng, F. (Fan), Milani, L. (Lili), Montgomery, G.W. (Grant W), Morris, D.W. (Derek W), Mühleisen, T.W. (Thomas W), Mullins, N. (Niamh), Nguyen, H. (Hoang), Nievergelt, C.M. (Caroline M), Adolfsson, A.N. (Annelie Nordin), Nwulia, E.A. (Evaristus A), O’Donovan, C. (Claire), Loohuis, L.M.O. (Loes M Olde), Ori, A.P.S. (Anil P S), Oruc, L. (Lilijana), Ösby, U. (Urban), Perlis, R.H. (Roy H), Perry, A. (Amy), Pfennig, A. (Andrea), Potash, J.B. (James B), Purcell, S.M. (Shaun M), Regeer, E.J. (Eline Janet), Reif, A. (Andreas), Reinbold, C.S. (Céline S), Rice, J.P. (John), Richards, A. (Alex), Rivas, F. (Fabio), Rivera, M. (Margarita), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Ryu, J. (Julie), Sánchez-Mora, C. (Cristina), Schatzberg, A.F. (Alan F), Scheftner, W.A. (William A), Schork, N.J. (Nicholas), Weickert, C.S. (Cynthia Shannon), Shehktman, T. (Tatyana), Shilling, P.D. (Paul D), Sigurdsson, E. (Engilbert), Slaney, C. (Claire), Smeland, O.B. (Olav B), Sobell, J.L. (Janet L), Hansen, C.S. (Christine Søholm), Spijker, A.T. (Anne T), Clair, D.S., Steffens, M. (Michael), Strauss, J.S. (John S), Szelinger, S. (Szabolcs), Thompson, R.C. (Robert C), EThorgeirsson, T. (Thorgeir), Vedde, H. (Helmut), Wang, W. (Weiqing), Watson, S.J. (Stanley J), Weickert, T.W. (Thomas W), Xi, S. (Simon), Xu, W. (Wei), Young, A.H. (Allan H), Zandi, P.P. (Peter P), Zhang, P. (Ping), Zöllner, S. (Sebastian), Adolfsson, R., Agartz, I. (Ingrid), Alda, M. (Martin), Backlund, L. (Lena), Baune, B.T. (Bernhard T), Bellivier, F. (Frank), Berrettini, W. (Wade), Biernacka, J.M. (Joanna M), Blackwood, D.H.R. (Douglas), Boehnke, M. (Michael), Børglum, A.D. (Anders D), Corvin, A. (Aiden), Craddock, N. (Nicholas), Daly, M.J. (Mark), Dannlowski, U. (Udo), Esko, T. (Tõnu), Etain, B. (Bruno), Frye, M.A. (Mark A), Fullerton, J.M. (Janice M), Gershon, E.S. (Elliot S), Gill, M. (Michael), Goes, F. (Fernando), Grigoroiu-Serbanescu, M. (Maria), Hauser, J. (J.), Hougaard, D.M. (David M), Hultman, C.M. (Christina), Jones, I. (Ian), Jones, L.A. (Lisa A), Kahn, R. (René), Kirov, G. (George), Landén, M. (Mikael), Leboyer, M. (Marion), Lewis, C.M. (Cathryn), Li, Q.S. (Qingqin S), Lissowska, J. (Jolanta), Martin, N.G. (Nicholas), Mayoral, F. (Fermin), McElroy, S.L. (Susan L), McIntosh, A.M. (Andrew), Mcmahon, F.J. (Francis J), Melle, I. (Ingrid), Metspalu, A. (Andres), Mitchell, P.B. (Philip B), Morken, G. (Gunnar), Mors, O. (Ole), Mortensen, P.B. (Preben Bo), Müller-Myhsok, B. (Bertram), Myers, R.H. (Richard), Neale, B.M. (Benjamin), Nimgaonkar, V. (Vishwajit), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O’Donovan, M.C. (Michael C), Oedegaard, K.J. (Ketil J), Owen, M.J. (Michael J), Paciga, S.A. (Sara A), Pato, C. (Carlos), Posthuma, D. (Danielle), Ramos-Quiroga, J.A. (Josep Antoni), Ribasés, M. (Marta), Rietschel, M. (Marcella), Rouleau, G.A. (Guy A), Schalling, M. (Martin), Schofield, P.R. (Peter R), Schulze, T.G. (Thomas G), Serretti, A. (Alessandro), Smoller, J.W., Stefansson, H. (Hreinn), Zwart, J-A. (John-Anker), Stordal, E. (Eystein), Sullivan, P.F. (Patrick F), Turecki, G. (Gustavo), Vaaler, A.E. (Arne E), Vieta, E. (Eduard), Vincent, J.B. (John B), Werge, T.M. (Thomas), Nurnberger, J.I. (John I), Wray, N.R. (Naomi), Florio, A.D. (Arianna Di), Edenberg, H.J. (Howard), Ophoff, R.A. (Roel), Scott, L.J. (Laura J), Andreassen, O.A. (Ole), Kelsoe, J.R. (John), Sklar, P. (Pamela), Wray, N.R. (Naomi R), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J), Air, T.M. (Tracy M), Bacanu, S.A. (Silviu), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B), Binder, E.B. (Elisabeth), Bryois, J. (Julien), Buttenschøn, H.N. (Henriette N), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Colodro-Conde, L. (Lucía), Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E), Davies, G. (Gail), Deary, I.J. (Ian J), Degenhardt, F., Derks, E.M. (Eske M), Direk, N. (Nese), Dolan, C.V. (Conor), Dunn, E.C. (Erin C.), Eley, T.C. (T.), Kiadeh, F.F.H. (Farnush Farhadi Hassan), Finucane, H.K. (Hilary K), Foo, J.C. (Jerome C), Goes, F.S. (Fernando S), Gordon, S.D. (Scott D.), Hall, L.S. (Lynsey S), Hansen, T.F. (Thomas F), Hickie, I.B. (Ian), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David), Howard, D.M. (David M), Ising, M. (Marcus), Jansen, R. (Rick), Jones, I., Jones, L. (Louisa), Jorgenson, E. (Eric), Kohane, I.S. (Isaac S), Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Kutalik, Z. (Zoltán), Li, Y. (Yihan), Lind, P.A. (Penelope), MacIntyre, D.J. (Donald J), MacKinnon, D.F. (Dean F), Maier, R.M. (Robert M), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), Mcguffin, P. (Peter), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel M), Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Mondimore, F.M. (Francis M), Montgomery, G.W. (Grant), Mostafavi, S. (Sara), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O’Reilly, P.F. (Paul F), Oskarsson, H. (Hogni), Owen, M.J. (Michael), Painter, J.N. (Jodie N.), Pedersen, C.B. (Carsten Bøcker), Peterson, R.E. (Roseann E), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Quiroz, J.A. (Jorge A), Qvist, P. (Per), Rice, J.P. (John P), Riley, B.P. (Brien P.), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C), Shen, L. (Li), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Sinnamon, G.C.B. (Grant C B), Smith, A.V. (Davey), Smith, D.J. (Daniel J), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A), Thorgeirsson, T.E. (Thorgeir E), Traylor, M. (Matthew), Uitterlinden, A.G. (André), Umbricht, D. (Daniel), Van der Auwera, S. (Sandra), van Hemert, A.M. (Albert M), Viktorin, A. (Alexander), Visscher, P.M. (Peter M), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Wu, Y. (Yang), Xi, H.S. (Hualin S), Yang, J. (Joanna), Zhang, F. (Futao), Arolt, V. (Volker), Baune, B.T., Berger, K. (Klaus), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Domenici, E. (Enrico), Domschke, K. (Katharina), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Lewis, G., Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Martin, N.G. (Nicholas G), McIntosh, A.M. (Andrew M), Mors, O., Müller-Myhsok, B. (B.), Nöthen, M.M. (Markus M), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Porteous, D.J. (David J.), Preisig, M. (Martin), Schaefer, C. (Catherine), Smoller, J.W. (Jordan W), Stefansson, K. (Kari), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Völzke, H. (Henry), Weissman, M.M., Werge, T. (Thomas), Lewis, C.M. (Cathryn M), Levinson, D.F. (Douglas F.), Borglum, A.D. (Anders), Sullivan, P.F. (Patrick), Mayoral, F. (Fermín), Muller-Myhsok, B. (B.), Forstner, A.J. (Andreas J.), and Nöthen, M.M. (Markus M.)
- Abstract
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.
- Published
- 2019
- Full Text
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6. Improving genetic prediction by leveraging genetic correlations among human diseases and traits
- Author
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Maier, R. M., Zhu, Z., Lee, S. H., Trzaskowski, M., Ruderfer, D. M., Stahl, E. A., Ripke, S., Wray, N. R., Yang, J., Visscher, P. M., Robinson, M. R., Forstner, A. J., Mcquillin, A., Trubetskoy, V., Wang, W., Wang, Y., Coleman, J. R. I., Gaspar, H. A., Leeuw, C. A., Whitehead Pavlides, J. M., Olde Loohuis, L. M., Pers, T. H., Lee, P. H., Charney, A. W., Dobbyn, A. L., Huckins, L., Boocock, J., Giambartolomei, C., Roussos, P., Mullins, N., Awasthi, S., Agerbo, E., Als, T. D., Pedersen, C. B., Grove, J., Kupka, R., Regeer, E. J., Anjorin, A., Casas, M., Mahon, P. B., Allardyce, J., Escott-Price, V., Forty, L., Fraser, C., Kogevinas, M., Frank, J., Streit, F., Strohmaier, J., Treutlein, J., Witt, S. H., Kennedy, J. L., Strauss, J. S., Garnham, J., O Donovan, C., Slaney, C., Steinberg, S., Thorgeirsson, T. E., Hautzinger, M., Steffens, M., Perlis, R. H., Sánchez-Mora, C., Hipolito, M., Lawson, W. B., Nwulia, E. A., Levy, S. E., Foroud, T. M., Jamain, S., Young, A. H., Mckay, J. D., Albani, D., Zandi, P., Potash, J. B., Zhang, P., Raymond Depaulo, J., Bergen, S. E., Juréus, A., Karlsson, R., Kandaswamy, R., Mcguffin, P., Rivera, M., Lissowska, J., Cruceanu, C., Lucae, S., Cervantes, P., Budde, M., Gade, K., Heilbronner, U., Pedersen, M. G., Morris, D. W., Weickert, C. S., Weickert, T. W., Macintyre, D. J., Lawrence, J., Elvsåshagen, T., Smeland, O. B., Djurovic, S., Xi, S., Green, E. K., Czerski, P. M., Hauser, J., Xu, W., Vedder, H., Oruc, L., Spijker, A. T., Gordon, S. D., Medland, S. E., Curtis, D., Mühleisen, T. W., Badner, J. A., Scheftner, W. A., Sigurdsson, E., Schork, N. J., Schatzberg, A. F., Bækvad-Hansen, M., Bybjerg-Grauholm, J., Hansen, C. S., Knowles, J. A., Szelinger, S., Montgomery, G. W., Boks, M., Adolfsson, A. N., Hoffmann, P., Bauer, M., Pfennig, A., Leber, M., Kittel-Schneider, S., Reif, A., Del-Favero, J., Fischer, S. B., Herms, S., Reinbold, C. S., Degenhardt, F., Koller, A. C., Maaser, A., Ori, A. P. S., Dale, A. M., Fan, C. C., Greenwood, T. A., Nievergelt, C. M., Shehktman, T., Shilling, P. D., Byerley, W., Bunney, W., Alliey-Rodriguez, N., Clarke, T. K., Liu, C., Coryell, W., Akil, H., Burmeister, M., Flickinger, M., Li, J. Z., Mcinnis, M. G., Meng, F., Thompson, R. C., Watson, S. J., Zollner, S., Guan, W., Green, M. J., Craig, D., Sobell, J. L., Milani, L., Gordon-Smith, Katherine, Knott, Sarah, Perry, Amy, Parra, J. G., Mayoral, F., Rivas, F., Rice, J. P., Barchas, J. D., Børglum, A. D., Mortensen, P. B., Mors, O., Grigoroiu-Serbanescu, M., Bellivier, F., Etain, B., Leboyer, M., Ramos-Quiroga, J. A., Agartz, I., Amin, F., Azevedo, M. H., Bass, N., Black, D. W., Blackwood, D. H. R., Bruggeman, R., Buccola, N. G., Choudhury, K., Cloninger, C. R., Corvin, A., Craddock, N., Daly, M. J., Datta, S., Donohoe, G. J., Duan, J., Dudbridge, F., Fanous, A., Freedman, R., Freimer, N. B., Friedl, M., Gill, M., Gurling, H., Haan, L., Hamshere, M. L., Hartmann, A. M., Holmans, P. A., Kahn, R. S., Keller, M. C., Kenny, E., Kirov, G. K., Krabbendam, L., Krasucki, R., Lencz, T., Levinson, D. F., Lieberman, J. A., Lin, D. -Y, Linszen, D. H., Magnusson, P. K. E., Maier, W., Malhotra, A. K., Mattheisen, M., Mattingsdal, M., Mccarroll, S. A., Medeiros, H., Melle, I., Milanova, V., Myin-Germeys, I., Neale, B. M., Ophoff, R. A., Owen, M. J., Pimm, J., Purcell, S. M., Puri, V., Digby Quested, Rossin, L., Sanders, A. R., Shi, J., Sklar, P., St Clair, D., Stroup, T. S., Os, J., Wiersma, D., Zammit, S., Maier, Robert M, Zhu, Zhihong, Lee, Sang Hong, Trzaskowski, Maciej, Ruderfer, Douglas M, Stahl, Eli A, Ripke, Stephan, Wray, Naomi R, Yang, Jian, Visscher, Peter M, Robinson, Matthew R, Bipolar Disorder Working Grp Psy, Schizophrenia Working Grp Psychiat, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, and Psychiatry
- Subjects
0301 basic medicine ,Bipolar Disorder ,Chemistry(all) ,Science ,General Physics and Astronomy ,Genomics ,Genome-wide association study ,Computational biology ,Biology ,Physics and Astronomy(all) ,Risk Assessment ,Biochemistry ,General Biochemistry, Genetics and Molecular Biology ,Article ,predictive medicine ,quantitative trait ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Pleiotropy ,Genetic Pleiotropy ,Humans ,Genetic Predisposition to Disease ,lcsh:Science ,Multidisciplinary ,Models, Statistical ,Bipolar Disorder/genetics ,Genome-Wide Association Study ,Schizophrenia/genetics ,Biochemistry, Genetics and Molecular Biology(all) ,General Chemistry ,Precision medicine ,R1 ,Biobank ,3. Good health ,genome wide association studies ,030104 developmental biology ,Trait ,Schizophrenia ,statistical methods ,lcsh:Q ,Risk assessment ,030217 neurology & neurosurgery ,Genetics and Molecular Biology(all) - Abstract
Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait., Genetic prediction of complex traits so far has limited accuracy because of insufficient understanding of the genetic risk. Here, Maier et al. develop an improved method for trait prediction that makes use of genetic correlations between traits and apply it to summary statistics of psychiatric diseases.
- Published
- 2018
7. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- Author
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de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, Shi, J, de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, and Shi, J
- Abstract
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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- 2018
8. A de novo splice site mutation inCASKcauses FG syndrome-4 and congenital nystagmus
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Dunn, P., primary, Prigatano, G. P., additional, Szelinger, S., additional, Roth, J., additional, Siniard, A. L., additional, Claasen, A. M., additional, Richholt, R. F., additional, De Both, M., additional, Corneveaux, J. J., additional, Moskowitz, A. M., additional, Balak, C., additional, Piras, I. S., additional, Russell, M., additional, Courtright, A. L., additional, Belnap, N., additional, Rangasamy, S., additional, Ramsey, K., additional, Opitz, J. M., additional, Craig, D. W., additional, Narayanan, V., additional, Huentelman, M. J., additional, and Schrauwen, I., additional
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- 2017
- Full Text
- View/download PDF
9. Rare variants in neuronal excitability genes influence risk for bipolar disorder
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Ament, SA, Szelinger, S, Glusman, G, Ashworth, J, Hou, L, Akula, N, Shekhtman, T, Badner, JA, Brunkow, ME, Mauldin, DE, Stittrich, AB, Rouleau, K, Detera-Wadleigh, SD, Nurnberger, JI, Edenberg, HJ, Gershon, ES, Schork, N, Price, ND, Gelinas, R, Hood, L, Craig, D, McMahon, FJ, Kelsoe, JR, Roach, JC, Ament, SA, Szelinger, S, Glusman, G, Ashworth, J, Hou, L, Akula, N, Shekhtman, T, Badner, JA, Brunkow, ME, Mauldin, DE, Stittrich, AB, Rouleau, K, Detera-Wadleigh, SD, Nurnberger, JI, Edenberg, HJ, Gershon, ES, Schork, N, Price, ND, Gelinas, R, Hood, L, Craig, D, McMahon, FJ, Kelsoe, JR, and Roach, JC
- Abstract
We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.
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- 2015
10. All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs
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Aj, Schork, Wk, Thompson, Pham P, Torkamani A, Jc, Roddey, Pf, Sullivan, Jr, Kelsoe, Donovan Mc, O., Furberg H, Tobacco and Genetics Consortium, Bipolar Disorder Psychiatric Genomics Consortium, Schizophrenia Psychiatric Genomics Consortium, Nj, Schork, Oa, Andreassen, Am, Dale, Absher D, Agudo A, Almgren P, Ardissino D, Tl, Assimes, Bandinelli S, Barzan L, Bencko V, Benhamou S, Ej, Benjamin, Bernardinelli L, Bis J, Boehnke M, Boerwinkle E, Di, Boomsma, Brennan P, Canova C, Castellsagué X, Chanock S, Chasman D, Di, Conway, Dackor J, Ej, Geus, Duan J, Elosua R, Everett B, Fabianova E, Ferrucci L, Foretova L, Sp, Fortmann, Franceschini N, Frayling T, Furberg C, Pv, Gejman, Groop L, Gu F, Guralnik J, Se, Hankinson, Haritunians T, Healy C, Hofman A, Holcátová I, Dj, Hunter, Sj, Hwang, Jp, Ioannidis, Iribarren C, Au, Jackson, Janout V, Kaprio J, Kim Y, Kjaerheim K, Jw, Knowles, Kraft P, Ladenvall C, Lagiou P, Lanthrop M, Lerman C, Df, Levinson, Levy D, Md, Li, Dy, Lin, Eh, Lips, Lissowska J, Lowry R, Lucas G, Tv, Macfarlane, Maes H, Pm, Mannucci, Mates D, Mauri F, Ja, Mcgovern, Jd, Mckay, McKnight B, Melander O, Pa, Merlini, Milaneschi Y, Kl, Mohlke, Donnell Cj, O., Pare G, Bw, Penninx, Perry J, Posthuma D, Sr, Preis, Psaty B, Quertermous T, Vs, Ramachandran, Richiardi L, Ridker P, Rose J, Rudnai P, Salomaa V, Ar, Sanders, Sm, Schwartz, Shi J, Jh, Smit, Hm, Stringham, Szeszenia-Dabrowska N, Tanaka T, Taylor K, Thacker E, Thornton L, Tiemeier H, Tuomilehto J, Ag, Uitterlinden, Cm, Duijn, Jm, Vink, Vogelzangs N, Bf, Voight, Walter S, Willemsen G, Zaridze D, Znaor A, Akil H, Anjorin A, Backlund L, Ja, Badner, Jd, Barchas, Tb, Barrett, Bass N, Bauer M, Bellivier F, Se, Bergen, Berrettini W, Blackwood D, Cs, Bloss, Breen G, Breuer R, We, Bunner, Burmeister M, Byerley W, Caesar S, Chambert K, Cichon S, St Clair D, Da, Collier, Corvin A, Wh, Coryell, Craddock N, Dw, Craig, Daly M, Day R, Degenhardt F, Djurovic S, Dudbridge F, Hj, Edenberg, Elkin A, Etain B, Ae, Farmer, Ma, Ferreira, Ferrier I, Flickinger M, Foroud T, Frank J, Fraser C, Frisén L, Es, Gershon, Gill M, Gordon-Smith K, Ek, Green, Ta, Greenwood, Grozeva D, Guan W, Gurling H, Ó, Gustafsson, Ml, Hamshere, Hautzinger M, Herms S, Hipolito M, Pa, Holmans, Cm, Hultman, Jamain S, Eg, Jones, Jones I, Jones L, Kandaswamy R, Jl, Kennedy, Gk, Kirov, Dl, Koller, Kwan P, Landén M, Langstrom N, Lathrop M, Lawrence J, Wb, Lawson, Leboyer M, Ph, Lee, Li J, Lichtenstein P, Lin D, Liu C, Fw, Lohoff, Lucae S, Pb, Mahon, Maier W, Ng, Martin, Mattheisen M, Matthews K, Mattingsdal M, Ka, Mcghee, McGuffin P, Mg, Mcinnis, McIntosh A, McKinney R, Aw, Mclean, Fj, Mcmahon, McQuillin A, Meier S, Melle I, Meng F, Pb, Mitchell, Gw, Montgomery, Moran J, Morken G, Dw, Morris, Moskvina V, Muglia P, Tw, Mühleisen, Wj, Muir, Müller-Myhsok B, Rm, Myers, Cm, Nievergelt, Nikolov I, Nimgaonkar V, Mm, Nöthen, Ji, Nurnberger, Ea, Nwulia, O'Dushlaine C, Osby U, Óskarsson H, Mj, Owen, Petursson H, Bs, Pickard, Porgeirsson P, Jb, Potash, Propping P, Sm, Purcell, Quinn E, Raychaudhuri S, Rice J, Rietschel M, Ruderfer D, Schalling M, Af, Schatzberg, Wa, Scheftner, Pr, Schofield, Tg, Schulze, Schumacher J, Mm, Schwarz, Scolnick E, Lj, Scott, Pd, Shilling, Sigurdsson E, Sklar P, En, Smith, Stefansson H, Stefansson K, Steffens M, Steinberg S, Strauss J, Strohmaier J, Szelinger S, Rc, Thompson, Tozzi F, Treutlein J, Jb, Vincent, Sj, Watson, Tf, Wienker, Williamson R, Sh, Witt, Wright A, Xu W, Ah, Young, Pp, Zandi, Zhang P, Zöllner S, Agartz I, Albus M, Alexander M, Rl, Amdur, Amin F, Bitter I, Dw, Black, Ad, Børglum, Ma, Brown, Bruggeman R, Ng, Buccola, Wf, Byerley, Cahn W, Rm, Cantor, Vj, Carr, Sv, Catts, Choudhury K, Cloninger C, Cormican P, Pa, Danoy, Datta S, DeHert M, Demontis D, Dikeos D, Donnelly P, Donohoe G, Duong L, Dwyer S, Fanous A, Fink-Jensen A, Freedman R, Nb, Freimer, Friedl M, Georgieva L, Giegling I, Glenthøj B, Godard S, Golimbet V, de Haan L, Hansen M, Hansen T, Am, Hartmann, Fa, Henskens, Dm, Hougaard, Ingason A, Av, Jablensky, Kd, Jakobsen, Jay M, Eg, Jönsson, Jürgens G, Rs, Kahn, Mc, Keller, Ks, Kendler, Kenis G, Kenny E, Konnerth H, Konte B, Krabbendam L, Krasucki R, Vk, Lasseter, Laurent C, Lencz T, Lerer F, Ky, Liang, Ja, Lieberman, Dh, Linszen, Lönnqvist J, Cm, Loughland, Aw, Maclean, Bs, Maher, Ak, Malhotra, Mallet J, Malloy P, Jj, Mcgrath, McLean DE, Pt, Michie, Milanova V, Mors O, Pb, Mortensen, Bj, Mowry, Myin-Germeys I, Neale B, Da, Nertney, Nestadt G, Nielsen J, Nordentoft M, Norton N, O'Neill F, Olincy A, Olsen L, Ra, Ophoff, Tf, Ørntoft, van Os J, Pantelis C, Papadimitriou G, Cn, Pato, Mt, Pato, Peltonen L, Pickard B, Op, Pietiläinen, Pimm J, Ae, Pulver, Puri V, Digby Quested, Hb, Rasmussen, Jm, Réthelyi, Ribble R, Bp, Riley, Rossin L, Ruggeri M, Rujescu D, Schall U, Sg, Schwab, Rj, Scott, Jm, Silverman, Cc, Spencer, Strange A, Strengman E, Stroup T, Suvisaari J, Terenius L, Thirumalai S, Timm S, Toncheva D, Tosato S, Ej, Den Oord, Veldink J, Pm, Visscher, Walsh D, Ag, Wang, Werge T, Wiersma D, Db, Wildenauer, Hj, Williams, Nm, Williams, van Winkel R, Wormley B., Biological Psychology, Functional Genomics, Educational Neuroscience, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, ANS - Amsterdam Neuroscience, Adult Psychiatry, Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Gibson, Greg, Germeys, Inez, van Winkel, Ruud, and De Hert, Marc
- Subjects
False discovery rate ,Netherlands Twin Register (NTR) ,Cancer Research ,Linkage disequilibrium ,Genome-wide association study ,Linkage Disequilibrium ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Aetiology ,Genetics (clinical) ,Genetics ,0303 health sciences ,Statistics ,Genomics ,Single Nucleotide ,Genome Scans ,Tobacco and Genetics Consortium ,Functional Genomics ,Phenotype ,complex trait ,Research Article ,Bipolar Disorder Psychiatric Genomics Consortium ,lcsh:QH426-470 ,SNP ,Single-nucleotide polymorphism ,Computational biology ,Biostatistics ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,"genome-wide association study" ,Genome Analysis Tools ,Clinical Research ,Schizophrenia Psychiatric Genomics Consortium ,Genome-Wide Association Studies ,Humans ,Genetic Predisposition to Disease ,Statistical Methods ,Polymorphism ,Molecular Biology ,Genetic Association Studies ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Genetic association ,Linkage (software) ,Human Genome ,Computational Biology ,Human Genetics ,Heritability ,R1 ,schizophrenia ,lcsh:Genetics ,Schizophrenia ,Mathematics ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Developmental Biology - Abstract
Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci., Author Summary Modern genome-wide association studies (GWAS) have failed to identify large portions of the genetic basis of common, complex traits. Recent work suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS. Moreover, these variants appear more abundantly in and near genes. Using genome annotations, summary statistics from several of the largest GWAS, and established statistical methods for quantifying distributions of test statistics, we show a consistency across studies. Namely, we show that, across all assessed traits, the test statistics resulting from SNPs that are related to the 5′ UTR of genes show the largest abundance of associations, while SNPs related to exons and the 3′UTR are also enriched. SNPs related to introns are only moderately enriched, and intergenic SNPs show a depletion of associations relative to the average SNP. This enrichment corresponds directly to increased replication across independent samples and can be incorporated a priori into statistical methods to improve discovery and prediction. Our results contribute to on-going debates about the functional nature of the genetic architecture of complex traits and point to avenues for leveraging existing GWAS data for discovery in future GWA and sequencing studies.
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- 2013
11. Identification of risk loci with shared effects on five major psychiatric disorders:a genome-wide analysis
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Smoller, J.W., Ripke, S., Lee, P.H., Neale, B., Nurnberger, J.I., Santangelo, S., Sullivan, P.F., Perlis, R.H., Purcell, S.M., Fanous, A., Neale, M.C., Rietschel, M., Schulze, T.G., Thapar, A., Anney, R., Buitelaar, J.K., Farone, S.V., Hoogendijk, W.J.G., Levinson, D.F., Lesch, K.P., Riley, B., Schachar, R., Sonuga-Barke, E.J., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen, O.A., Anjorin, A., Arking, D., Asherson, P., Azevedo, M.H., Backlund, L., Badner, J.A., Banaschewski, T., Barchas, J.D., Barnes, M.R., Bass, N., Bauer, M.C.R., Bellivier, F., Bergen, S.E., Berrettini, W., Bettecken, T., Biederman, J, Binder, E.B., Black, D.W., Blackwood, D.H., Bloss, C.S., Boehnke, M., Boomsma, D.I., Breen, G., Breuer, R., Buccola, N.G., Bunner, W.E., Burmeister, M., Buxbaum, J.D., Byerley, W. F., Sian, C., Cantor, R.M., Chakravarti, A., Chambert, K., Chicon, S., Cloniger, C.R., Collier, D.A., Cook, E., Coon, H., Corvin, A., Coryell, W.H., Craig, D.W., Craig, I.W., Curtis, D., Czamara, D., Daly, M., Datta, S., Day, R., de Geus, E.J.C., Degenhardt, F., Devlin, B., Srdjan, D., Doyle, A.E., Duan, J., Dudbridge, F., Edenberg, H.J., Elkin, A., Etain, B., Farmer, A.E., Ferreira, M.A.R., Ferrier, I.N., Flickinger, M., Foroud, T., Frank, J., Franke, B., Fraser, C., Freedman, R., Freimer, N.B., Friedl, M., Frisén, L., Gejman, P.V., Georgieva, L., Gershon, E.S., Giegling, I., Gill, M., Gordon, S.D., Gordon-Smith, K., Green, E.K., Greenwood, T.A., Gross, M., Grozeva, D., Guan, W., Gurling, H., Gustafsson, O., Hakonarson, H., Hamilton, S.P., Hamshere, M.L., Hansen, T.F., Hartmann, A.M., Hautzinger, M., Heath, A.C., Henders, A.K., Herms, S., Hickie, I.B., Hipolito, M., Hoefels, S., Holmans, P.A., Holsboer, F., Hottenga, J.J., Hultman, C. M., Ingason, A., Ising, M., Jamain, S., Jones, E.G., Jones, L., Jones, I., Jung-Ying, T., Kahler, A., Kandaswamy, R., Keller, M.C., Kelsoe, J., Kennedy, J.L., Kenny, E., Kim, Y., Kirov, G. K., Knowles, J.A., Kohli, M.A., Koller, D.L., Konte, B., Korszun, A., Krasucki, R., Kuntsi, J., Phoenix, K., Landén, M., Langstrom, N., Lathrop, M., Lawrence, J., Lawson, W.B., Leboyer, M., Lencz, T., Lewis, C.M., Li, J., Lichtenstein, P., Lieberman, J. A., Lin, D., Liu, C., Lohoff, F.W., Loo, S.K., Lucae, S., MacIntyre, D.J., Madden, P.A.F., Magnusson, P., Mahon, P.B., Maier, W., Malhotra, A.K., Mattheisen, M., Matthews, K., Mattingsdal, M., McCarroll, S., McGhee, K.A., McGough, J.J., McGrath, P.J., McGuffin, P., McInnis, M.G., McIntosh, A., McKinney, R., McClean, A.W., McMahon, F.J., McQuillin, A., Medeiros, H., Medland, S.E., Meier, S., Melle, I., Meng, F., Middeldorp, C.M., Middleton, L., Vihra, M., Mitchell, P.B., Montgomery, G.W., Moran, J., Morken, G., Morris, D.W., Moskvina, V., Mowry, B. J., Muglia, P., Mühleisen, T.W., Muir, W.J., Müller-Myhsok, B., Myers, R.M., Nelson, S.F., Nievergelt, C.M., Nikolovq, I., Nimgaonkar, V.L., Nolen, W.A., Nöthen, M.M., Nwulia, E.A., Nyholt, DR, O'Donovan, M.C., O'Dushlaine, C., Oades, R.D., Olincy, A., Olsen, L., Ophoff, R.A., Osby, U., Óskarsson, H., Owen, M.J., Palotie, A., Pato, M.T., Pato, C.N., Penninx, B.W.J.H., Pergadia, M.L., Petursson, H., Pickard, B.S., Pimm, J., Piven, J., Porgeirsson, P., Posthuma, D., Potash, J.B., Propping, J., Puri, V., Quested, D., Quinn, E.M., Rasmussen, H.B., Raychaudhuri, S., Rehnström, K., Reif, A., Rice, J., Rossin, L., Rothenberger, A., Rouleau, G., Ruderfer, D., Rujescu, D., Sanders, A.R., Schalling, M., Schatzberg, A.F., Scheftner, W.A., Schellenberg, G.D., Schofield, P.R., Schork, N.J., Schumacher, J., Schwarz, M.M., Scolnick, E., Scott, L.J., Shi, J., Shillling, P.D., Shyn, S.I., Sigurdsson, E., Silverman, J.M., Sklar, P., Slager, S.L., Smalley, S.L., Smit, J.H., Smith, E.N., Sonuga-Barke, E., St Clair, D., State, M., Stefansson, K., Stefansson, H., Steffans, M., Steinberg, S., Steinhausen, H.C., Strauss, J., Strohmaier, J., Stroup, T.S., Sutcliffe, J., Szatmari, P., Szelinger, S., Thirumalai, S., Thompson, R.C., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E.J., Grootheest, G., Vieland, V., Vincent, J.B., Visscher, P.M., Watson, S.J., Weissman, M.M., Werge, T., Wienker, T.F., Willemsen, G., Williamson, R., Witt, S.H., Wray, N.R., Wright, A., Xu, W., Young, A.H., Zammit, S., Zandi, P.P., Zhang, P., Zitman, F.G., Zöllner, S., Kendler, K.S., Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Oades, Robert D. (Beitragende*r), and Oades, Robert D.
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Netherlands Twin Register (NTR) ,Adult ,medicine.medical_specialty ,Bipolar Disorder ,Calcium Channels, L-Type ,Population ,Medizin ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] ,medicine ,ddc:61 ,Attention deficit hyperactivity disorder ,Humans ,DCN PAC - Perception action and control NCEBP 9 - Mental health ,ddc:610 ,Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters ,Bipolar disorder ,Age of Onset ,Psychiatry ,education ,Child ,Genetics ,education.field_of_study ,Depressive Disorder, Major ,General Medicine ,Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3] ,medicine.disease ,Logistic Models ,Autism spectrum disorder ,Schizophrenia ,Attention Deficit Disorder with Hyperactivity ,Child Development Disorders, Pervasive ,Genetic Loci ,Expression quantitative trait loci ,Major depressive disorder ,Genome-Wide Association Study - Abstract
Item does not contain fulltext BACKGROUND: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS: SNPs at four loci surpassed the cutoff for genome-wide significance (p
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- 2013
12. Identification of pathways for bipolar disorder: A meta-analysis
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Nurnberger, JI, Koller, DL, Jung, J, Edenberg, HJ, Foroud, T, Guella, I, Vawter, MP, Kelsoe, JR, Sklar, P, Ripke, S, Scott, LJ, Andreassen, OA, Cichon, S, Craddock, N, Rietschel, M, Blackwood, D, Corvin, A, Flickinger, M, Guan, W, Mattingsdal, M, McQuillin, A, Kwan, P, Wienker, TF, Daly, M, Dudbridge, F, Holmans, PA, Lin, D, Burmeister, M, Greenwood, TA, Hamshere, ML, Muglia, P, Smith, EN, Zandi, PP, Nievergelt, CM, McKinney, R, Shilling, PD, Schork, NJ, Bloss, CS, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Schulze, TG, Berrettini, W, Lohoff, FW, Potash, JB, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Craig, DW, Szelinger, S, Barrett, TB, Breuer, R, Meier, S, Strohmaier, J, Witt, SH, Tozzi, F, Farmer, A, McGuffin, P, Strauss, J, Xu, W, Kennedy, JL, Vincent, JB, Matthews, K, Day, R, Ferreira, MA, O'Dushlaine, C, Perlis, R, Raychaudhuri, S, Ruderfer, D, Lee, PH, Smoller, JW, Li, J, Absher, D, Bunney, WE, Barchas, JD, Schatzberg, AF, Jones, EG, Meng, F, Thompson, RC, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, EM, Djurovic, S, Melle, I, Morken, G, Gill, M, Morris, D, Nurnberger, JI, Koller, DL, Jung, J, Edenberg, HJ, Foroud, T, Guella, I, Vawter, MP, Kelsoe, JR, Sklar, P, Ripke, S, Scott, LJ, Andreassen, OA, Cichon, S, Craddock, N, Rietschel, M, Blackwood, D, Corvin, A, Flickinger, M, Guan, W, Mattingsdal, M, McQuillin, A, Kwan, P, Wienker, TF, Daly, M, Dudbridge, F, Holmans, PA, Lin, D, Burmeister, M, Greenwood, TA, Hamshere, ML, Muglia, P, Smith, EN, Zandi, PP, Nievergelt, CM, McKinney, R, Shilling, PD, Schork, NJ, Bloss, CS, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Schulze, TG, Berrettini, W, Lohoff, FW, Potash, JB, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Craig, DW, Szelinger, S, Barrett, TB, Breuer, R, Meier, S, Strohmaier, J, Witt, SH, Tozzi, F, Farmer, A, McGuffin, P, Strauss, J, Xu, W, Kennedy, JL, Vincent, JB, Matthews, K, Day, R, Ferreira, MA, O'Dushlaine, C, Perlis, R, Raychaudhuri, S, Ruderfer, D, Lee, PH, Smoller, JW, Li, J, Absher, D, Bunney, WE, Barchas, JD, Schatzberg, AF, Jones, EG, Meng, F, Thompson, RC, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, EM, Djurovic, S, Melle, I, Morken, G, Gill, M, and Morris, D
- Abstract
IMPORTANCE Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders. OBJECTIVE To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS). DATA SOURCES Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data. STUDY SELECTION The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample. DATA EXTRACTION AND SYNTHESIS We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12 127 [5253 cases, 6874 controls]). Simulations using 10 000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from ameta-analysis of gene expression in the dorsolateral prefrontal cortex. MAIN OUTCOMES AND MEASURES Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy
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- 2014
13. Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of AD patients and controls by array-based resequencing
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Coon, K D, Valla, J, Szelinger, S, Schneider, L E, Niedzielko, T L, Brown, K M, Pearson, J V, Halperin, R, Dunckley, T, Papassotiropoulos, A, Caselli, R J, Reiman, E M, Stephan, D A, University of Zurich, and Stephan, D A
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1307 Cell Biology ,1313 Molecular Medicine ,1312 Molecular Biology ,610 Medicine & health ,11359 Institute for Regenerative Medicine (IREM) - Published
- 2006
14. A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.
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Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., Russell, M., Courtright, A. L., Belnap, N., Rangasamy, S., Ramsey, K., Opitz, J. M., Craig, D. W., and Narayanan, V.
- Abstract
Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants
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Gamazon, E R, primary, Badner, J A, additional, Cheng, L, additional, Zhang, C, additional, Zhang, D, additional, Cox, N J, additional, Gershon, E S, additional, Kelsoe, J R, additional, Greenwood, T A, additional, Nievergelt, C M, additional, Chen, C, additional, McKinney, R, additional, Shilling, P D, additional, Schork, N J, additional, Smith, E N, additional, Bloss, C S, additional, Nurnberger, J I, additional, Edenberg, H J, additional, Foroud, T, additional, Koller, D L, additional, Scheftner, W A, additional, Coryell, W, additional, Rice, J, additional, Lawson, W B, additional, Nwulia, E A, additional, Hipolito, M, additional, Byerley, W, additional, McMahon, F J, additional, Schulze, T G, additional, Berrettini, W H, additional, Potash, J B, additional, Zandi, P P, additional, Mahon, P B, additional, McInnis, M G, additional, Zöllner, S, additional, Zhang, P, additional, Craig, D W, additional, Szelinger, S, additional, Barrett, T B, additional, and Liu, C, additional
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- 2012
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16. Singleton deletions throughout the genome increase risk of bipolar disorder
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Zhang, D, primary, Cheng, L, additional, Qian, Y, additional, Alliey-Rodriguez, N, additional, Kelsoe, J R, additional, Greenwood, T, additional, Nievergelt, C, additional, Barrett, T B, additional, McKinney, R, additional, Schork, N, additional, Smith, E N, additional, Bloss, C, additional, Nurnberger, J, additional, Edenberg, H J, additional, Foroud, T, additional, Sheftner, W, additional, Lawson, W B, additional, Nwulia, E A, additional, Hipolito, M, additional, Coryell, W, additional, Rice, J, additional, Byerley, W, additional, McMahon, F, additional, Schulze, T G, additional, Berrettini, W, additional, Potash, J B, additional, Belmonte, P L, additional, Zandi, P P, additional, McInnis, M G, additional, Zöllner, S, additional, Craig, D, additional, Szelinger, S, additional, Koller, D, additional, Christian, S L, additional, Liu, C, additional, and Gershon, E S, additional
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- 2008
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17. Comparison of ecdysteroid concentration in different morphs of aphids
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Polgár, L.A., primary, Darvas, B., additional, Völkl, W., additional, Porcheron, P., additional, Székács, A., additional, and Szelinger, S., additional
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- 1996
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18. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder.
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de Jong, S., Abdalla Diniz, M.J., Saloma, A., Gadelha, A., Santoro, M.L., Ota, V.K., Noto, C., Curtis, C., Newhouse, S.J., Patel, H., Hall, L.S., O'Reilly, P.F., Belangero, S.I., Bressan, R.A., Breen, G., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, T.F.M., Bacanu, S-A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T-K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Forstner, A.J., Franklin, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J-J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, E.J.C., DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Mueller-Myhsok, B., Nordentoft, M., Noethen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Voelzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Borglum, A.D., Sullivan, P.F., Meier, S., Strauss, J., Xu, W., Vincent, J.B., Matthews, K., Ferreira, M., O'Dushlaine, C., Purcell, S., Raychaudhuri, S., Ruderfer, D.M., Sklar, P., Scott, L.J., Flickinger, M., Burmeister, M., Li, J., Guan, W., Absher, D., Thompson, R.C., Meng, F.G., Schatzberg, A.F., Bunney, W.E., Barchas, J.D., Watson, S.J., Myers, R.M., Akil, H., Boehnke, M., Chambert, K., Moran, J., Scolnick, E., Djurovic, S., Melle, I., Morken, G, Corvin, A., Anjorin, A., Kandaswamy, R., Lawrence, J., McLean, A.W., Pickard, B.S., Bergen, S.E., Nimgaonkar, V., Landen, M., Schalling, M., Osby, U., Backlund, L., Frisen, L., Langstrom, N., Stahl, E., Dobbyn, A., Jamain, S., Etain, B., Bellivier, F., Leber, M., Maaser, A., Fischer, S.B., Reinbold, C.S., Kittel-Schneider, S., Fullerton, J.M., Oruc, L., Para, J.G., Mayoral, F., Rivas, F., Czerski, P.M., Kammerer-Ciernioch, J., Vedder, H., Borrmann-Hassenbach, M., Pfennig, A., Brennan, P., McKay, J.D., Kogevinas, M., Schwarz, M., Schofield, P.R., Muehleisen, T.W., Schumacher, J., Bauer, M., Wright, A., Mitchell, P.B., Hautzinger, M., Kelsoe, J.R., Greenwood, T.A., Nievergelt, C.M., Shilling, P.D., Smith, E.N., Bloss, C.S., Edenberg, H.J., Koller, D.L., Gershon, E.S., Liu, C., Badner, J.A., Scheftner, W.A., Lawson, W.B., Nwulia, E.A., Hipolito, M., Coryell, W., Rice, J., Byerley, W., McMahon, F.J., Lohoff, F.W., Zandi, P.P., Mahon, P.B., McInnis, M.G., Zollner, S., Zhang, P., Szelinger, S., St Clair, D., Caesar, S., Gordon-Smith, K., Fraser, C., Green, E.K., Grozeva, D., Hamshere, M.L., Kirov, G., Nikolov, I., Collier, D.A., Elkin, A., Williamson, R., Young, A.H., Ferrier, I.N., Milanova, V., Alda, M., Cervantes, P., Cruceanu, C., Rouleau, G.A., Turecki, G., Paciga, S., Winslow, A.R., Grigoroiu-Serbanescu, M., Ophoff, R., Adolfsson, R., Adolfsson, A.N., Del-Favero, J., Pato, C., Biernacka, J.M., Frye, M.A., Morris, D., Schork, N.J., Reif, A., Lissowska, J., Hauser, J., Szeszenia-Dabrowska, N., McGhee, Kevin, Quinn, E., Moskvina, V., Holmans, P.A., Farmer, A., Kennedy, J.L., 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- Abstract
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
19. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders
- Author
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M., Heilbronner U., Hipolito M., Holland D., Huckins L., Jamain S., Johnson J.S., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Muhleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Loohuis L.M.O., Ori A.P.S., Oruc L., Osby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Richards A.L., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Weickert C.S., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Hansen C.S., Spijker A.T., Clair D.S., Steffens M., Strauss J.S., Szelinger S., Thompson R.C., EThorgeirsson T., Vedde H., Wang W., Watson S.J., Weickert T.W., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zollner S., Adolfsson R., Agartz I., Alda M., Backlund L., Baune B.T., Bellivier F., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Borglum A.D., Corvin A., Craddock N., Daly M.J., Dannlowski U., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., Gill M., Goes F., Grigoroiu-Serbanescu M., Hauser J., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Posthuma D., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Werge T., Nurnberger J.I., Wray N.R., Florio A.D., Edenberg H.J., Ophoff R.A., Scott L.J., Andreassen O.A., Kelsoe J., Sklar P., Byrne E.M., Abdellaoui A., Adams M.J., Air T.M., Bacanu S.-A., Beekman A.T.F., Bigdeli T.B., Binder E.B., Bryois J., Buttenschon H.N., Cai N., Castelao E., Christensen J.H., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Deary I.J., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Kiadeh F.F.H., Finucane H.K., Goes F.S., Hall L.S., Hansen T.F., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Howard D.M., Ising M., Jansen R., Jorgenson E., Kohane I.S., Hill, Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacKinnon D.F., Maier R.M., Marchini J., Mbarek H., McGrath P., Mehta D., Middeldorp C.M., Mihailov E., Milaneschi Y., Mondimore F.M., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Painter J.N., Peterson R.E., Pettersson E., Peyrot W.J., Pistis G., Quiroz J.A., Qvist P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Shi J., Shyn S.I., Sinnamon G.C.B., Smit J.H., Smith D.J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Uitterlinden A.G., Umbricht D., Van der Auwera S., van Hemert A.M., Viktorin A., Visscher P.M., Webb B.T., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Berger K., Boomsma D.I., de Geus E.J.C., Domenici E., Domschke K., Grabe H.J., Hamilton S.P., Hayward C., Heath A.C., Kendler K.S., Kloiber S., Lewis G., Madden P.A.F., Magnusson P.K., Pedersen N.L., Penninx B.W.J.H., Porteous D.J., Preisig M., Schaefer C., Tiemeier H., Uher R., Volzke H., Weissman M.M., Levinson D.F., Child and Adolescent Psychiatry / Psychology, Epidemiology, Internal Medicine, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Complex Trait Genetics, and Adult Psychiatry
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Netherlands Twin Register (NTR) ,Genetic variants ,Bipolar Disorder ,Specific risk ,Disease ,0302 clinical medicine ,Multiplex ,Genetic risk ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Depression (differential diagnoses) ,0303 health sciences ,Depression ,ddc ,3. Good health ,Geðraskanir ,Psychiatry and Mental health ,Schizophrenia ,Cohort ,Major depressive disorder ,Case-Control Studie ,Human ,medicine.medical_specialty ,Bipolar disorder ,Article ,Cellular and Molecular Neuroscience ,03 medical and health sciences ,Geðklofi ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Psychiatry ,Þunglyndi ,Molecular Biology ,030304 developmental biology ,Depressive Disorder, Major ,Geðhvarfasýki ,business.industry ,Psychiatric disorder ,medicine.disease ,Genarannsóknir ,Case-Control Studies ,Multiple comparisons problem ,business ,030217 neurology & neurosurgery - Abstract
Publisher's version, Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development., The study was supported by the German Federal Ministry of Education and Research (BMBF), through the Integrated Network IntegraMent, under the auspices of the e:Med programme (grants 01ZX1314A to MMN and SC; 01ZX1314G to MR; 01ZX1614J to BMM) through grants 01EE1406C to MR and 01EE1409C to MR and SHW, and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation” (01EW1810 to MR) and BMBF grants 01EE1409C and 01EE1406C to MR and SHW; by the German Research Foundation (DFG grants FOR2107; RI908/11-2 to MR; NO246/10-2 to MMN; MU1315/8-2 to BMM; WI 3439/3-2 to SHW), by the Andalusian regional Health and Innovation Government (grants PI-0060-2017, RC-0006-2015 the Nicolas Monarde Programme for YDO and CTS-546) and by the Swiss National Science Foundation (SNSF grant 156791 to SC). MMN is a member of the DFG-funded cluster of excellence ImmunoSensation. The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). We thank the research participants and employees of 23andMe, Inc. for their contribution to the MDD meta-analysis published in [14]. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for the present analyses. See the Supplementary Data for extended Acknowledgements.
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- 2021
20. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls
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Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.
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0301 basic medicine ,Netherlands Twin Register (NTR) ,Genetic correlation ,Genome-wide association study ,Mood Disorder ,Bipolar disorder ,Population ,BF ,Genomics ,Major depressive disorder ,Affective disorder ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,mental disorders ,medicine ,Animals ,ddc:610 ,education ,Depression (differential diagnoses) ,Biological Psychiatry ,030304 developmental biology ,Genetic association ,Genetics ,Depressive Disorder, Major ,0303 health sciences ,education.field_of_study ,Animal ,business.industry ,Risk Factor ,medicine.disease ,3. Good health ,Affective disorders ,030104 developmental biology ,Mood ,Mood disorders ,RC0321 ,Biological psychiatry ,business ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.
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- 2020
21. Whole-genome analysis of sporadic amyotrophic lateral sclerosis.
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Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K, Halperin RF, Stamper C, Jensen KR, Letizia D, Hesterlee SE, Pestronk A, Levine T, Bertorini T, Graves MC, Mozaffar T, Jackson CE, Bosch P, McVey A, and Dick A
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- 2007
22. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
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Peter P. Zandi, Lisa Jones, Aartjan T.F. Beekman, Christine Fraser, Andreas J. Forstner, Nese Direk, Mark Lathrop, Jesper Krogh, Merete Nordentoft, Bradley T. Webb, Yihan Li, Michael Bauer, Qingqin S. Li, Daniel J. Smith, Carsten Horn, Robert C. Thompson, René Breuer, Eli A. Stahl, David A. Collier, Richard Williamson, Boomsma, Dorret, I, Céline S. Reinbold, Laura J. Scott, Manolis Kogevinas, Jacob Lawrence, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Wade H. Berrettini, John B. Vincent, Toni-Kim Clarke, Henry Voelzke, Stacy Steinberg, Hreinn Stefansson, Dean F. MacKinnon, Thorgeir E. Thorgeirsson, Niamh Mullins, Esben Agerbo, Rudolf Uher, Christina M. Hultman, Pamela A. F. Madden, Eva C. Schulte, Matthew Flickinger, Sebastian Zöllner, Kenneth S. Kendler, Urban Ösby, Enrique Castelao, Michael John Owen, Colm O'Dushlaine, Jens Treutlein, Joanna Hauser, Markus M. Noethen, Erin N. Smith, James McKay, Sandra Van der Auwera, Erin C. Dunn, Steven P. Hamilton, Martin Schalling, Helmut Vedder, Katherine Gordon-Smith, Fabio Rivas, Matthias Nauck, James B. Potash, Morten Mattingsdal, Ling Shen, Tim B. Bigdeli, Kimberly Chambert, Volker Arolt, Daniel L. Koller, Annelie Nordin Adolfsson, Na Cai, Nicholas G. Martin, Carlos N. Pato, Georg Homuth, Jonas Bybjerg-Grauholm, Alexander Teumer, Wesley K. Thompson, Hamel Patel, Jian Yang, Margit Burmeister, Frank Bellivier, Jodie N. Painter, Enda M. Byrne, Margarita Rivera, Nicholas John Craddock, Tatiana Foroud, Shaun Purcell, Paul D. Shilling, David Craig, Vanessa Kiyomi Ota, Michael Boehnke, Devin Absher, Stéphane Jamain, Anne Farmer, Yunpeng Wang, Ole Mors, William A. Scheftner, Jack D. Barchas, Robert Maier, Stanley J. Watson, Allan H. Young, Baptiste Couvy-Duchesne, Jakob Grove, Rick Jansen, John P. Rice, Gerome Breen, Eske M. Derks, Ingrid Melle, Tiffany A. Greenwood, Manuel Mattheisen, Bernard Ng, Edward M. Scolnick, Stefan Kloiber, Lili Milani, Yuri Milaneschi, Fermín Mayoral, Engilbert Sigurdsson, Sarah E. Medland, Wolfgang Maier, Alan F. Schatzberg, Myrna M. Weissman, Jun Li, John R. Kelsoe, Eric Jorgenson, Grant C.B. Sinnamon, Preben Bo Mortensen, Jana Strohmaier, William Byerley, Michel G. Nivard, Richard M. Myers, Evelin Mihailov, Gustavo Turecki, Benjamin S. Pickard, Ian J. Deary, Bernhard T. Baune, Marian L. Hamshere, Stephanie H. Witt, Patrick F. Sullivan, Jennifer L. Moran, Farnush Farhadi Hassan Kiadeh, Cathryn M. Lewis, Srdjan Djurovic, Ian B. Hickie, Hans J. Grabe, Helena Gaspar, Francis J. McMahon, Catherine Schaefer, Guy A. Rouleau, Sandra Meier, Derek W. Morris, Tõnu Esko, Wouter J. Peyrot, Markus Schwarz, Silviu-Alin Bacanu, Adam Wright, Melvin G. McInnis, Elaine K. Green, Douglas M. Ruderfer, Danielle Posthuma, Franziska Degenhardt, Per Qvist, Henriette N. Buttenschøn, Jolanta Lissowska, Stephan Ripke, Nicholas Bass, Giorgio Pistis, Emma M. Quinn, Shantel Weinsheimer, Howard J. Edenberg, Sintia Iole Belangero, Charles Curtis, Ashley R. Winslow, Tracy M. Air, Johannes H. Smit, Isaac S. Kohane, Wei Xu, Pamela B. Mahon, Neonila Szeszenia-Dabrowska, Gonneke Willemsen, Ivan Nikolov, Sven Cichon, Gregory E. Crawford, David M. Hougaard, E.J.C. de Geus, Klaus Berger, Evaristus A. Nwulia, Fernando S. Goes, Pablo Cervantes, Udo Dannlowski, Rolf Adolfsson, Thomas G. Schulze, Bruno Etain, Mark J. Adams, Thomas Hansen, Hugh Gurling, Fan Guo Meng, Judith A. Badner, Julien Bryois, Mateus Jose Abdalla Diniz, Rodrigo A. Bressan, Radhika Kandaswamy, Josef Frank, I. Nicol Ferrier, Bertram Mueller-Myhsok, Manuel A. R. Ferreira, Marion Leboyer, Futao Zhang, Valentina Moskvina, Patrik K. E. Magnusson, Laura M. Huckins, Douglas Blackwood, Michael Gill, Jianxin Shi, Dale R. Nyholt, Nancy L. Pedersen, André G. Uitterlinden, Henning Tiemeier, Vassily Trubetskoy, Scott D. Gordon, Ian Jones, Grant W. Montgomery, Martin Preisig, Cristiana Cruceanu, Sara A. Paciga, Lena Backlund, Abdel Abdellaoui, Andres Metspalu, Gunnar Morken, Marcus Ising, Sascha B. Fischer, Lilijana Oruc, Sian Caesar, Sarah Kittel-Schneider, Thalia C. Eley, Vihra Milanova, Thomas Werge, Andrew Heath, Katherine E. Tansey, Thomas W. Muehleisen, Jane H. Christensen, Chunyu Liu, Mikael Landén, Douglas F. Levinson, Julia Kraft, Juergen Wellmann, Coleman, Jonathan R., I, Peng Zhang, Glyn Lewis, Henning Teismann, Hamdi Mbarek, Carsten Bøcker Pedersen, Szabolcs Szelinger, Alexander Viktorin, Paul Brennan, Brenda W.J.H. Penninx, Maciej Trzaskowski, Yang Wu, Katharina Domschke, John Strauss, Hilary K. Finucane, Detelina Grozeva, Peter Holmans, Saira Saeed Mirza, Ole A. Andreassen, John I. Nurnberger, Lynsey S Hall, Till F. M. Andlauer, Sara Mostafavi, Andreas Reif, Joanna M. Biernacka, Christine Søholm Hansen, Hualin S. Xi, Stephen Newhouse, William E. Bunney, Andrew M. McIntosh, Anna Maaser, Enrico Domenici, Shyn, Stanley, I, Gail Davies, Warren W. Kretzschmar, Simone de Jong, Lucía Colodro-Conde, Pippa A. Thomson, Francis M. Mondimore, Martin Hautzinger, Cinnamon S. Bloss, Fabian Streit, James L. Kennedy, Erik Pettersson, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Johannes Schumacher, Kevin A. McGhee, Divya Mehta, Naomi R. Wray, Robert A. Schoevers, John A. Rice, Jordan W. Smoller, Anders D. Børglum, Susanne Lucae, Jorge A. Quiroz, Daniel Umbricht, Jouke-Jan Hottenga, Kari Stefansson, Marcella Rietschel, Zoltán Kutalik, Sarah E. Bergen, Paul F. O'Reilly, Amanda Dobbyn, Michael Conlon O'Donovan, Falk W. Lohoff, Caroline M. Nievergelt, David J. Porteous, Matthew Traylor, Brien P. Riley, Roy H. Perlis, J. Raymond DePaulo, Martin Alda, James A. Knowles, Cristiano Noto, Keith Matthews, Mark A. Frye, Patrick J. McGrath, Roseann E. Peterson, David St Clair, Roel A. Ophoff, William Coryell, Peter McGuffin, Andiara Calado Saloma Rodrigues, Elliot S. Gershon, Conor V. Dolan, Janice M. Fullerton, Weihua Guan, Niklas Långström, Pamela Sklar, Paul Lichtenstein, Per Hoffmann, Ary Gadelha, Alan W. McLean, Andrew McQuillin, Philip B. Mitchell, Huda Akil, Piotr M. Czerski, Michael Steffens, Hogni Oskarsson, Soumya Raychaudhuri, Marcos L. Santoro, Elisabeth B. Binder, Christel M. Middeldorp, Jose G. Para, Jurgen Del-Favero, Vishwajit L. Nimgaonkar, Peter R. Schofield, Stefan Herms, Marie Bækvad-Hansen, Andrea Pfennig, Albert M. van Hemert, Jutta Kammerer-Ciernioch, Adebayo Anjorin, Sara Paciga, William Lawson, George Kirov, Aiden Corvin, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Jonathan Marchini, Markus Leber, Maria Hipolito, Louise Frisén, Margitta Borrmann-Hassenbach, Amanda Elkin, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, TFM, Bacanu, S.A., Bækvad-Hansen, M., Beekman, ATF, Bigdeli, T.B., Binder, E.B., Blackwood, DHR, Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, JRI, Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, FFH, Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shyn, S.I., Sigurdsson, E., Sinnamon, GCB, Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, EJC, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, PAF, Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, BWJH, Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Børglum, A.D., Sullivan, P.F., Meier, S., Strauss, J., Xu, W., Vincent, J.B., Matthews, K., Ferreira, M., O'Dushlaine, C., Purcell, S., Raychaudhuri, S., Ruderfer, D.M., Sklar, P., Scott, L.J., Flickinger, M., Burmeister, M., Li, J., Guan, W., Absher, D., Thompson, R.C., Meng, F.G., Schatzberg, A.F., Bunney, W.E., Barchas, J.D., Watson, S.J., Myers, R.M., Akil, H., Boehnke, M., Chambert, K., Moran, J., Scolnick, E., Djurovic, S., Melle, I., Morken, G., Corvin, A., Anjorin, A., Kandaswamy, R., Lawrence, J., McLean, A.W., Pickard, B.S., Bergen, S.E., Nimgaonkar, V., Landén, M., Schalling, M., Osby, U., Backlund, L., Frisén, L., Langstrom, N., Stahl, E., Dobbyn, A., Jamain, S., Etain, B., Bellivier, F., Leber, M., Maaser, A., Fischer, S.B., Reinbold, C.S., Kittel-Schneider, S., Fullerton, J.M., Oruč, L., Para, J.G., Mayoral, F., Rivas, F., Czerski, P.M., Kammerer-Ciernioch, J., Vedder, H., Borrmann-Hassenbach, M., Pfennig, A., Brennan, P., McKay, J.D., Kogevinas, M., Schwarz, M., Schofield, P.R., Mühleisen, T.W., Schumacher, J., Bauer, M., Wright, A., Mitchell, P.B., Hautzinger, M., Kelsoe, J.R., Greenwood, T.A., Nievergelt, C.M., Shilling, P.D., Smith, E.N., Bloss, C.S., Edenberg, H.J., Koller, D.L., Gershon, E.S., Liu, C., Badner, J.A., Scheftner, W.A., Lawson, W.B., Nwulia, E.A., Hipolito, M., Coryell, W., Rice, J., Byerley, W., McMahon, F.J., Lohoff, F.W., Zandi, P.P., Mahon, P.B., McInnis, M.G., Zöllner, S., Zhang, P., Szelinger, S., St Clair, D., Caesar, S., Gordon-Smith, K., Fraser, C., Green, E.K., Grozeva, D., Hamshere, M.L., Kirov, G., Nikolov, I., Collier, D.A., Elkin, A., Williamson, R., Young, A.H., Ferrier, I.N., Milanova, V., Alda, M., Cervantes, P., Cruceanu, C., Rouleau, G.A., Turecki, G., Paciga, S., Winslow, A.R., Grigoroiu-Serbanescu, M., Ophoff, R., Adolfsson, R., Adolfsson, A.N., Del-Favero, J., Pato, C., Biernacka, J.M., Frye, M.A., Morris, D., Schork, N.J., Reif, A., Lissowska, J., Hauser, J., Szeszenia-Dabrowska, N., McGhee, K., Quinn, E., Moskvina, V., Holmans, P.A., Farmer, A., Kennedy, J.L., Andreassen, O.A., Mattingsdal, M., Bass, N.J., Gurling, H., McQuillin, A., Breuer, R., Hultman, C., Lichtenstein, P., Huckins, L.M., Leboyer, M., Lathrop, M., Nurnberger, J., Steffens, M., Foroud, T.M., Berrettini, W.H., Craig, D.W., Shi, J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Major Depressive Disorder Bipolar, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Pediatric Surgery, Epidemiology, Child and Adolescent Psychiatry / Psychology, Psychiatry, and Internal Medicine
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Netherlands Twin Register (NTR) ,0301 basic medicine ,Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium ,Bipolar Disorder ,SAMPLE ,Medicine (miscellaneous) ,Pedigree chart ,Disease ,0302 clinical medicine ,SCHIZOPHRENIA ,2.1 Biological and endogenous factors ,Medicine ,Aetiology ,ANTICIPATION ,lcsh:QH301-705.5 ,Psychiatry ,0303 health sciences ,Depression ,ASSOCIATION ,Serious Mental Illness ,Mental Health ,Schizophrenia ,Major depressive disorder ,General Agricultural and Biological Sciences ,Engineering sciences. Technology ,medicine.medical_specialty ,Context (language use) ,Article ,Psykiatri ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,AGE ,SDG 3 - Good Health and Well-being ,ddc:570 ,Behavioral and Social Science ,Genetics ,PLINK ,Genetic Testing ,Bipolar disorder ,Biology ,030304 developmental biology ,business.industry ,Prevention ,Human Genome ,Assortative mating ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Mood ,lcsh:Biology (General) ,Mood disorders ,Anticipation (genetics) ,ONSET ,Human medicine ,business ,030217 neurology & neurosurgery - Abstract
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.
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- 2018
23. Genome-wide association study identifies 30 loci associated with bipolar disorder
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Euijung Ryu, Danfeng Chen, Allan H. Young, Olav B. Smeland, James McKay, Frank Bellivier, Qingqin S. Li, Yunpeng Wang, Tõnu Esko, Bertram Müller-Myhsok, Weiqing Wang, Thomas W. Weickert, Joanna M. Biernacka, Ralph W. Kupka, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Marian L. Hamshere, Derek W. Morris, Douglas M. Ruderfer, Stephan Ripke, Nelson B. Freimer, Tatiana Foroud, Shaun Purcell, Ashley Dumont, Shawn Levy, Dominic Holland, Joanna Hauser, Anders D. Børglum, Liz Forty, Alan F. Schatzberg, Christine Fraser, Jennifer M. Whitehead Pavlides, William E. Bunney, Merete Nordentoft, Andres Metspalu, Gunnar Morken, Susanne Lucae, Roy H. Perlis, Anne T. Spijker, Richard A. Belliveau, Sarah E. Bergen, Fan Meng, Eduard Vieta, Cynthia Shannon Weickert, J. Raymond DePaulo, Martin Alda, Lina Martinsson, Melvin G. McInnis, Jacob Lawrence, Markus Leber, James A. Knowles, Franziska Degenhardt, Melissa J. Green, Jaqueline Goldstein, Amanda Dobbyn, Radhika Kandaswamy, Steve McCarroll, Katrin Gade, Jack D. Barchas, Christina M. Hultman, Sarah Kittel-Schneider, Martin Hautzinger, Maria Hipolito, Louise Frisén, Kari Stefansson, Michael Conlon O'Donovan, Markus M. Nöthen, Eline J. Regeer, Jens Treutlein, Robert Karlsson, Ian Jones, Nicholas G. Martin, William A. Scheftner, Caroline M. Nievergelt, Marta Ribasés, Simone de Jong, Szabolcs Szelinger, Thomas W. Mühleisen, Michele T. Pato, Manuel Mattheisen, Maciej Trzaskowski, Urs Heilbronner, Diane Gage, Jakob Grove, Ingrid Melle, Ole A. Andreassen, Claudia Giambartolomei, Kimberly Chambert, Arne E. Vaaler, William Coryell, Peter R. Schofield, Preben Bo Mortensen, Roel A. Ophoff, Fabian Streit, Manolis Kogevinas, Ingrid Agartz, John Strauss, James L. Kennedy, Anders M. Dale, Stefan Herms, Douglas Blackwood, Torbjørn Elvsåshagen, Bernhard T. Baune, Grant W. Montgomery, Andreas Reif, Fabio Rivas, Andrew McQuillin, Jordan W. Smoller, Chun Chieh Fan, James B. Potash, Jun Li, Ketil J. Oedegaard, David Curtis, Martin Schalling, John R. Kelsoe, Valentina Escott-Price, Sascha B. Fischer, Tatyana Shehktman, Jonathan R. I. Coleman, Stanley J. Watson, Donald J. MacIntyre, Tune H. Pers, Eystein Stordal, Richard M. Myers, Jose Guzman-Parra, Danielle Posthuma, John I. Nurnberger, William Lawson, Janet L. Sobell, Felecia Cerrato, Judith A. Badner, Elliot S. Gershon, Gerome Breen, Naomi R. Wray, Thomas Werge, Lilijana Oruc, Claire Slaney, Anil P.S. Ori, Alexander W. Charney, Marianne Giørtz Pedersen, Marie Bækvad-Hansen, Michael Boehnke, Marcella Rietschel, George Kirov, Aiden Corvin, Piotr M. Czerski, Peter Holmans, Michael Steffens, Margarita Rivera, Maria Grigoroiu-Serbanescu, René S. Kahn, Laura M. Huckins, Monika Budde, Michael Gill, Lili Milani, Christiaan de Leeuw, Peng Zhang, Nicholas Bass, Jana Strohmaier, John P. Rice, Wei Xu, Cristiana Cruceanu, Vassily Trubetskoy, Philip B. Mitchell, Helena Medeiros, Thomas Damm Als, Anna C. Koller, Huda Akil, Jessica S. Johnson, Toni-Kim Clarke, Janice M. Fullerton, Guy A. Rouleau, Fernando S. Goes, Weihua Guan, Wolfgang Maier, Pamela Sklar, Diego Albani, Laura J. Scott, Pamela B. Mahon, Anna Maaser, Katherine Gordon-Smith, Urban Ösby, Jurgen Del-Favero, Jolanta Lissowska, Howard J. Edenberg, Sven Cichon, Annelie Nordin Adolfsson, Julie Garnham, Josef Frank, Hoang T. Nguyen, Michael Bauer, Helmut Vedder, Vishwajit L. Nimgaonkar, Loes M. Olde Loohuis, Thomas G. Schulze, Cristina Sánchez-Mora, Udo Dannlowski, Rolf Adolfsson, Benjamin M. Neale, Verneri Antilla, Andrea Pfennig, John B. Vincent, Niamh Mullins, Per Hoffmann, Peter McGuffin, Erlend Bøen, Ney Alliey-Rodriguez, Adebayo Anjorin, Fermín Mayoral, Arianna Di Florio, Claire Churchhouse, David M. Hougaard, Nicholas J. Schork, Tiffany A. Greenwood, Carlos N. Pato, Thorgeir E. Thorgeirsson, Nicholas John Craddock, Stephanie H. Witt, Liam Abbott, Swapnil Awasthi, Miquel Casas, Jonas Bybjerg-Grauholm, Cathryn M. Lewis, Srdjan Djurovic, Bruno Etain, Margit Burmeister, Phil Lee, Elaine K. Green, Sara A. Paciga, Lena Backlund, Engilbert Sigurdsson, Patrick F. Sullivan, Amy Perry, Pablo Cervantes, Marco P. Boks, Catharina Lavebratt, Andrew M. McIntosh, Panos Roussos, Enda M. Byrne, Alexander Richards, Eli A. Stahl, Stéphane Jamain, Hreinn Stefansson, Ole Mors, Esben Agerbo, Susan L. McElroy, Wade H. Berrettini, Peter P. Zandi, Lisa Jones, Andreas J. Forstner, Alessandro Serretti, Céline S. Reinbold, Robert C. Thompson, Matthew Flickinger, William Byerley, Michael John Owen, Helena Gaspar, Francis J. McMahon, David St Clair, Mark A. Frye, Christine Søholm Hansen, Scott D. Gordon, Mikael Landén, Gustavo Turecki, Simon Xi, Evaristus A. Nwulia, Anders Juréus, James Boocock, Stacy Steinberg, Paul D. Shilling, David Craig, Mark J. Daly, Sarah E. Medland, Marion Leboyer, Chunyu Liu, Carsten Bøcker Pedersen, Sebastian Zöllner, APH - Mental Health, Psychiatry, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Stahl E.A., Breen G., Forstner A.J., McQuillin A., Ripke S., Trubetskoy V., Mattheisen M., Wang Y., Coleman J.R.I., Gaspar H.A., de Leeuw C.A., Steinberg S., Pavlides J.M.W., Trzaskowski M., Byrne E.M., Pers T.H., Holmans P.A., Richards A.L., Abbott L., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Anjorin A., Antilla V., Awasthi S., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Belliveau R., Bergen S.E., Pedersen C.B., Boen E., Boks M.P., Boocock J., Budde M., Bunney W., Burmeister M., Bybjerg-Grauholm J., Byerley W., Casas M., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Churchhouse C., Clarke T.-K., Coryell W., Craig D.W., Cruceanu C., Curtis D., Czerski P.M., Dale A.M., de Jong S., Degenhardt F., Del-Favero J., DePaulo J.R., Djurovic S., Dobbyn A.L., Dumont A., Elvsashagen T., Escott-Price V., Fan C.C., Fischer S.B., Flickinger M., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Pedersen M.G., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Guzman-Parra J., Hamshere M.L., Hautzinger M., Heilbronner U., Herms S., Hipolito M., Hoffmann P., Holland D., Huckins L., Jamain S., Johnson J.S., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Muhleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Loohuis L.M.O., Ori A.P.S., Oruc L., Osby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Shannon Weickert C., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Soholm Hansen C., Spijker A.T., St Clair D., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Thompson R.C., Thorgeirsson T.E., Treutlein J., Vedder H., Wang W., Watson S.J., Weickert T.W., Witt S.H., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zollner S., Adolfsson R., Agartz I., Alda M., Backlund L., Baune B.T., Bellivier F., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Borglum A.D., Corvin A., Craddock N., Daly M.J., Dannlowski U., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., Gill M., Goes F., Grigoroiu-Serbanescu M., Hauser J., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Posthuma D., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Werge T., Nurnberger J.I., Wray N.R., Di Florio A., Edenberg H.J., Cichon S., Ophoff R.A., Scott L.J., Andreassen O.A., Kelsoe J., Sklar P., eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, and Complex Trait Genetics
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Male ,Bipolar Disorder ,Bipolar I disorder ,Schizophrenia/genetics ,LD SCORE REGRESSION ,Genome-wide association study ,VARIANTS ,Bipolar II disorder ,0302 clinical medicine ,SCHIZOPHRENIA ,GWAS ,Psychotic Disorders/genetics ,Non-U.S. Gov't ,RISK ,Genetics ,0303 health sciences ,HERITABILITY ,Research Support, Non-U.S. Gov't ,Systems Biology ,Major/genetics ,Single Nucleotide ,3. Good health ,Schizophrenia ,Major depressive disorder ,Female ,Case-Control Studie ,Depressive Disorder, Major/genetics ,Human ,Psychosis ,GENES ,Biology ,Psychotic Disorder ,Research Support ,Polymorphism, Single Nucleotide ,Article ,Bipolar Disorder/classification ,N.I.H ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,medicine ,Journal Article ,POLYGENICITY ,Humans ,Genetic Predisposition to Disease ,Bipolar disorder ,Polymorphism ,METAANALYSIS ,030304 developmental biology ,Intramural ,Depressive Disorder, Major ,Depressive Disorder ,Genetic heterogeneity ,Research Support, N.I.H., Intramural ,medicine.disease ,INDIVIDUALS ,Psychotic Disorders ,Genetic Loci ,Case-Control Studies ,Human medicine ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Meta-Analysis - Abstract
This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu)., Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P, This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch.
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- 2019
24. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways
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Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
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Netherlands Twin Register (NTR) ,Statistical methods ,Autism ,Medizin ,LOCI ,Genome-wide association study ,heritability ,Genome-wide association studies ,Histones ,Genètica mèdica ,0302 clinical medicine ,Histone methylation ,Databases, Genetic ,2.1 Biological and endogenous factors ,Psychology ,GWAS ,Aetiology ,Psychiatric genetics ,R2C ,bipolar disorder ,Psychiatry ,0303 health sciences ,Disorders ,Loci ,Depression ,General Neuroscience ,Mental Disorders ,Medical genetics ,METHYLATION ,Brain ,3rd-DAS ,Serious Mental Illness ,Psychiatric Disorders ,3. Good health ,Histone ,Mental Health ,Schizophrenia ,Mental Disorder ,Cognitive Sciences ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Promoters ,BDC ,BURDEN ,RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry ,Human ,Signal Transduction ,medicine.medical_specialty ,DISORDERS ,Genomics ,Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium ,Burden ,Biology ,Methylation ,Article ,Biological pathway ,PROMOTERS ,03 medical and health sciences ,Databases ,Genetic ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,histone methylation ,Bipolar disorder ,Psiquiatria ,AUTISM ,030304 developmental biology ,Genetic association ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Neurology & Neurosurgery ,Neuroscience (all) ,Human Genome ,Neurosciences ,medicine.disease ,Brain Disorders ,Good Health and Well Being ,DE-NOVO MUTATIONS ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,RC0321 ,Genome-wide Association Studies ,De-novo mutations ,major depression ,Neuroscience ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
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- 2015
25. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder
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Robert Maier, Gerhard Moser, Guo-Bo Chen, Stephan Ripke, William Coryell, James B. Potash, William A. Scheftner, Jianxin Shi, Myrna M. Weissman, Christina M. Hultman, Mikael Landén, Douglas F. Levinson, Kenneth S. Kendler, Jordan W. Smoller, Naomi R. Wray, S. Hong Lee, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A. Andreassen, Adebayo Anjorin, Richard Anney, Dan E. Arking, Philip Asherson, Maria H. Azevedo, Lena Backlund, Judith A. Badner, Anthony J. Bailey, Tobias Banaschewski, Jack D. Barchas, Michael R. Barnes, Thomas B. Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B. Binder, Donald W. Black, Douglas H.R. Blackwood, Cinnamon S. Bloss, Michael Boehnke, Dorret I. Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Nancy G. Buccola, Jan K. Buitelaar, William E. Bunney, Joseph D. Buxbaum, William F. Byerley, Sian Caesar, Wiepke Cahn, Rita M. Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C. Robert Cloninger, David A. Collier, Edwin H. Cook, Hilary Coon, Bru Cormand, Paul Cormican, Aiden Corvin, William H. Coryell, Nicholas Craddock, David W. Craig, Ian W. Craig, Jennifer Crosbie, Michael L. Cuccaro, David Curtis, Darina Czamara, Mark J. Daly, Susmita Datta, Geraldine Dawson, Richard Day, Eco J. De Geus, Franziska Degenhardt, Bernie Devlin, Srdjan Djurovic, Gary J. Donohoe, Alysa E. Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P. Ebstein, Howard J. Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Stephen V. Faraone, Anne E. Farmer, I. Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B. Freimer, Christine M. Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V. Gejman, Lyudmila Georgieva, Elliot S. Gershon, Daniel H. Geschwind, Ina Giegling, Michael Gill, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Tiffany A. Greenwood, Dorothy E. Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe De Haan, Jonathan L. Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P. Hamilton, Marian L. Hamshere, Thomas F. Hansen, Annette M. Hartmann, Martin Hautzinger, Andrew C. Heath, Anjali K. Henders, Stefan Herms, Ian B. Hickie, Maria Hipolito, Susanne Hoefels, Peter A. Holmans, Florian Holsboer, Witte J. Hoogendijk, Jouke-Jan Hottenga, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Ian Jones, Lisa Jones, Anna K. Kähler, René S. Kahn, Radhika Kandaswamy, Matthew C. Keller, John R. Kelsoe, James L. Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K. Kirov, Sabine M. Klauck, Lambertus Klei, James A. Knowles, Martin A. Kohli, Daniel L. Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B. Lawson, Marion Leboyer, David H. Ledbetter, Phil H. Lee, Todd Lencz, Klaus-Peter Lesch, Cathryn M. Lewis, Jun Li, Paul Lichtenstein, Jeffrey A. Lieberman, Dan-Yu Lin, Don H. Linszen, Chunyu Liu, Falk W. Lohoff, Sandra K. Loo, Catherine Lord, Jennifer K. Lowe, Susanne Lucae, Donald J. MacIntyre, Pamela A.F. Madden, Elena Maestrini, Patrik K.E. Magnusson, Pamela B. Mahon, Wolfgang Maier, Anil K. Malhotra, Shrikant M. Mane, Christa L. Martin, Nicholas G. Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A. McCarroll, Kevin A. McGhee, James J. McGough, Patrick J. McGrath, Peter McGuffin, Melvin G. McInnis, Andrew McIntosh, Rebecca McKinney, Alan W. McLean, Francis J. McMahon, William M. McMahon, Andrew McQuillin, Helena Medeiros, Sarah E. Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M. Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P. Monaco, Grant W. Montgomery, Jennifer L. Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W. Morris, Eric M. Morrow, Valentina Moskvina, Bryan J. Mowry, Pierandrea Muglia, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael Murtha, Richard M. Myers, Inez Myin-Germeys, Benjamin M. Neale, Stan F. Nelson, Caroline M. Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A. Nolen, Markus M. Nöthen, John I. Nurnberger, Evaristus A. Nwulia, Dale R. Nyholt, Michael C. O’Donovan, Colm O’Dushlaine, Robert D. Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A. Ophoff, Urban Osby, Michael J. Owen, Aarno Palotie, Jeremy R. Parr, Andrew D. Paterson, Carlos N. Pato, Michele T. Pato, Brenda W. Penninx, Michele L. Pergadia, Margaret A. Pericak-Vance, Roy H. Perlis, Benjamin S. Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, Fritz Poustka, Peter Propping, Shaun M. Purcell, Vinay Puri, Digby J. Quested, Emma M. Quinn, Josep Antoni Ramos-Quiroga, Henrik B. Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P. Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R. Sanders, Stephan J. Sanders, Susan L. Santangelo, Russell Schachar, Martin Schalling, Alan F. Schatzberg, Gerard D. Schellenberg, Stephen W. Scherer, Nicholas J. Schork, Thomas G. Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J. Scott, Joseph A. Sergeant, Paul D. Shilling, Stanley I. Shyn, Jeremy M. Silverman, Pamela Sklar, Susan L. Slager, Susan L. Smalley, Johannes H. Smit, Erin N. Smith, Edmund J.S. Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S. Strauss, Jana Strohmaier, T. Scott Stroup, Patrick F. Sullivan, James Sutcliffe, Peter Szatmari, Szabocls Szelinger, Anita Thapar, Srinivasa Thirumalai, Robert C. Thompson, Alexandre A. Todorov, Federica Tozzi, Jens Treutlein, Jung-Ying Tzeng, Manfred Uhr, Edwin J.C.G. van den Oord, Gerard Van Grootheest, Jim Van Os, Astrid M. Vicente, Veronica J. Vieland, John B. Vincent, Peter M. Visscher, Christopher A. Walsh, Thomas H. Wassink, Stanley J. Watson, Lauren A. Weiss, Thomas Werge, Thomas F. Wienker, Durk Wiersma, Ellen M. Wijsman, Gonneke Willemsen, Nigel Williams, A. Jeremy Willsey, Stephanie H. Witt, Wei Xu, Allan H. Young, Timothy W. Yu, Stanley Zammit, Peter P. Zandi, Peng Zhang, Frans G. Zitman, Sebastian Zöllner, University of Zurich, Lee, S Hong, Epidemiology and Data Science, Psychiatry, EMGO - Mental health, NCA - Neurobiology of mental health, Human genetics, NCA - Brain mechanisms in health and disease, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Maier, Robert, Moser, Gerhard, Chen, Guo-Bo, Ripke, Stephan, Coryell, William, Potash, James B, Scheftner, William A, Shi, Jianxin, Weissman, Myrna M, Hultman, Christina M, Landen, Mikael, Levinson, Douglas F, Kendler, Kenneth S, Smoller, Jordan, Wray, Naomi R, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Oades, Robert D. (Beitragende*r), Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Maier R., Moser G., Chen G.-B., Ripke S., Coryell W., Potash J.B., Scheftner W.A., Shi J., Weissman M.M., Hultman C.M., Landen M., Levinson D.F., Kendler K.S., Smoller J.W., Wray N.R., Lee S.H., Absher D., Agartz I., Akil H., Amin F., Andreassen O.A., Anjorin A., Anney R., Arking D.E., Asherson P., Azevedo M.H., Backlund L., Badner J.A., Bailey A.J., Banaschewski T., Barchas J.D., Barnes M.R., Barrett T.B., Bass N., Battaglia A., Bauer M., Bayes M., Bellivier F., Bergen S.E., Berrettini W., Betancur C., Bettecken T., Biederman J., Binder E.B., Black D.W., Blackwood D.H.R., Bloss C.S., Boehnke M., Boomsma D.I., Breen G., Breuer R., Bruggeman R., Buccola N.G., Buitelaar J.K., Bunney W.E., Buxbaum J.D., Byerley W.F., Caesar S., Cahn W., Cantor R.M., Casas M., Chakravarti A., Chambert K., Choudhury K., Cichon S., Robert Cloninger C., Collier D.A., Cook E.H., Coon H., Cormand B., Cormican P., Corvin A., Coryell W.H., Craddock N., Craig D.W., Craig I.W., Crosbie J., Cuccaro M.L., Curtis D., Czamara D., Daly M.J., Datta S., Dawson G., Day R., De Geus E.J., Degenhardt F., Devlin B., Djurovic S., Donohoe G.J., Doyle A.E., Duan J., Dudbridge F., Duketis E., Ebstein R.P., Edenberg H.J., Elia J., Ennis S., Etain B., Fanous A., Faraone S.V., Farmer A.E., Nicol Ferrier I., Flickinger M., Fombonne E., Foroud T., Frank J., Franke B., Fraser C., Freedman R., Freimer N.B., Freitag C.M., Friedl M., Frisen L., Gallagher L., Gejman P.V., Georgieva L., Gershon E.S., Geschwind D.H., Giegling I., Gill M., Gordon S.D., Gordon-Smith K., Green E.K., Greenwood T.A., Grice D.E., Gross M., Grozeva D., Guan W., Gurling H., De Haan L., Haines J.L., Hakonarson H., Hallmayer J., Hamilton S.P., Hamshere M.L., Hansen T.F., Hartmann A.M., Hautzinger M., Heath A.C., Henders A.K., Herms S., Hickie I.B., Hipolito M., Hoefels S., Holmans P.A., Holsboer F., Hoogendijk W.J., Hottenga J.-J., Hus V., Ingason A., Ising M., Jamain S., Jones I., Jones L., Kahler A.K., Kahn R.S., Kandaswamy R., Keller M.C., Kelsoe J.R., Kennedy J.L., Kenny E., Kent L., Kim Y., Kirov G.K., Klauck S.M., Klei L., Knowles J.A., Kohli M.A., Koller D.L., Konte B., Korszun A., Krabbendam L., Krasucki R., Kuntsi J., Kwan P., Langstrom N., Lathrop M., Lawrence J., Lawson W.B., Leboyer M., Ledbetter D.H., Lee P.H., Lencz T., Lesch K.-P., Lewis C.M., Li J., Lichtenstein P., Lieberman J.A., Lin D.-Y., Linszen D.H., Liu C., Lohoff F.W., Loo S.K., Lord C., Lowe J.K., Lucae S., MacIntyre D.J., Madden P.A.F., Maestrini E., Magnusson P.K.E., Mahon P.B., Maier W., Malhotra A.K., Mane S.M., Martin C.L., Martin N.G., Mattheisen M., Matthews K., Mattingsdal M., McCarroll S.A., McGhee K.A., McGough J.J., McGrath P.J., McGuffin P., McInnis M.G., McIntosh A., McKinney R., McLean A.W., McMahon F.J., McMahon W.M., McQuillin A., Medeiros H., Medland S.E., Meier S., Melle I., Meng F., Meyer J., Middeldorp C.M., Middleton L., Milanova V., Miranda A., Monaco A.P., Montgomery G.W., Moran J.L., Moreno-De-Luca D., Morken G., Morris D.W., Morrow E.M., Moskvina V., Mowry B.J., Muglia P., Muhleisen T.W., Muller-Myhsok B., Murtha M., Myers R.M., Myin-Germeys I., Neale B.M., Nelson S.F., Nievergelt C.M., Nikolov I., Nimgaonkar V., Nolen W.A., Nothen M.M., Nurnberger J.I., Nwulia E.A., Nyholt D.R., O'Donovan M.C., O'Dushlaine C., Oades R.D., Olincy A., Oliveira G., Olsen L., Ophoff R.A., Osby U., Owen M.J., Palotie A., Parr J.R., Paterson A.D., Pato C.N., Pato M.T., Penninx B.W., Pergadia M.L., Pericak-Vance M.A., Perlis R.H., Pickard B.S., Pimm J., Piven J., Posthuma D., Poustka F., Propping P., Purcell S.M., Puri V., Quested D.J., Quinn E.M., Ramos-Quiroga J.A., Rasmussen H.B., Raychaudhuri S., Rehnstrom K., Reif A., Ribases M., Rice J.P., Rietschel M., Roeder K., Roeyers H., Rossin L., Rothenberger A., Rouleau G., Ruderfer D., Rujescu D., Sanders A.R., Sanders S.J., Santangelo S.L., Schachar R., Schalling M., Schatzberg A.F., Schellenberg G.D., Scherer S.W., Schork N.J., Schulze T.G., Schumacher J., Schwarz M., Scolnick E., Scott L.J., Sergeant J.A., Shilling P.D., Shyn S.I., Silverman J.M., Sklar P., Slager S.L., Smalley S.L., Smit J.H., Smith E.N., Sonuga-Barke E.J.S., St Clair D., State M., Steffens M., Steinhausen H.-C., Strauss J.S., Strohmaier J., Scott Stroup T., Sullivan P.F., Sutcliffe J., Szatmari P., Szelinger S., Thapar A., Thirumalai S., Thompson R.C., Todorov A.A., Tozzi F., Treutlein J., Tzeng J.-Y., Uhr M., van den Oord E.J.C.G., Van Grootheest G., Van Os J., Vicente A.M., Vieland V.J., Vincent J.B., Visscher P.M., Walsh C.A., Wassink T.H., Watson S.J., Weiss L.A., Werge T., Wienker T.F., Wiersma D., Wijsman E.M., Willemsen G., Williams N., Jeremy Willsey A., Witt S.H., Xu W., Young A.H., Yu T.W., Zammit S., Zandi P.P., Zhang P., Zitman F.G., and Zollner S.
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Netherlands Twin Register (NTR) ,Multifactorial Inheritance ,Multivariate analysis ,Bipolar Disorder ,genome annotation ,Medizin ,R Medicine (General) ,Medical and Health Sciences ,Genome-wide association studies ,0302 clinical medicine ,2.5 Research design and methodologies (aetiology) ,GWAS ,Genetics(clinical) ,Aetiology ,Multivariate Analysi ,Genetics (clinical) ,Genetics & Heredity ,bipolar disorder ,0303 health sciences ,education.field_of_study ,Depression ,Mental Disorders ,Single Nucleotide ,3rd-DAS ,Biological Sciences ,10058 Department of Child and Adolescent Psychiatry ,Serious Mental Illness ,Psychiatric Disorders ,3. Good health ,Mental Health ,Schizophrenia ,Mental Disorder ,Linear Model ,Major depressive disorder ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Risk assessment ,Human ,medicine.medical_specialty ,2716 Genetics (clinical) ,Genetics, Medical ,Population ,SNP ,610 Medicine & health ,QH426 Genetics ,Best linear unbiased prediction ,Polymorphism, Single Nucleotide ,Risk Assessment ,03 medical and health sciences ,1311 Genetics ,Medical ,Report ,medicine ,Genetics ,Humans ,Bipolar disorder ,Genetic Testing ,Polymorphism ,education ,Psychiatry ,QH426 ,030304 developmental biology ,Depressive Disorder ,Depressive Disorder, Major ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Cross-Disorder Working Group of the Psychiatric Genomics Consortium ,Prevention ,Human Genome ,Major ,medicine.disease ,genetic risk prediction ,R1 ,Brain Disorders ,schizophrenia ,Sample size determination ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,Multivariate Analysis ,Linear Models ,business ,depressive disorders ,030217 neurology & neurosurgery - Abstract
Cross-Disorder Working Group of the Psychiatric Genomics Consortium - Vicente A.M. Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25640677/ Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk
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- 2015
26. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
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Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
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Netherlands Twin Register (NTR) ,Medizin ,Inheritance Patterns ,Social Sciences ,AUTISM SPECTRUM DISORDERS ,nosology ,heritability ,COMMON SNPS ,0302 clinical medicine ,Crohn Disease ,SCHIZOPHRENIA ,Child ,Psychiatric genetics ,Genetics & Heredity ,MAJOR DEPRESSIVE DISORDER ,RISK ,0303 health sciences ,ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ,120 000 Neuronal Coherence ,Mental Disorders ,Variants ,BIPOLAR DISORDER ,ASSOCIATION ,Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3] ,Psychiatric Disorders ,CROHNS-DISEASE ,3. Good health ,Schizophrenia ,genetic association study ,Medical genetics ,Major depressive disorder ,SNPs ,Adult ,medicine.medical_specialty ,genetic etiology ,medical genetics ,DEFICIT HYPERACTIVITY DISORDER ,Biology ,Polymorphism, Single Nucleotide ,behavioral disciplines and activities ,Article ,Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] ,Heritability ,Genetic Heterogeneity ,03 medical and health sciences ,Prevalence of mental disorders ,mental disorders ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,medicine ,ddc:61 ,Humans ,Attention deficit hyperactivity disorder ,Genetic Predisposition to Disease ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,DCN PAC - Perception action and control NCEBP 9 - Mental health ,ddc:610 ,Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters ,Bipolar disorder ,Psychiatry ,030304 developmental biology ,Depressive Disorder, Major ,Genome, Human ,Genetic heterogeneity ,medicine.disease ,schizophrenia ,Attention Deficit Disorder with Hyperactivity ,Child Development Disorders, Pervasive ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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- 2013
27. Expanded carrier screening for inherited genetic disease using exome and genome sequencing.
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Belnap N, Ramsey K, Abraham A, Ryan A, Rangasamy S, Bonfitto A, Naymik M, Huentelman M, Strom S, Perry D, Subramaniam A, Grody WW, Szelinger S, and Narayanan V
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The goal of this study was to assess the feasibility of using exome (ES) and genome sequencing (GS) in guiding preconception genetic screening (PCGS) for couples who are planning to conceive by creating a workflow for identifying risk alleles for autosomal recessive (AR) and X-linked (XL) disorders without the constraints of a predetermined, targeted gene panel. There were several limitations and challenges related to reporting and the technical aspects of ES and GS, which are listed in the discussion. We selected 150 couples from a cohort of families (trios) enrolled in a research protocol where the goal was to define the genetic etiology of disease in an affected child. Pre-existing, de-identified parental sequencing data were analyzed to define variants that would place the couple at risk of having a child affected by an AR or XL disorder. We identified 17 families who would be selected for counseling about risk alleles. We noted that only 3 of these at-risk couples would be identified if we limited ourselves to the current ACMG-recommended expanded carrier screening gene panel. ES and GS successfully identified couples who are at risk of having a child with a rare AR or XL disorder that would have been missed by the current recommended guidelines. Current limitations of this approach include ethical concerns, difficulties in reporting results including variant calling due to the rare nature of some of the variants, determining which disorders to report, as well as technical difficulties in detecting certain variants such as repeat expansions., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)
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- 2024
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28. Implementation, Evolution, and Laboratory Performance of Methods-Based Proficiency Testing for Next-Generation Sequencing Detection of Germline Sequence Variants.
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Tsuchiya KD, Funke B, Hegde M, Santani A, Souers RJ, Szelinger S, Halley J, Zhao Q, Mot N, Roy A, Smith VL, Zhang BM, Voelkerding K, and Moyer AM
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- Humans, Genetic Testing methods, Genetic Testing standards, Laboratories, Clinical, Laboratory Proficiency Testing, High-Throughput Nucleotide Sequencing standards, High-Throughput Nucleotide Sequencing methods, Germ-Line Mutation
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Context.—: Next-generation sequencing (NGS)-based assays are used for diagnosis of diverse inherited disorders. Limited data are available pertaining to interlaboratory analytical performance of these assays., Objective.—: To report on the College of American Pathologists (CAP) NGS Germline Program, which is methods based, and explore the evolution in laboratory testing practices., Design.—: Results from the NGS Germline Program from 2016-2020 were analyzed for interlaboratory analytical performance. Self-reported laboratory testing practices were also evaluated., Results.—: From 2016-2020, a total of 297 laboratories participated in at least 1 program mailing. Of the 289 laboratories that provided information on tests offered, 138 (47.8%) offered only panel testing throughout their enrollment, while 35 (12.1%) offered panels and exome testing, 30 (10.4%) offered only exomes, 9 (3.1%) offered only genomes, and 15 (5.2%) offered panels, exomes, and genomes. The remainder (62 laboratories, 21.4%) changed their test offerings during the 2016-2020 timeframe. Considering each genomic position/interval, the median detection percentage at variant positions across the 2016-2020 mailings ranged from 94.3% to 100%, while at reference positions (no variant detected), the median correct response percentage was 100% across all mailings. When considering performance of individual laboratories, 89.5% (136 of 152) to 98.0% (149 of 152) of laboratories successfully met the detection threshold (≥90% of the variants present), while 94.6% (87 of 92) to 100% (163 of 163) of laboratories met the 95% specificity threshold across mailings., Conclusions.—: Since the inception of this program, laboratories have consistently performed well. The median sensitivity and specificity of detection of sequence variants included in this program (eg, single nucleotide variants, insertions, and deletions) were 100.0%., (© 2024 College of American Pathologists.)
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- 2024
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29. FGF12 copy number variant associated with epileptic encephalopathy.
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Abraham A, Ramsey K, Belnap N, Szelinger S, Jepsen W, Balak C, Sanchez-Castillo M, Naymik M, Bonfitto A, Rangasamy S, Kruglyak S, Huentelman M, and Narayanan V
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- Humans, Male, Female, Phenotype, DNA Copy Number Variations genetics, Fibroblast Growth Factors genetics, Epilepsy genetics
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FGF12 related epilepsy presents with variable phenotypes. We report another patient with a duplication involving the FGF12 gene who presented similar to other published cases having normal early development and responded to phenytoin., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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30. Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.
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Currey M, Solomon I, McGraw S, Shen J, Munoz F, Sosa E, Puello-Lozano V, Wing S, Lopez L, Afkhami M, LoBello J, Szelinger S, and Gray SW
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- Humans, United States, Delivery of Health Care, Neoplasms genetics, Neoplasms therapy
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Purpose: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings., Methods: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education., Results: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider., Conclusion: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education., Competing Interests: Conflict of Interest Dr Sam Wing declares employment by Intuitive Surgical. Sam Wing: Employed by Intuitive Surgical. Drs Janine LoBello and Szabolcs Szelinger: Employed by Exact Sciences., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2024
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31. Underreporting of SMARCB1 alteration by clinical sequencing: Integrative patho-genomic analysis captured SMARCB1 /INI-1 deficiency in a vulvar yolk sac tumor.
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Wei CH, Wang E, Sadimin E, Rodriguez-Rodriguez L, Agulnik M, Yoon J, LoBello J, Szelinger S, and Anderson C
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• SMARCB1 /INI1-deficient gynecologic tumors are rare and clinically aggressive. A subset shows primitive yolk sac tumor features.•Due to technical limitation of next generation sequencing (NGS) and interlaboratory variability in sequencing methodologies and analytical pipelines, SMARCB1 deficiency caused by somatic copy number variations (SCNV) may be underreported by NGS.•To improve identification of SMARCB1 /INI1-deficient neoplasm, we propose the following strategy: First, careful pathology slide review and detection of rhabdoid cells should raise the possibility of SMARCB1 /INI1 deficiency. Second, INI1 IHC is a useful complementary test to exclude clinical suspicion of SMARCB1 deficiency in the context of negative molecular reporting. Third, knowledge of potential underreporting of SMARCB1 mutation would avoid underdiagnosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)
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- 2023
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32. Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders.
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Frankel E, Podder A, Sharifi M, Pillai R, Belnap N, Ramsey K, Dodson J, Venugopal P, Brzezinski M, Llaci L, Gerald B, Mills G, Sanchez-Castillo M, Balak CD, Szelinger S, Jepsen WM, Siniard AL, Richholt R, Naymik M, Schrauwen I, Craig DW, Piras IS, Huentelman MJ, Schork NJ, Narayanan V, and Rangasamy S
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- Humans, Methyl-CpG-Binding Protein 2 genetics, Mutation genetics, Phenotype, Transcription Factors genetics, Rett Syndrome genetics, Neurodevelopmental Disorders
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Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 ( MECP2 ) cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a 'Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein-protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes. Functional enrichment analysis of RTT and RTT-L genes identified a number of intuitive biological processes. We also identified transcription factors (TFs) whose binding sites are common across the set of RTT and RTT-L genes and appear as important regulatory motifs for them. Investigation of the most significant over-represented pathway analysis suggests that HDAC1 and CHD4 likely play a central role in the interactome between RTT and RTT-L genes.
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- 2023
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33. A Case Report of Immunotherapy-Resistant MSI-H Gastric Cancer with Significant Intrapatient Tumoral Heterogeneity Characterized by Histologic Dedifferentiation.
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Kethireddy N, Arvanitis L, LoBello J, Woo Y, Szelinger S, and Chao J
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We describe a patient with both gastric adenocarcinoma and metastatic squamous cell carcinoma (SCC) of unknown primary site. The possibility of a single malignant clonal process as opposed to differing primaries was supported by the finding of both histologies exhibiting high microsatellite instability. Despite evidence of tumor microsatellite instability, the patient's disease process did not respond to immune checkpoint inhibition. Our pursuit of whole-exome sequencing and comparing the single-nucleotide variant profiles of both tumors supported a single clonal process with the development of significant intratumoral heterogeneity. High intratumoral heterogeneity has posed a challenge to precision medicine approaches, but we also provide a review of the literature of this phenomenon mediating resistance to immunotherapy strategies.
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- 2022
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34. Comprehensive Genomic Profiling of High-Risk Pediatric Cancer Patients Has a Measurable Impact on Clinical Care.
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Summers RJ, Castellino SM, Porter CC, MacDonald TJ, Basu GD, Szelinger S, Bhasin MK, Cash T, Carter AB, Castellino RC, Fangusaro JR, Mitchell SG, Pauly MG, Pencheva B, Wechsler DS, Graham DK, and Goldsmith KC
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- Child, Genomics methods, Germ-Line Mutation genetics, Humans, Prospective Studies, Exome Sequencing, Antineoplastic Agents, Neoplasms drug therapy
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Purpose: Profiling of pediatric cancers through deep sequencing of large gene panels and whole exomes is rapidly being adopted in many clinical settings. However, the most impactful approach to genomic profiling of pediatric cancers remains to be defined., Methods: We conducted a prospective precision medicine trial, using whole-exome sequencing of tumor and germline tissue and whole-transcriptome sequencing (RNA Seq) of tumor tissue to characterize the mutational landscape of 127 tumors from 126 unique patients across the spectrum of pediatric brain tumors, hematologic malignancies, and extracranial solid tumors., Results: We identified somatic tumor alterations in 121/127 (95.3%) tumor samples and identified cancer predisposition syndromes on the basis of known pathogenic or likely pathogenic germline mutations in cancer predisposition genes in 9/126 patients (7.1%). Additionally, we developed a novel scoring system for measuring the impact of tumor and germline sequencing, encompassing therapeutically relevant genomic alterations, cancer-related germline findings, recommendations for treatment, and refinement of risk stratification or prognosis. At least one impactful finding from the genomic results was identified in 108/127 (85%) samples sequenced. A recommendation to consider a targeted agent was provided for 82/126 (65.1%) patients. Twenty patients ultimately received therapy with a molecularly targeted agent, representing 24% of those who received a targeted agent recommendation and 16% of the total cohort., Conclusion: Paired tumor/normal whole-exome sequencing and tumor RNA Seq of de novo or relapsed/refractory tumors was feasible and clinically impactful in high-risk pediatric cancer patients., Competing Interests: Gargi D. BasuEmployment: Exact SciencesStock and Other Ownership Interests: Exact Sciences Szabolcs SzelingerEmployment: Exact SciencesStock and Other Ownership Interests: Exact Sciences Manoj K. BhasinConsulting or Advisory Role: Sanofi Thomas CashHonoraria: EUSA PharmaConsulting or Advisory Role: Y-mAbs TherapeuticsResearch Funding: Celgene, Roche/Genentech (Inst)Uncompensated Relationships: United Therapeutics, Lilly Alexis B. CarterEmployment: Envision HealthcareOther Relationship: American Medical Informatics Association Robert Craig CastellinoStock and Other Ownership Interests: Pfizer, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Corning, EI Dupont Jason R. FangusaroHonoraria: AstraZeneca, Pyramid BiosciencesConsulting or Advisory Role: Celgene, AstraZeneca Douglas K. GrahamStock and Other Ownership Interests: Meryx PharmaceuticalsConsulting or Advisory Role: SEAK TherapeuticsOther Relationship: Meryx PharmaceuticalsNo other potential conflicts of interest were reported.
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- 2022
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35. Next-Generation Sequencing Somatic and Germline Assay Troubleshooting Guide Derived From Proficiency Testing Data.
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Nardi V, Tsuchiya KD, Kim AS, Bean LJH, Halley JG, Long TA, Szelinger S, Vasalos P, Thorson JA, Moyer AM, and Moncur JT
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- Biological Assay, Germ Cells, High-Throughput Nucleotide Sequencing methods, Humans, Laboratories, Laboratory Proficiency Testing methods, Hematologic Neoplasms, Neoplasms genetics
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Context.—: Next-generation sequencing-based assays are increasingly used in clinical molecular laboratories to detect somatic variants in solid tumors and hematologic malignancies and to detect constitutional variants. Proficiency testing data are potential sources of information about challenges in performing these assays., Objective.—: To examine the most common sources of unacceptable results from the College of American Pathologists Next-Generation Sequencing Bioinformatics, Hematological Malignancies, Solid Tumor, and Germline surveys and provide recommendations on how to avoid these pitfalls and improve performance., Design.—: The College of American Pathologists next-generation sequencing somatic and germline proficiency testing survey results from 2016 to 2019 were analyzed to identify the most common causes of unacceptable results., Results.—: On somatic and germline proficiency testing surveys, 95.9% (18 815/19 623) and 97.8% (33 890/34 641) of all variants were correctly identified, respectively. The most common causes of unacceptable results related to sequencing were false-negative errors in genomic regions that were difficult to sequence because of high GC content. False-positive errors occurred in the context of homopolymers and pseudogenes. Recurrent errors in variant annotation were seen for dinucleotide and duplication variants and included unacceptable transcript selection and outdated variant nomenclature. A small percentage of preanalytic or postanalytic errors were attributed to specimen swaps and transcription errors., Conclusions.—: Laboratories demonstrate overall excellent performance for detecting variants in both somatic and germline proficiency testing surveys. Proficiency testing survey results highlight infrequent, but recurrent, analytic and nonanalytic challenges in performing next- generation sequencing-based assays and point to remedies to help laboratories improve performance., Competing Interests: The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the authors, DoD, or any component agency. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government. All others declare no potential conflicts of interest with the contents of this manuscript.
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- 2022
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36. Progressive cerebellar atrophy caused by heterozygous TECPR2 mutations.
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Ramsey K, Belnap N, Bonfitto A, Jepsen W, Naymik M, Sanchez-Castillo M, Craig DW, Szelinger S, Huentelman MJ, Narayanan V, and Rangasamy S
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- Atrophy genetics, Heterozygote, Humans, Mutation, Carrier Proteins genetics, Nerve Tissue Proteins genetics
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- 2022
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37. Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.
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Byron SA, Hendricks WPD, Nagulapally AB, Kraveka JM, Ferguson WS, Brown VI, Eslin DE, Mitchell D, Cornelius A, Roberts W, Isakoff MS, Oesterheld JE, Wada RK, Rawwas J, Neville K, Zage PE, Harrod VL, Bergendahl G, VanSickle E, Dykema K, Bond J, Chou HC, Wei JS, Wen X, Reardon HV, Roos A, Nasser S, Izatt T, Enriquez D, Hegde AM, Cisneros F, Christofferson A, Turner B, Szelinger S, Keats JJ, Halperin RF, Khan J, Saulnier Sholler GL, and Trent JM
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- Adolescent, Adult, Child, Child, Preschool, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Infant, Longitudinal Studies, Male, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local immunology, Neoplasms drug therapy, Neoplasms genetics, Neoplasms immunology, Prognosis, Survival Rate, Transcriptome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Drug Resistance, Neoplasm, Immune Evasion, Mutation, Neoplasm Recurrence, Local pathology, Neoplasms pathology
- Abstract
Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors., (©2021 American Association for Cancer Research.)
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- 2021
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38. Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra ® .
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White T, Szelinger S, LoBello J, King A, Aldrich J, Garinger N, Halbert M, Richholt RF, Mastrian SD, Babb C, Ozols AA, Goodman LJ, Basu GD, and Royce T
- Abstract
We developed and analytically validated a comprehensive genomic profiling (CGP) assay, GEM ExTra, for patients with advanced solid tumors that uses Next Generation Sequencing (NGS) to characterize whole exomes employing a paired tumor-normal subtraction methodology. The assay detects single nucleotide variants (SNV), indels, focal copy number alterations (CNA), TERT promoter region, as well as tumor mutation burden (TMB) and microsatellite instability (MSI) status. Additionally, the assay incorporates whole transcriptome sequencing of the tumor sample that allows for the detection of gene fusions and select special transcripts, including AR-V7, EGFR vIII, EGFRvIV, and MET exon 14 skipping events. The assay has a mean target coverage of 180X for the normal (germline) and 400X for tumor DNA including enhanced probe design to facilitate the sequencing of difficult regions. Proprietary bioinformatics, paired with comprehensive clinical curation results in reporting that defines clinically actionable, FDA-approved, and clinical trial drug options for the management of the patient's cancer. GEM ExTra demonstrated analytic specificity (PPV) of > 99.9% and analytic sensitivity of 98.8%. Application of GEM ExTra to 1,435 patient samples revealed clinically actionable alterations in 83.9% of reports, including 31 (2.5%) where therapeutic recommendations were based on RNA fusion findings only., Competing Interests: CONFLICTS OF INTEREST All authors have a financial relationship as employees of Ashion Analytics., (Copyright: © 2021 White et al.)
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- 2021
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39. Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice.
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Nakajima K, Miranda A, Craig DW, Shekhtman T, Kmoch S, Bleyer A, Szelinger S, Kato T, and Kelsoe JR
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- Animals, Depression, Mice, Mutation, Bipolar Disorder genetics, Kidney Diseases, Receptor, trkA genetics
- Abstract
Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.
- Published
- 2020
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40. Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1 .
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Szelinger S, Krate J, Ramsey K, Strom SP, Shieh PB, Lee H, Belnap N, Balak C, Siniard AL, Russell M, Richholt R, Both M, Claasen AM, Schrauwen I, Nelson SF, Huentelman MJ, Craig DW, Yang SP, Moore SA, Sivakumar K, Narayanan V, and Rangasamy S
- Abstract
Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 ( GFPT1 ) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families., Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed., Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology., Conclusions: These results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2020
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41. Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia.
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McCullough CG, Szelinger S, Belnap N, Ramsey K, Schrauwen I, Claasen AM, Burke LW, Siniard AL, Huentelman MJ, Narayanan V, and Craig DW
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- Alleles, Female, Genotype, Humans, Pedigree, Phenotype, Adaptor Protein Complex 4 genetics, Alternative Splicing, Genetic Association Studies methods, Genetic Predisposition to Disease, Introns, Siblings, Spastic Paraplegia, Hereditary diagnosis, Spastic Paraplegia, Hereditary genetics
- Abstract
We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms., (© 2019 Wiley Periodicals, Inc.)
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- 2020
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42. Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD).
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Llaci L, Ramsey K, Belnap N, Claasen AM, Balak CD, Szelinger S, Jepsen WM, Siniard AL, Richholt R, Izat T, Naymik M, De Both M, Piras IS, Craig DW, Huentelman MJ, Narayanan V, Schrauwen I, and Rangasamy S
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- Child, Humans, Male, Prognosis, Exome Sequencing, Hereditary Central Nervous System Demyelinating Diseases genetics, Hereditary Central Nervous System Demyelinating Diseases pathology, Heterozygote, Mutation, Qb-SNARE Proteins genetics, Qc-SNARE Proteins genetics
- Abstract
Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient's blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.
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- 2019
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43. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation.
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Balak C, Benard M, Schaefer E, Iqbal S, Ramsey K, Ernoult-Lange M, Mattioli F, Llaci L, Geoffroy V, Courel M, Naymik M, Bachman KK, Pfundt R, Rump P, Ter Beest J, Wentzensen IM, Monaghan KG, McWalter K, Richholt R, Le Béchec A, Jepsen W, De Both M, Belnap N, Boland A, Piras IS, Deleuze JF, Szelinger S, Dollfus H, Chelly J, Muller J, Campbell A, Lal D, Rangasamy S, Mandel JL, Narayanan V, Huentelman M, Weil D, and Piton A
- Subjects
- Humans, DEAD-box RNA Helicases genetics, Intellectual Disability genetics, Mutation, Missense, Proto-Oncogene Proteins genetics, RNA genetics
- Abstract
The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2019
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44. Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2.
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Jepsen WM, Ramsey K, Szelinger S, Llaci L, Balak C, Belnap N, Bilagody C, De Both M, Gupta R, Naymik M, Pandey R, Piras IS, Sanchez-Castillo M, Rangasamy S, Narayanan V, and Huentelman MJ
- Subjects
- Heterogeneous-Nuclear Ribonucleoprotein Group F-H, Humans, Male, Mutation, Syndrome, Intellectual Disability, Mental Retardation, X-Linked
- Published
- 2019
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45. Genome-wide association study identifies 30 loci associated with bipolar disorder.
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Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, Mattheisen M, Wang Y, Coleman JRI, Gaspar HA, de Leeuw CA, Steinberg S, Pavlides JMW, Trzaskowski M, Byrne EM, Pers TH, Holmans PA, Richards AL, Abbott L, Agerbo E, Akil H, Albani D, Alliey-Rodriguez N, Als TD, Anjorin A, Antilla V, Awasthi S, Badner JA, Bækvad-Hansen M, Barchas JD, Bass N, Bauer M, Belliveau R, Bergen SE, Pedersen CB, Bøen E, Boks MP, Boocock J, Budde M, Bunney W, Burmeister M, Bybjerg-Grauholm J, Byerley W, Casas M, Cerrato F, Cervantes P, Chambert K, Charney AW, Chen D, Churchhouse C, Clarke TK, Coryell W, Craig DW, Cruceanu C, Curtis D, Czerski PM, Dale AM, de Jong S, Degenhardt F, Del-Favero J, DePaulo JR, Djurovic S, Dobbyn AL, Dumont A, Elvsåshagen T, Escott-Price V, Fan CC, Fischer SB, Flickinger M, Foroud TM, Forty L, Frank J, Fraser C, Freimer NB, Frisén L, Gade K, Gage D, Garnham J, Giambartolomei C, Pedersen MG, Goldstein J, Gordon SD, Gordon-Smith K, Green EK, Green MJ, Greenwood TA, Grove J, Guan W, Guzman-Parra J, Hamshere ML, Hautzinger M, Heilbronner U, Herms S, Hipolito M, Hoffmann P, Holland D, Huckins L, Jamain S, Johnson JS, Juréus A, Kandaswamy R, Karlsson R, Kennedy JL, Kittel-Schneider S, Knowles JA, Kogevinas M, Koller AC, Kupka R, Lavebratt C, Lawrence J, Lawson WB, Leber M, Lee PH, Levy SE, Li JZ, Liu C, Lucae S, Maaser A, MacIntyre DJ, Mahon PB, Maier W, Martinsson L, McCarroll S, McGuffin P, McInnis MG, McKay JD, Medeiros H, Medland SE, Meng F, Milani L, Montgomery GW, Morris DW, Mühleisen TW, Mullins N, Nguyen H, Nievergelt CM, Adolfsson AN, Nwulia EA, O'Donovan C, Loohuis LMO, Ori APS, Oruc L, Ösby U, Perlis RH, Perry A, Pfennig A, Potash JB, Purcell SM, Regeer EJ, Reif A, Reinbold CS, Rice JP, Rivas F, Rivera M, Roussos P, Ruderfer DM, Ryu E, Sánchez-Mora C, Schatzberg AF, Scheftner WA, Schork NJ, Shannon Weickert C, Shehktman T, Shilling PD, Sigurdsson E, Slaney C, Smeland OB, Sobell JL, Søholm Hansen C, Spijker AT, St Clair D, Steffens M, Strauss JS, Streit F, Strohmaier J, Szelinger S, Thompson RC, Thorgeirsson TE, Treutlein J, Vedder H, Wang W, Watson SJ, Weickert TW, Witt SH, Xi S, Xu W, Young AH, Zandi P, Zhang P, Zöllner S, Adolfsson R, Agartz I, Alda M, Backlund L, Baune BT, Bellivier F, Berrettini WH, Biernacka JM, Blackwood DHR, Boehnke M, Børglum AD, Corvin A, Craddock N, Daly MJ, Dannlowski U, Esko T, Etain B, Frye M, Fullerton JM, Gershon ES, Gill M, Goes F, Grigoroiu-Serbanescu M, Hauser J, Hougaard DM, Hultman CM, Jones I, Jones LA, Kahn RS, Kirov G, Landén M, Leboyer M, Lewis CM, Li QS, Lissowska J, Martin NG, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Melle I, Metspalu A, Mitchell PB, Morken G, Mors O, Mortensen PB, Müller-Myhsok B, Myers RM, Neale BM, Nimgaonkar V, Nordentoft M, Nöthen MM, O'Donovan MC, Oedegaard KJ, Owen MJ, Paciga SA, Pato C, Pato MT, Posthuma D, Ramos-Quiroga JA, Ribasés M, Rietschel M, Rouleau GA, Schalling M, Schofield PR, Schulze TG, Serretti A, Smoller JW, Stefansson H, Stefansson K, Stordal E, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Werge T, Nurnberger JI, Wray NR, Di Florio A, Edenberg HJ, Cichon S, Ophoff RA, Scott LJ, Andreassen OA, Kelsoe J, and Sklar P
- Subjects
- Bipolar Disorder classification, Case-Control Studies, Depressive Disorder, Major genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Psychotic Disorders genetics, Schizophrenia genetics, Systems Biology, Bipolar Disorder genetics, Genetic Loci
- Abstract
Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10
-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.- Published
- 2019
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46. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.
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McCarthy MJ, Wei H, Nievergelt CM, Stautland A, Maihofer AX, Welsh DK, Shilling P, Alda M, Alliey-Rodriguez N, Anand A, Andreasson OA, Balaraman Y, Berrettini WH, Bertram H, Brennand KJ, Calabrese JR, Calkin CV, Claasen A, Conroy C, Coryell WH, Craig DW, D'Arcangelo N, Demodena A, Djurovic S, Feeder S, Fisher C, Frazier N, Frye MA, Gage FH, Gao K, Garnham J, Gershon ES, Glazer K, Goes F, Goto T, Harrington G, Jakobsen P, Kamali M, Karberg E, Kelly M, Leckband SG, Lohoff F, McInnis MG, Mondimore F, Morken G, Nurnberger JI, Obral S, Oedegaard KJ, Ortiz A, Ritchey M, Ryan K, Schinagle M, Schoeyen H, Schwebel C, Shaw M, Shekhtman T, Slaney C, Stapp E, Szelinger S, Tarwater B, Zandi PP, and Kelsoe JR
- Subjects
- Adult, Animals, Bipolar Disorder genetics, Cells, Cultured, Genotyping Techniques, Humans, Inositol 1,4,5-Trisphosphate Receptors genetics, Luminescent Measurements, Mice, NIH 3T3 Cells, Period Circadian Proteins, Polymorphism, Single Nucleotide, Prospective Studies, Antimanic Agents pharmacology, Bipolar Disorder drug therapy, Bipolar Disorder physiopathology, Circadian Rhythm drug effects, Circadian Rhythm physiology, Fibroblasts drug effects, Fibroblasts physiology, Lithium Compounds pharmacology
- Abstract
Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP
3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.- Published
- 2019
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47. Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.
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Budde M, Friedrichs S, Alliey-Rodriguez N, Ament S, Badner JA, Berrettini WH, Bloss CS, Byerley W, Cichon S, Comes AL, Coryell W, Craig DW, Degenhardt F, Edenberg HJ, Foroud T, Forstner AJ, Frank J, Gershon ES, Goes FS, Greenwood TA, Guo Y, Hipolito M, Hood L, Keating BJ, Koller DL, Lawson WB, Liu C, Mahon PB, McInnis MG, McMahon FJ, Meier SM, Mühleisen TW, Murray SS, Nievergelt CM, Nurnberger JI Jr, Nwulia EA, Potash JB, Quarless D, Rice J, Roach JC, Scheftner WA, Schork NJ, Shekhtman T, Shilling PD, Smith EN, Streit F, Strohmaier J, Szelinger S, Treutlein J, Witt SH, Zandi PP, Zhang P, Zöllner S, Bickeböller H, Falkai PG, Kelsoe JR, Nöthen MM, Rietschel M, Schulze TG, and Malzahn D
- Subjects
- Adolescent, Adult, Aged, Bipolar Disorder physiopathology, Bipolar Disorder psychology, Case-Control Studies, Female, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium genetics, Male, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide genetics, Prognosis, Psychiatric Status Rating Scales, White People genetics, Young Adult, Bipolar Disorder diagnosis, Bipolar Disorder genetics, Genetic Predisposition to Disease genetics
- Abstract
Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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48. Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics.
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Breuer R, Mattheisen M, Frank J, Krumm B, Treutlein J, Kassem L, Strohmaier J, Herms S, Mühleisen TW, Degenhardt F, Cichon S, Nöthen MM, Karypis G, Kelsoe J, Greenwood T, Nievergelt C, Shilling P, Shekhtman T, Edenberg H, Craig D, Szelinger S, Nurnberger J, Gershon E, Alliey-Rodriguez N, Zandi P, Goes F, Schork N, Smith E, Koller D, Zhang P, Badner J, Berrettini W, Bloss C, Byerley W, Coryell W, Foroud T, Guo Y, Hipolito M, Keating B, Lawson W, Liu C, Mahon P, McInnis M, Murray S, Nwulia E, Potash J, Rice J, Scheftner W, Zöllner S, McMahon FJ, Rietschel M, and Schulze TG
- Abstract
Background: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted., Results: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings., Conclusion: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.
- Published
- 2018
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49. A novel variant in TAF1 affects gene expression and is associated with X-linked TAF1 intellectual disability syndrome.
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Hurst SE, Liktor-Busa E, Moutal A, Parker S, Rice S, Szelinger S, Senner G, Hammer MF, Johnstone L, Ramsey K, Narayanan V, Perez-Miller S, Khanna M, Dahlin H, Lewis K, Craig D, Wang EH, Khanna R, and Nelson MA
- Abstract
We investigated the genome of a 5-year-old male who presented with global developmental delay (motor, cognitive, and speech), hypotonia, possibly ataxia, and cerebellar hypoplasia of unknown origin. Whole genome sequencing (WGS) and mRNA sequencing (RNA-seq) were performed on a family having an affected proband, his unaffected parents, and maternal grandfather. To explore the molecular and functional consequences of the variant, we performed cell proliferation assays, quantitative real-time PCR (qRT-PCR) array, immunoblotting, calcium imaging, and neurite outgrowth experiments in SH-SY5Y neuroblastoma cells to compare the properties of the wild-type TATA-box-binding protein factor 1 ( TAF1 ), deletion of TAF1 , and TAF1 variant p.Ser1600Gly samples. The whole genome data identified several gene variants. However, the genome sequence data failed to implicate a candidate gene as many of the variants were of unknown significance. By combining genome sequence data with transcriptomic data, a probable candidate variant, p.Ser1600Gly, emerged in TAF1 . Moreover, the RNA-seq data revealed a 90:10 extremely skewed X-chromosome inactivation (XCI) in the mother. Our results showed that neuronal ion channel genes were differentially expressed between TAF1 deletion and TAF1 variant p.Ser1600Gly cells, when compared with their respective controls, and that the TAF1 variant may impair neuronal differentiation and cell proliferation. Taken together, our data suggest that this novel variant in TAF1 plays a key role in the development of a recently described X-linked syndrome, TAF1 intellectual disability syndrome, and further extends our knowledge of a potential link between TAF1 deficiency and defects in neuronal cell function., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (© 2018 The Author(s).)
- Published
- 2018
- Full Text
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50. A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41-q42 deletion phenotype.
- Author
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Balak C, Belnap N, Ramsey K, Joss S, Devriendt K, Naymik M, Jepsen W, Siniard AL, Szelinger S, Parker ME, Richholt R, Izatt T, LaFleur M, Terraf P, Llaci L, De Both M, Piras IS, Rangasamy S, Schrauwen I, Craig DW, Huentelman M, and Narayanan V
- Subjects
- Body Dysmorphic Disorders pathology, Child, Preschool, Developmental Disabilities pathology, Drug Resistant Epilepsy pathology, Exome, Female, Humans, Phenotype, Prognosis, Exome Sequencing, Body Dysmorphic Disorders genetics, Chromosome Deletion, Chromosomes, Human, Pair 1 genetics, Developmental Disabilities genetics, Drug Resistant Epilepsy genetics, Frameshift Mutation, SKP Cullin F-Box Protein Ligases genetics
- Abstract
Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
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