Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
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2016-11-21Author
Marshall, Christian R
Howrigan, Daniel P
Merico, Daniele
Thiruvahindrapuram, Bhooma
Wu, Wenting
Greer, Douglas S
Antaki, Danny
Shetty, Aniket
Holmans, Peter A
Pinto, Dalila
Gujral, Madhusudan
Brandler, William M
Malhotra, Dheeraj
Wang, Zhouzhi
Fajarado, Karin V Fuentes
Maile, Michelle S
Ripke, Stephan
Agartz, Ingrid
Albus, Margot
Alexander, Madeline
Amin, Farooq
Atkins, Joshua
Bacanu, Silviu A
Belliveau, Richard A
Bergen, Sarah E
Bertalan, Marcelo
Bevilacqua, Elizabeth
Bigdeli, Tim B
Black, Donald W
Bruggeman, Richard
Buccola, Nancy G
Buckner, Randy L
Bulik-Sullivan, Brendan
Byerley, William
Cahn, Wiepke
Cai, Guiqing
Cairns, Murray J
Campion, Dominique
Cantor, Rita M
Carr, Vaughan J
Carrera, Noa
Catts, Stanley V
Chambert, Kimberley D
Cheng, Wei
Cloninger, C Robert
Cohen, David
Cormican, Paul
Craddock, Nick
Crespo-Facorro, Benedicto
Crowley, James J
Curtis, David
Davidson, Michael
Davis, Kenneth L
Degenhardt, Franziska
Del Favero, Jurgen
DeLisi, Lynn E
Dikeos, Dimitris
Dinan, Timothy
Djurovic, Srdjan
Donohoe, Gary
Drapeau, Elodie
Duan, Jubao
Dudbridge, Frank
Eichhammer, Peter
Eriksson, Johan
Escott-Price, Valentina
Essioux, Laurent
Fanous, Ayman H
Farh, Kai-How
Farrell, Martilias S
Frank, Josef
Franke, Lude
Freedman, Robert
Freimer, Nelson B
Friedman, Joseph I
Forstner, Andreas J
Fromer, Menachem
Genovese, Giulio
Georgieva, Lyudmila
Gershon, Elliot S
Giegling, Ina
Giusti-Rodríguez, Paola
Godard, Stephanie
Goldstein, Jacqueline I
Gratten, Jacob
de Haan, Lieuwe
Hamshere, Marian L
Hansen, Mark
Hansen, Thomas
Haroutunian, Vahram
Hartmann, Annette M
Henskens, Frans A
Herms, Stefan
Hirschhorn, Joel N
Hoffmann, Per
Hofman, Andrea
Huang, Hailiang
Ikeda, Masashi
Joa, Inge
Kähler, Anna K
Kahn, René S
Kalaydjieva, Luba
Karjalainen, Juha
Kavanagh, David
Keller, Matthew C
Kelly, Brian J
Kennedy, James L
Kim, Yunjung
Knowles, James A
Konte, Bettina
Laurent, Claudine
Lee, Phil
Lee, S Hong
Legge, Sophie E
Lerer, Bernard
Levy, Deborah L
Liang, Kung-Yee
Lieberman, Jeffrey
Lönnqvist, Jouko
Loughland, Carmel M
Magnusson, Patrik K E
Maher, Brion S
Maier, Wolfgang
Mallet, Jacques
Mattheisen, Manuel
Mattingsdal, Morten
McCarley, Robert W
McDonald, Colm
McIntosh, Andrew M
Meier, Sandra
Meijer, Carin J
Melle, Ingrid
Mesholam-Gately, Raquelle I
Metspalu, Andres
Michie, Patricia T
Milani, Lili
Milanova, Vihra
Mokrab, Younes
Morris, Derek W.
Müller-Myhsok, Bertram
Murphy, Kieran C
Murray, Robin M
Myin-Germeys, Inez
Nenadic, Igor
Nertney, Deborah A
Nestadt, Gerald
Nicodemus, Kristin K
Nisenbaum, Laura
Nordin, Annelie
O'Callaghan, Eadbhard
O'Dushlaine, Colm
Oh, Sang-Yun
Olincy, Ann
Olsen, Line
O'Neill, F Anthony
Van Os, Jim
Pantelis, Christos
Papadimitriou, George N
Parkhomenko, Elena
Pato, Michele T
Paunio, Tiina
Perkins, Diana O
Pers, Tune H
Pietiläinen, Olli
Pimm, Jonathan
Pocklington, Andrew J
Powell, John
Price, Alkes
Pulver, Ann E
Purcell, Shaun M
Quested, Digby
Rasmussen, Henrik B
Reichenberg, Abraham
Reimers, Mark A
Richards, Alexander L
Roffman, Joshua L
Roussos, Panos
Ruderfer, Douglas M
Salomaa, Veikko
Sanders, Alan R
Savitz, Adam
Schall, Ulrich
Schulze, Thomas G
Schwab, Sibylle G
Scolnick, Edward M
Scott, Rodney J
Seidman, Larry J
Shi, Jianxin
Silverman, Jeremy M
Smoller, Jordan W
Söderman, Erik
Spencer, Chris C A
Stahl, Eli A
Strengman, Eric
Strohmaier, Jana
Stroup, T Scott
Suvisaari, Jaana
Svrakic, Dragan M
Szatkiewicz, Jin P
Thirumalai, Srinivas
Tooney, Paul A
Veijola, Juha
Visscher, Peter M
Waddington, John
Walsh, Dermot
Webb, Bradley T
Weiser, Mark
Wildenauer, Dieter B
Williams, Nigel M
Williams, Stephanie
Witt, Stephanie H
Wolen, Aaron R
Wormley, Brandon K
Wray, Naomi R
Wu, Jing Qin
Zai, Clement C
Adolfsson, Rolf
Andreassen, Ole A
Blackwood, Douglas H R
Bramon, Elvira
Buxbaum, Joseph D
Cichon, Sven
Collier, David A
Corvin, Aiden
Daly, Mark J
Darvasi, Ariel
Domenici, Enrico
Esko, Tõnu
Gejman, Pablo V
Gill, Michael
Gurling, Hugh
Hultman, Christina M
Iwata, Nakao
Jablensky, Assen V
Jönsson, Erik G
Kendler, Kenneth S
Kirov, George
Knight, Jo
Levinson, Douglas F
Li, Qingqin S
McCarroll, Steven A
McQuillin, Andrew
Moran, Jennifer L
Mowry, Bryan J
Nöthen, Markus M
Ophoff, Roel A
Owen, Michael J
Palotie, Aarno
Pato, Carlos N
Petryshen, Tracey L
Posthuma, Danielle
Rietschel, Marcella
Riley, Brien P
Rujescu, Dan
Sklar, Pamela
St Clair, David
Walters, James T R
Werge, Thomas
Sullivan, Patrick F
O'Donovan, Michael C
Scherer, Stephen W
Neale, Benjamin M
Sebat, Jonathan
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Marshall, Christian R; Howrigan, Daniel P; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wu, Wenting; Greer, Douglas S; Antaki, Danny; Shetty, Aniket; Holmans, Peter A; Pinto, Dalila; Gujral, Madhusudan; Brandler, William M; Malhotra, Dheeraj; Wang, Zhouzhi; Fajarado, Karin V Fuentes; Maile, Michelle S; Ripke, Stephan; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amin, Farooq; Atkins, Joshua; Bacanu, Silviu A; Belliveau, Richard A; Bergen, Sarah E; Bertalan, Marcelo; Bevilacqua, Elizabeth; Bigdeli, Tim B; Black, Donald W; Bruggeman, Richard; Buccola, Nancy G; Buckner, Randy L; Bulik-Sullivan, Brendan; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J; Campion, Dominique; Cantor, Rita M; Carr, Vaughan J; Carrera, Noa; Catts, Stanley V; Chambert, Kimberley D; Cheng, Wei; Cloninger, C Robert; Cohen, David; Cormican, Paul; Craddock, Nick; Crespo-Facorro, Benedicto; Crowley, James J; Curtis, David; Davidson, Michael; Davis, Kenneth L; Degenhardt, Franziska; Del Favero, Jurgen; DeLisi, Lynn E; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H; Farh, Kai-How; Farrell, Martilias S; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B; Friedman, Joseph I; Forstner, Andreas J; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I; Gratten, Jacob; de Haan, Lieuwe; Hamshere, Marian L; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M; Henskens, Frans A; Herms, Stefan; Hirschhorn, Joel N; Hoffmann, Per; Hofman, Andrea; Huang, Hailiang; Ikeda, Masashi; Joa, Inge; Kähler, Anna K; Kahn, René S; Kalaydjieva, Luba; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C; Kelly, Brian J; Kennedy, James L; Kim, Yunjung; Knowles, James A; Konte, Bettina; Laurent, Claudine; Lee, Phil; Lee, S Hong; Legge, Sophie E; Lerer, Bernard; Levy, Deborah L; Liang, Kung-Yee; Lieberman, Jeffrey; Lönnqvist, Jouko; Loughland, Carmel M; Magnusson, Patrik K E; Maher, Brion S; Maier, Wolfgang; Mallet, Jacques; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W; McDonald, Colm; McIntosh, Andrew M; Meier, Sandra; Meijer, Carin J; Melle, Ingrid; Mesholam-Gately, Raquelle I; Metspalu, Andres; Michie, Patricia T; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W; Müller-Myhsok, Bertram; Murphy, Kieran C; Murray, Robin M; Myin-Germeys, Inez; Nenadic, Igor; Nertney, Deborah A; Nestadt, Gerald; Nicodemus, Kristin K; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; O'Neill, F Anthony; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N; Parkhomenko, Elena; Pato, Michele T; Paunio, Tiina; Perkins, Diana O; Pers, Tune H; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J; Powell, John; Price, Alkes; Pulver, Ann E; Purcell, Shaun M; Quested, Digby; Rasmussen, Henrik B; Reichenberg, Abraham; Reimers, Mark A; Richards, Alexander L; Roffman, Joshua L; Roussos, Panos; Ruderfer, Douglas M; Salomaa, Veikko; Sanders, Alan R; Savitz, Adam; Schall, Ulrich; Schulze, Thomas G; Schwab, Sibylle G; Scolnick, Edward M; Scott, Rodney J; Seidman, Larry J; Shi, Jianxin; Silverman, Jeremy M; Smoller, Jordan W; Söderman, Erik; Spencer, Chris C A; Stahl, Eli A; Strengman, Eric; Strohmaier, Jana; Stroup, T Scott; Suvisaari, Jaana; Svrakic, Dragan M; Szatkiewicz, Jin P; Thirumalai, Srinivas; Tooney, Paul A; Veijola, Juha; Visscher, Peter M; Waddington, John; Walsh, Dermot; Webb, Bradley T; Weiser, Mark; Wildenauer, Dieter B; Williams, Nigel M; Williams, Stephanie; Witt, Stephanie H; Wolen, Aaron R; Wormley, Brandon K; Wray, Naomi R; Wu, Jing Qin; Zai, Clement C; Adolfsson, Rolf; Andreassen, Ole A; Blackwood, Douglas H R; Bramon, Elvira; Buxbaum, Joseph D; Cichon, Sven; Collier, David A; Corvin, Aiden; Daly, Mark J; Darvasi, Ariel; Domenici, Enrico; Esko, Tõnu; Gejman, Pablo V; Gill, Michael; Gurling, Hugh; Hultman, Christina M; Iwata, Nakao; Jablensky, Assen V; Jönsson, Erik G; Kendler, Kenneth S; Kirov, George; Knight, Jo; Levinson, Douglas F; Li, Qingqin S; McCarroll, Steven A; McQuillin, Andrew; Moran, Jennifer L; Mowry, Bryan J; Nöthen, Markus M; Ophoff, Roel A; Owen, Michael J; Palotie, Aarno; Pato, Carlos N; Petryshen, Tracey L; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P; Rujescu, Dan; Sklar, Pamela; St Clair, David; Walters, James T R; Werge, Thomas; Sullivan, Patrick F; O'Donovan, Michael C; Scherer, Stephen W; Neale, Benjamin M; Sebat, Jonathan (2016). Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics 49 (1), 27-35
Published Version
Abstract
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M (Springer Nature, 2016-10-03)Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a ... -
Novel genetic loci associated with hippocampal volume
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M.; van ’t Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N.; Vellas, Bruno; Veltman, Dick J.; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M.; Wassink, Thomas H.; Weale, Michael E.; Weinberger, Daniel R.; Weiner, Michael W.; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y.; Wright, Clinton B.; Zielke, Ronald H.; Zonderman, Alan B.; Martin, Nicholas G.; Van Duijn, Cornelia M.; Wright, Margaret J.; Longstreth, W. T.; Schumann, Gunter; Grabe, Hans J.; Franke, Barbara; Launer, Lenore J.; Medland, Sarah E.; Seshadri, Sudha; Thompson, Paul M.; Ikram, M. Arfan (Springer Nature, 2017-01-18)The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several ...