Abstract
Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10-6) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10-6) and manic symptoms (BD, p=2×10-5), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10-10, BD p=5.3×10-5) and age of onset (SCZ p=7.9×10-4). Finally, we show that psychotic features in BD has significant SNP-heritability (h2snp=0.15, SE=0.06), and a significant genetic correlation with SCZ (rg=0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.
| Original language | English (US) |
|---|---|
| Journal | Unknown Journal |
| DOIs | |
| State | Published - Aug 8 2017 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Neuroscience(all)
- Pharmacology, Toxicology and Pharmaceutics(all)
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Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes. / Ruderfer, Douglas M.; Ripke, Stephan; McQuillin, Andrew; Boocock, James; Stahl, Eli A.; Pavlides, Jennifer M.Whitehead; Mullins, Niamh; Charney, Alexander W.; Ori, Anil P.S.; Loohuis, Loes M.Olde; Domenici, Enrico; Di Florio, Arianna; Papiol, Sergi; Kalman, Janos L.; Adolfsson, Rolf; Agartz, Ingrid; Agerbo, Esben; Akil, Huda; Albani, Diego; Albus, Margot; Alda, Martin; Alexander, Madeline; Allardyce, Judith; Alliey-Rodriguez, Ney; Als, Thomas D.; Amin, Farooq; Anjorin, Adebayo; Arranz, Maria J.; Awasthi, Swapnil; Bacanu, Silviu A.; Badner, Judith A.; Baekvad-Hansen, Marie; Bakker, Steven; Band, Gavin; Barchas, Jack D.; Barroso, Ines; Bass, Nicholas; Bauer, Michael; Baune, Bernhard T.; Begemann, Martin; Bellenguez, Celine; Belliveau, Richard A.; Bellivier, Frank; Bender, Stephan; Bene, Judit; Bergen, Sarah E.; Berrettini, Wade H.; Bevilacqua, Elizabeth; Biernacka, Joanna M.; Bigdeli, Tim B.; Black, Donald W.; Blackburn, Hannah; Blackwell, Jenefer M.; Blackwood, Douglas H.R.; Pedersen, Carsten Bocker; Boehnke, Michael; Boks, Marco; Borglum, Anders D.; Bramon, Elvira; Breen, Gerome; Brown, Matthew A.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Budde, Monika; Bulik-Sullivan, Brendan; Bumpstead, Suzannah J.; Bunney, William; Burmeister, Margit; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Casas, Juan P.; Casas, Miquel; Catts, Stanley V.; Cervantes, Pablo; Chambert, Kimberley D.; Chan, Raymond C.K.; Chen, Eric Y.H.; Chen, Ronald Y.L.; Cheng, Wei; Cheung, Eric F.C.; Chong, Siow Ann; Clarke, Toni Kim; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Coleman, Jonathan R.I.; Collier, David A.; Cormican, Paul; Coryell, William; Craddock, Nicholas; Craig, David W.; Crespo-Facorro, Benedicto; Crowley, James J.; Cruceanu, Cristiana; Curtis, David; Czerski, Piotr M.; Dale, Anders M.; Daly, Mark J.; Dannlowski, Udo; Darvasi, Ariel; Davidson, Michael; Davis, Kenneth L.; de Leeuw, Christiaan A.; Degenhardt, Franziska; Favero, Jurgen Del; DeLisi, Lynn E.; Deloukas, Panos; Demontis, Ditte; Raymond DePaulo, J.; di Forti, Marta; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Dobbyn, Amanda L.; Donnelly, Peter; Donohoe, Gary; Drapeau, Elodie; Dronov, Serge; Duan, Jubao; Dudbridge, Frank; Duncanson, Audrey; Edenberg, Howard; Edkins, Sarah; Ehrenreich, Hannelore; Eichhammer, Peter; Elvsashagen, Torbjorn; Eriksson, Johan; Escott-Price, Valentina; Esko, Tonu; Essioux, Laurent; Etain, Bruno; Fan, Chun Chieh; Farh, Kai How; Farrell, Martilias S.; Flickinger, Matthew; Foroud, Tatiana M.; Forty, Liz; Frank, Josef; Franke, Lude; Fraser, Christine; Freedman, Robert; Freeman, Colin; Freimer, Nelson B.; Friedman, Joseph I.; Fromer, Menachem; Frye, Mark A.; Fullerton, Janice M.; Gade, Katrin; Garnham, Julie; Gaspar, Helena A.; Gejman, Pablo V.; Genovese, Giulio; Georgieva, Lyudmila; Giambartolomei, Claudia; Giannoulatou, Eleni; Giegling, Ina; Gill, Michael; Gillman, Matthew; Pedersen, Marianne Giortz; Giusti-Rodriguez, Paola; Godard, Stephanie; Goes, Fernando; Goldstein, Jacqueline I.; Gopal, Srihari; Gordon, Scott D.; Gordon-Smith, Katherine; Gratten, Jacob; Gray, Emma; Green, Elaine K.; Green, Melissa J.; Greenwood, Tiffany A.; Grigoroiu-Serbanescu, Maria; Grove, Jakob; Guan, Weihua; Gurling, Hugh; Parra, Jose Guzman; Gwilliam, Rhian; de Haan, Lieuwe; Hall, Jeremy; Hall, Mei Hua; Hammer, Christian; Hammond, Naomi; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Hauser, Joanna; Hautzinger, Martin; Heilbronner, Urs; Hellenthal, Garrett; Henskens, Frans A.; Herms, Stefan; Hipolito, Maria; Hirschhorn, Joel N.; Hoffmann, Per; Hollegaard, Mads V.; Hougaard, David M.; Huang, Hailiang; Huckins, Laura; Hultman, Christina M.; Hunt, Sarah E.; Ikeda, Masashi; Iwata, Nakao; Iyegbe, Conrad; Jablensky, Assen V.; Jamain, Stephane; Jankowski, Janusz; Jayakumar, Alagurevathi; Joa, Inge; Jones, Ian; Jones, Lisa A.; Jonsson, Erik G.; Julia, Antonio; Jureus, Anders; Kahler, Anna K.; Kahn, Rene S.; Kalaydjieva, Luba; Kandaswamy, Radhika; Karachanak-Yankova, Sena; Karjalainen, Juha; Karlsson, Robert; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kelsoe, John; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Kirov, George; Kittel-Schneider, Sarah; Klovins, Janis; Knight, Jo; Knott, Sarah V.; Knowles, James A.; Kogevinas, Manolis; Konte, Bettina; Kravariti, Eugenia; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kupka, Ralph; Kuzelova-Ptackova, Hana; Landen, Mikael; Langford, Cordelia; Laurent, Claudine; Lawrence, Jacob; Lawrie, Stephen; Lawson, William B.; Leber, Markus; Leboyer, Marion; Lee, Phil H.; Keong, Jimmy Lee Chee; Legge, Sophie E.; Lencz, Todd; Lerer, Bernard; Levinson, Douglas F.; Levy, Shawn E.; Lewis, Cathryn M.; Li, Jun Z.; Li, Miaoxin; Li, Qingqin S.; Li, Tao; Liang, Kung-Yee; Liddle, Jennifer; Lieberman, Jeffrey; Limborska, Svetlana; Lin, Kuang; Linszen, Don H.; Lissowska, Jolanta; Liu, Chunyu; Liu, Jianjun; Lonnqvist, Jouko; Loughland, Carmel M.; Lubinski, Jan; Lucae, Susanne; Macek, Milan; MacIntyre, Donald J.; Magnusson, Patrik K.E.; Maher, Brion S.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mallet, Jacques; Malt, Ulrik F.; Markus, Hugh S.; Marsal, Sara; Martin, Nicholas G.; Mata, Ignacio; Mathew, Christopher G.; Mattheisen, Manuel; Mattingsdal, Morten; Mayoral, Fermin; McCann, Owen T.; McCarley, Robert W.; McCarroll, Steven A.; McCarthy, Mark I.; McDonald, Colm; McElroy, Susan L.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew M.; McKay, James D.; McMahon, Francis J.; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Meng, Fan; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mitchell, Philip B.; Mokrab, Younes; Montgomery, Grant W.; Moran, Jennifer L.; Morken, Gunnar; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Mowry, Bryan J.; Mühleisen, Thomas W.; Müller-Myhsok, Bertram; Murphy, Kieran C.; Murray, Robin M.; Myers, Richard M.; Myin-Germeys, Inez; Neale, Benjamin M.; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nievergelt, Caroline M.; Nikitina-Zake, Liene; Nimgaonkar, Vishwajit; Nisenbaum, Laura; Nordentoft, Merete; Nordin, Annelie; Nöthen, Markus M.; Nwulia, Evaristus A.; O'Callaghan, Eadbhard; O'Donovan, Claire; O'Dushlaine, Colm; Anthony O'Neill, F.; Oedegaard, Ketil J.; Oh, Sang Yun; Olincy, Ann; Olsen, Line; Oruc, Lilijana; Os, Jim Van; Owen, Michael J.; Paciga, Sara A.; Palmer, Colin N.A.; Palotie, Aarno; Pantelis, Christos; Papadimitriou, George N.; Parkhomenko, Elena; Pato, Carlos; Pato, Michele T.; Paunio, Tiina; Pearson, Richard; Perkins, Diana O.; Perlis, Roy H.; Perry, Amy; Pers, Tune H.; Petryshen, Tracey L.; Pfennig, Andrea; Picchioni, Marco; Pietilainen, Olli; Pimm, Jonathan; Pirinen, Matti; Plomin, Robert; Pocklington, Andrew J.; Posthuma, Danielle; Potash, James B.; Potter, Simon C.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Rautanen, Anna; Ravindrarajah, Radhi; Regeer, Eline J.; Reichenberg, Abraham; Reif, Andreas; Reimers, Mark A.; Ribases, Marta; Rice, John P.; Richards, Alexander L.; Ricketts, Michelle; Riley, Brien P.; Rivas, Fabio; Rivera, Margarita; Roffman, Joshua L.; Rouleau, Guy A.; Roussos, Panos; Rujescu, Dan; Salomaa, Veikko; Sanchez-Mora, Cristina; Sanders, Alan R.; Sawcer, Stephen J.; Schall, Ulrich; Schatzberg, Alan F.; Scheftner, William A.; Schofield, Peter R.; Schork, Nicholas J.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Laura J.; Scott, Rodney J.; Seidman, Larry J.; Serretti, Alessandro; Sham, Pak C.; Weickert, Cynthia Shannon; Shehktman, Tatyana; Shi, Jianxin; Shilling, Paul D.; Sigurdsson, Engilbert; Silverman, Jeremy M.; Sim, Kang; Slaney, Claire; Slominsky, Petr; Smeland, Olav B.; Smoller, Jordan W.; So, Hon Cheong; Sobell, Janet L.; Soderman, Erik; Hansen, Christine Soholm; Spencer, Chris C.A.; Spijker, Anne T.; St Clair, David; Stefansson, Hreinn; Stefansson, Kari; Steinberg, Stacy; Stogmann, Elisabeth; Stordal, Eystein; Strange, Amy; Straub, Richard E.; Strauss, John S.; Streit, Fabian; Strengman, Eric; Strohmaier, Jana; Scott Stroup, T.; Su, Zhan; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Szelinger, Szabolcs; Tashakkori-Ghanbaria, Avazeh; Thirumalai, Srinivas; Thompson, Robert C.; Thorgeirsson, Thorgeir E.; Toncheva, Draga; Tooney, Paul A.; Tosato, Sarah; Toulopoulou, Timothea; Trembath, Richard C.; Treutlein, Jens; Trubetskoy, Vassily; Turecki, Gustavo; Vaaler, Arne E.; Vedder, Helmut; Vieta, Eduard; Vincent, John; Visscher, Peter M.; Viswanathan, Ananth C.; Vukcevic, Damjan; Waddington, John; Waller, Matthew; Walsh, Dermot; Walshe, Muriel; Walters, James T.R.; Wang, Dai; Wang, Qiang; Wang, Weiqing; Wang, Yunpeng; Watson, Stanley J.; Webb, Bradley T.; Weickert, Thomas W.; Weinberger, Daniel R.; Weisbrod, Matthias; Weiser, Mark; Werge, Thomas; Weston, Paul; Whittaker, Pamela; Widaa, Sara; Wiersma, Durk; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H.M.; Wood, Nicholas W.; Wormley, Brandon K.; Wu, Jing Qin; Xi, Simon; Xu, Wei; Young, Allan H.; Zai, Clement C.; Zandi, Peter; Zhang, Peng; Zheng, Xuebin; Zimprich, Fritz; Zollner, Sebastian; Corvin, Aiden; Fanous, Ayman H.; Cichon, Sven; Rietschel, Marcella; Gershon, Elliot S.; Schulze, Thomas G.; Cuellar-Barboza, Alfredo B.; Forstner, Andreas J.; Holmans, Peter A.; Nurnberger, John I.; Andreassen, Ole A.; Hong Lee, S.; O'Donovan, Michael C.; Sullivan, Patrick F.; Ophoff, Roel A.; Wray, Naomi R.; Sklar, Pamela; Kendler, Kenneth S.
In: Unknown Journal, 08.08.2017.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes
AU - Ruderfer, Douglas M.
AU - Ripke, Stephan
AU - McQuillin, Andrew
AU - Boocock, James
AU - Stahl, Eli A.
AU - Pavlides, Jennifer M.Whitehead
AU - Mullins, Niamh
AU - Charney, Alexander W.
AU - Ori, Anil P.S.
AU - Loohuis, Loes M.Olde
AU - Domenici, Enrico
AU - Di Florio, Arianna
AU - Papiol, Sergi
AU - Kalman, Janos L.
AU - Adolfsson, Rolf
AU - Agartz, Ingrid
AU - Agerbo, Esben
AU - Akil, Huda
AU - Albani, Diego
AU - Albus, Margot
AU - Alda, Martin
AU - Alexander, Madeline
AU - Allardyce, Judith
AU - Alliey-Rodriguez, Ney
AU - Als, Thomas D.
AU - Amin, Farooq
AU - Anjorin, Adebayo
AU - Arranz, Maria J.
AU - Awasthi, Swapnil
AU - Bacanu, Silviu A.
AU - Badner, Judith A.
AU - Baekvad-Hansen, Marie
AU - Bakker, Steven
AU - Band, Gavin
AU - Barchas, Jack D.
AU - Barroso, Ines
AU - Bass, Nicholas
AU - Bauer, Michael
AU - Baune, Bernhard T.
AU - Begemann, Martin
AU - Bellenguez, Celine
AU - Belliveau, Richard A.
AU - Bellivier, Frank
AU - Bender, Stephan
AU - Bene, Judit
AU - Bergen, Sarah E.
AU - Berrettini, Wade H.
AU - Bevilacqua, Elizabeth
AU - Biernacka, Joanna M.
AU - Bigdeli, Tim B.
AU - Black, Donald W.
AU - Blackburn, Hannah
AU - Blackwell, Jenefer M.
AU - Blackwood, Douglas H.R.
AU - Pedersen, Carsten Bocker
AU - Boehnke, Michael
AU - Boks, Marco
AU - Borglum, Anders D.
AU - Bramon, Elvira
AU - Breen, Gerome
AU - Brown, Matthew A.
AU - Bruggeman, Richard
AU - Buccola, Nancy G.
AU - Buckner, Randy L.
AU - Budde, Monika
AU - Bulik-Sullivan, Brendan
AU - Bumpstead, Suzannah J.
AU - Bunney, William
AU - Burmeister, Margit
AU - Buxbaum, Joseph D.
AU - Bybjerg-Grauholm, Jonas
AU - Byerley, William
AU - Cahn, Wiepke
AU - Cai, Guiqing
AU - Cairns, Murray J.
AU - Campion, Dominique
AU - Cantor, Rita M.
AU - Carr, Vaughan J.
AU - Carrera, Noa
AU - Casas, Juan P.
AU - Casas, Miquel
AU - Catts, Stanley V.
AU - Cervantes, Pablo
AU - Chambert, Kimberley D.
AU - Chan, Raymond C.K.
AU - Chen, Eric Y.H.
AU - Chen, Ronald Y.L.
AU - Cheng, Wei
AU - Cheung, Eric F.C.
AU - Chong, Siow Ann
AU - Clarke, Toni Kim
AU - Cloninger, C. Robert
AU - Cohen, David
AU - Cohen, Nadine
AU - Coleman, Jonathan R.I.
AU - Collier, David A.
AU - Cormican, Paul
AU - Coryell, William
AU - Craddock, Nicholas
AU - Craig, David W.
AU - Crespo-Facorro, Benedicto
AU - Crowley, James J.
AU - Cruceanu, Cristiana
AU - Curtis, David
AU - Czerski, Piotr M.
AU - Dale, Anders M.
AU - Daly, Mark J.
AU - Dannlowski, Udo
AU - Darvasi, Ariel
AU - Davidson, Michael
AU - Davis, Kenneth L.
AU - de Leeuw, Christiaan A.
AU - Degenhardt, Franziska
AU - Favero, Jurgen Del
AU - DeLisi, Lynn E.
AU - Deloukas, Panos
AU - Demontis, Ditte
AU - Raymond DePaulo, J.
AU - di Forti, Marta
AU - Dikeos, Dimitris
AU - Dinan, Timothy
AU - Djurovic, Srdjan
AU - Dobbyn, Amanda L.
AU - Donnelly, Peter
AU - Donohoe, Gary
AU - Drapeau, Elodie
AU - Dronov, Serge
AU - Duan, Jubao
AU - Dudbridge, Frank
AU - Duncanson, Audrey
AU - Edenberg, Howard
AU - Edkins, Sarah
AU - Ehrenreich, Hannelore
AU - Eichhammer, Peter
AU - Elvsashagen, Torbjorn
AU - Eriksson, Johan
AU - Escott-Price, Valentina
AU - Esko, Tonu
AU - Essioux, Laurent
AU - Etain, Bruno
AU - Fan, Chun Chieh
AU - Farh, Kai How
AU - Farrell, Martilias S.
AU - Flickinger, Matthew
AU - Foroud, Tatiana M.
AU - Forty, Liz
AU - Frank, Josef
AU - Franke, Lude
AU - Fraser, Christine
AU - Freedman, Robert
AU - Freeman, Colin
AU - Freimer, Nelson B.
AU - Friedman, Joseph I.
AU - Fromer, Menachem
AU - Frye, Mark A.
AU - Fullerton, Janice M.
AU - Gade, Katrin
AU - Garnham, Julie
AU - Gaspar, Helena A.
AU - Gejman, Pablo V.
AU - Genovese, Giulio
AU - Georgieva, Lyudmila
AU - Giambartolomei, Claudia
AU - Giannoulatou, Eleni
AU - Giegling, Ina
AU - Gill, Michael
AU - Gillman, Matthew
AU - Pedersen, Marianne Giortz
AU - Giusti-Rodriguez, Paola
AU - Godard, Stephanie
AU - Goes, Fernando
AU - Goldstein, Jacqueline I.
AU - Gopal, Srihari
AU - Gordon, Scott D.
AU - Gordon-Smith, Katherine
AU - Gratten, Jacob
AU - Gray, Emma
AU - Green, Elaine K.
AU - Green, Melissa J.
AU - Greenwood, Tiffany A.
AU - Grigoroiu-Serbanescu, Maria
AU - Grove, Jakob
AU - Guan, Weihua
AU - Gurling, Hugh
AU - Parra, Jose Guzman
AU - Gwilliam, Rhian
AU - de Haan, Lieuwe
AU - Hall, Jeremy
AU - Hall, Mei Hua
AU - Hammer, Christian
AU - Hammond, Naomi
AU - Hamshere, Marian L.
AU - Hansen, Mark
AU - Hansen, Thomas
AU - Haroutunian, Vahram
AU - Hartmann, Annette M.
AU - Hauser, Joanna
AU - Hautzinger, Martin
AU - Heilbronner, Urs
AU - Hellenthal, Garrett
AU - Henskens, Frans A.
AU - Herms, Stefan
AU - Hipolito, Maria
AU - Hirschhorn, Joel N.
AU - Hoffmann, Per
AU - Hollegaard, Mads V.
AU - Hougaard, David M.
AU - Huang, Hailiang
AU - Huckins, Laura
AU - Hultman, Christina M.
AU - Hunt, Sarah E.
AU - Ikeda, Masashi
AU - Iwata, Nakao
AU - Iyegbe, Conrad
AU - Jablensky, Assen V.
AU - Jamain, Stephane
AU - Jankowski, Janusz
AU - Jayakumar, Alagurevathi
AU - Joa, Inge
AU - Jones, Ian
AU - Jones, Lisa A.
AU - Jonsson, Erik G.
AU - Julia, Antonio
AU - Jureus, Anders
AU - Kahler, Anna K.
AU - Kahn, Rene S.
AU - Kalaydjieva, Luba
AU - Kandaswamy, Radhika
AU - Karachanak-Yankova, Sena
AU - Karjalainen, Juha
AU - Karlsson, Robert
AU - Kavanagh, David
AU - Keller, Matthew C.
AU - Kelly, Brian J.
AU - Kelsoe, John
AU - Kennedy, James L.
AU - Khrunin, Andrey
AU - Kim, Yunjung
AU - Kirov, George
AU - Kittel-Schneider, Sarah
AU - Klovins, Janis
AU - Knight, Jo
AU - Knott, Sarah V.
AU - Knowles, James A.
AU - Kogevinas, Manolis
AU - Konte, Bettina
AU - Kravariti, Eugenia
AU - Kucinskas, Vaidutis
AU - Kucinskiene, Zita Ausrele
AU - Kupka, Ralph
AU - Kuzelova-Ptackova, Hana
AU - Landen, Mikael
AU - Langford, Cordelia
AU - Laurent, Claudine
AU - Lawrence, Jacob
AU - Lawrie, Stephen
AU - Lawson, William B.
AU - Leber, Markus
AU - Leboyer, Marion
AU - Lee, Phil H.
AU - Keong, Jimmy Lee Chee
AU - Legge, Sophie E.
AU - Lencz, Todd
AU - Lerer, Bernard
AU - Levinson, Douglas F.
AU - Levy, Shawn E.
AU - Lewis, Cathryn M.
AU - Li, Jun Z.
AU - Li, Miaoxin
AU - Li, Qingqin S.
AU - Li, Tao
AU - Liang, Kung-Yee
AU - Liddle, Jennifer
AU - Lieberman, Jeffrey
AU - Limborska, Svetlana
AU - Lin, Kuang
AU - Linszen, Don H.
AU - Lissowska, Jolanta
AU - Liu, Chunyu
AU - Liu, Jianjun
AU - Lonnqvist, Jouko
AU - Loughland, Carmel M.
AU - Lubinski, Jan
AU - Lucae, Susanne
AU - Macek, Milan
AU - MacIntyre, Donald J.
AU - Magnusson, Patrik K.E.
AU - Maher, Brion S.
AU - Mahon, Pamela B.
AU - Maier, Wolfgang
AU - Malhotra, Anil K.
AU - Mallet, Jacques
AU - Malt, Ulrik F.
AU - Markus, Hugh S.
AU - Marsal, Sara
AU - Martin, Nicholas G.
AU - Mata, Ignacio
AU - Mathew, Christopher G.
AU - Mattheisen, Manuel
AU - Mattingsdal, Morten
AU - Mayoral, Fermin
AU - McCann, Owen T.
AU - McCarley, Robert W.
AU - McCarroll, Steven A.
AU - McCarthy, Mark I.
AU - McDonald, Colm
AU - McElroy, Susan L.
AU - McGuffin, Peter
AU - McInnis, Melvin G.
AU - McIntosh, Andrew M.
AU - McKay, James D.
AU - McMahon, Francis J.
AU - Medeiros, Helena
AU - Medland, Sarah E.
AU - Meier, Sandra
AU - Meijer, Carin J.
AU - Melegh, Bela
AU - Melle, Ingrid
AU - Meng, Fan
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T.
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mitchell, Philip B.
AU - Mokrab, Younes
AU - Montgomery, Grant W.
AU - Moran, Jennifer L.
AU - Morken, Gunnar
AU - Morris, Derek W.
AU - Mors, Ole
AU - Mortensen, Preben B.
AU - Mowry, Bryan J.
AU - Mühleisen, Thomas W.
AU - Müller-Myhsok, Bertram
AU - Murphy, Kieran C.
AU - Murray, Robin M.
AU - Myers, Richard M.
AU - Myin-Germeys, Inez
AU - Neale, Benjamin M.
AU - Nelis, Mari
AU - Nenadic, Igor
AU - Nertney, Deborah A.
AU - Nestadt, Gerald
AU - Nicodemus, Kristin K.
AU - Nievergelt, Caroline M.
AU - Nikitina-Zake, Liene
AU - Nimgaonkar, Vishwajit
AU - Nisenbaum, Laura
AU - Nordentoft, Merete
AU - Nordin, Annelie
AU - Nöthen, Markus M.
AU - Nwulia, Evaristus A.
AU - O'Callaghan, Eadbhard
AU - O'Donovan, Claire
AU - O'Dushlaine, Colm
AU - Anthony O'Neill, F.
AU - Oedegaard, Ketil J.
AU - Oh, Sang Yun
AU - Olincy, Ann
AU - Olsen, Line
AU - Oruc, Lilijana
AU - Os, Jim Van
AU - Owen, Michael J.
AU - Paciga, Sara A.
AU - Palmer, Colin N.A.
AU - Palotie, Aarno
AU - Pantelis, Christos
AU - Papadimitriou, George N.
AU - Parkhomenko, Elena
AU - Pato, Carlos
AU - Pato, Michele T.
AU - Paunio, Tiina
AU - Pearson, Richard
AU - Perkins, Diana O.
AU - Perlis, Roy H.
AU - Perry, Amy
AU - Pers, Tune H.
AU - Petryshen, Tracey L.
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N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2017/8/8
Y1 - 2017/8/8
N2 - Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10-6) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10-6) and manic symptoms (BD, p=2×10-5), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10-10, BD p=5.3×10-5) and age of onset (SCZ p=7.9×10-4). Finally, we show that psychotic features in BD has significant SNP-heritability (h2snp=0.15, SE=0.06), and a significant genetic correlation with SCZ (rg=0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.
AB - Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10-6) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10-6) and manic symptoms (BD, p=2×10-5), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10-10, BD p=5.3×10-5) and age of onset (SCZ p=7.9×10-4). Finally, we show that psychotic features in BD has significant SNP-heritability (h2snp=0.15, SE=0.06), and a significant genetic correlation with SCZ (rg=0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.
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U2 - 10.1101/173435
DO - 10.1101/173435
M3 - Article
AN - SCOPUS:85095629710
JO - Advances in Water Resources
JF - Advances in Water Resources
SN - 0309-1708
ER -