Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes
Authors: 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 HR , 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 CK , Chen Eric YH , Chen Ronald YL , Cheng Wei , Cheung Eric FC , 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 , DePaulo J Raymond , 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 KE , 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 , Mclnnis 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 , Colm O’Dushlaine , O’Neill F Anthony , 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 ,   Psychosis Endophenotypes International Consortium, 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 , Clair David St , Stefansson Hreinn , Stefansson Kari , Steinberg Stacy , Stogmann Elisabeth , Stordal Eystein , Strange Amy , Straub Richard E , Strauss John S , Streit Fabian , Strengman Eric , Strohmaier Jana , Stroup T Scott , 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 TR , 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 HM , Wood Nicholas W , Wormley Brandon K ,   Wellcome Trust Case-Control Consortium, 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 , Lee S Hong , O’Donovan Michael C , Sullivan Patrick F , Ophoff Roel A , Wray Naomi R , Sklar Pamela , Kendler Kenneth S 
Published: August 2017

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,DCAKDandGATAD2A) 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.