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Cell. 2018 Jun 14;173(7):1705-1715.e16. doi: 10.1016/j.cell.2018.05.046.

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes.

Collaborators (540)

Ruderfer DM, Ripke S, McQuillin A, Boocock J, Stahl EA, Pavlides JMW, Mullins N, Charney AW, Ori APS, Loohuis LMO, Domenici E, Di Florio A, Papiol S, Kalman JL, Trubetskoy V, Adolfsson R, Agartz I, Agerbo E, Akil H, Albani D, Albus M, Alda M, Alexander M, Alliey-Rodriguez N, Als TD, Amin F, Anjorin A, Arranz MJ, Awasthi S, Bacanu SA, Badner JA, Baekvad-Hansen M, Bakker S, Band G, Barchas JD, Barroso I, Bass N, Bauer M, Baune BT, Begemann M, Bellenguez C, Belliveau RA Jr, Bellivier F, Bender S, Bene J, Bergen SE, Berrettini WH, Bevilacqua E, Biernacka JM, Bigdeli TB, Black DW, Blackburn H, Blackwell JM, Blackwood DHR, Pedersen CB, Boehnke M, Boks M, Borglum AD, Bramon E, Breen G, Brown MA, Bruggeman R, Buccola NG, Buckner RL, Budde M, Bulik-Sullivan B, Bumpstead SJ, Bunney W, Burmeister M, Buxbaum JD, Bybjerg-Grauholm J, Byerley W, Cahn W, Cai G, Cairns MJ, Campion D, Cantor RM, Carr VJ, Carrera N, Casas JP, Casas M, Catts SV, Cervantes P, Chambert KD, Chan RCK, Chen EYH, Chen RYL, Cheng W, Cheung EFC, Chong SA, Clarke TK, Cloninger CR, Cohen D, Cohen N, Coleman JRI, Collier DA, Cormican P, Coryell W, Craddock N, Craig DW, Crespo-Facorro B, Crowley JJ, Cruceanu C, Curtis D, Czerski PM, Dale AM, Daly MJ, Dannlowski U, Darvasi A, Davidson M, Davis KL, de Leeuw CA, Degenhardt F, Del Favero J, DeLisi LE, Deloukas P, Demontis D, DePaulo JR, di Forti M, Dikeos D, Dinan T, Djurovic S, Dobbyn AL, Donnelly P, Donohoe G, Drapeau E, Dronov S, Duan J, Dudbridge F, Duncanson A, Edenberg H, Edkins S, Ehrenreich H, Eichhammer P, Elvsashagen T, Eriksson J, Escott-Price V, Esko T, Essioux L, Etain B, Fan CC, Farh KH, Farrell MS, Flickinger M, Foroud TM, Forty L, Frank J, Franke L, Fraser C, Freedman R, Freeman C, Freimer NB, Friedman JI, Fromer M, Frye MA, Fullerton JM, Gade K, Garnham J, Gaspar HA, Gejman PV, Genovese G, Georgieva L, Giambartolomei C, Giannoulatou E, Giegling I, Gill M, Gillman M, Pedersen MG, Giusti-Rodriguez P, Godard S, Goes F, Goldstein JI, Gopal S, Gordon SD, Gordon-Smith K, Gratten J, Gray E, Green EK, Green MJ, Greenwood TA, Grigoroiu-Serbanescu M, Grove J, Guan W, Gurling H, Parra JG, Gwilliam R, de Haan L, Hall J, Hall MH, Hammer C, Hammond N, Hamshere ML, Hansen M, Hansen T, Haroutunian V, Hartmann AM, Hauser J, Hautzinger M, Heilbronner U, Hellenthal G, Henskens FA, Herms S, Hipolito M, Hirschhorn JN, Hoffmann P, Hollegaard MV, Hougaard DM, Huang H, Huckins L, Hultman CM, Hunt SE, Ikeda M, Iwata N, Iyegbe C, Jablensky AV, Jamain S, Jankowski J, Jayakumar A, Joa I, Jones I, Jones LA, Jonsson EG, Julia A, Jureus A, Kahler AK, Kahn RS, Kalaydjieva L, Kandaswamy R, Karachanak-Yankova S, Karjalainen J, Karlsson R, Kavanagh D, Keller MC, Kelly BJ, Kelsoe J, Kennedy JL, Khrunin A, Kim Y, Kirov G, Kittel-Schneider S, Klovins J, Knight J, Knott SV, Knowles JA, Kogevinas M, Konte B, Kravariti E, Kucinskas V, Kucinskiene ZA, Kupka R, Kuzelova-Ptackova H, Landen M, Langford C, Laurent C, Lawrence J, Lawrie S, Lawson WB, Leber M, Leboyer M, Lee PH, Keong JLC, Legge SE, Lencz T, Lerer B, Levinson DF, Levy SE, Lewis CM, Li JZ, Li M, Li QS, Li T, Liang KY, Liddle J, Lieberman J, Limborska S, Lin K, Linszen DH, Lissowska J, Liu C, Liu J, Lonnqvist J, Loughland CM, Lubinski J, Lucae S, Macek M Jr, MacIntyre DJ, Magnusson PKE, Maher BS, Mahon PB, Maier W, Malhotra AK, Mallet J, Malt UF, Markus HS, Marsal S, Martin NG, Mata I, Mathew CG, Mattheisen M, Mattingsdal M, Mayoral F, McCann OT, McCarley RW, McCarroll SA, McCarthy MI, McDonald C, McElroy SL, McGuffin P, McInnis MG, McIntosh AM, McKay JD, McMahon FJ, Medeiros H, Medland SE, Meier S, Meijer CJ, Melegh B, Melle I, Meng F, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mitchell PB, Mokrab Y, Montgomery GW, Moran JL, Morken G, Morris DW, Mors O, Mortensen PB, Mowry BJ, Mühleisen TW, Müller-Myhsok B, Murphy KC, Murray RM, Myers RM, Myin-Germeys I, Neale BM, Nelis M, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nievergelt CM, Nikitina-Zake L, Nimgaonkar V, Nisenbaum L, Nordentoft M, Nordin A, Nöthen MM, Nwulia EA, O'Callaghan E, O'Donovan C, O'Dushlaine C, O'Neill FA, Oedegaard KJ, Oh SY, Olincy A, Olsen L, Oruc L, Van Os J, Owen MJ, Paciga SA, Palmer CNA, Palotie A, Pantelis C, Papadimitriou GN, Parkhomenko E, Pato C, Pato MT, Paunio T, Pearson R, Perkins DO, Perlis RH, Perry A, Pers TH, Petryshen TL, Pfennig A, Picchioni M, Pietilainen O, Pimm J, Pirinen M, Plomin R, Pocklington AJ, Posthuma D, Potash JB, Potter SC, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Ramos-Quiroga JA, Rasmussen HB, Rautanen A, Ravindrarajah R, Regeer EJ, Reichenberg A, Reif A, Reimers MA, Ribases M, Rice JP, Richards AL, Ricketts M, Riley BP, Rivas F, Rivera M, Roffman JL, Rouleau GA, Roussos P, Rujescu D, Salomaa V, Sanchez-Mora C, Sanders AR, Sawcer SJ, Schall U, Schatzberg AF, Scheftner WA, Schofield PR, Schork NJ, Schwab SG, Scolnick EM, Scott LJ, Scott RJ, Seidman LJ, Serretti A, Sham PC, Weickert CS, Shehktman T, Shi J, Shilling PD, Sigurdsson E, Silverman JM, Sim K, Slaney C, Slominsky P, Smeland OB, Smoller JW, So HC, Sobell JL, Soderman E, Hansen CS, Spencer CCA, Spijker AT, St Clair D, Stefansson H, Stefansson K, Steinberg S, Stogmann E, Stordal E, Strange A, Straub RE, Strauss JS, Streit F, Strengman E, Strohmaier J, Stroup TS, Su Z, Subramaniam M, Suvisaari J, Svrakic DM, Szatkiewicz JP, Szelinger S, Tashakkori-Ghanbaria A, Thirumalai S, Thompson RC, Thorgeirsson TE, Toncheva D, Tooney PA, Tosato S, Toulopoulou T, Trembath RC, Treutlein J, Trubetskoy V, Turecki G, Vaaler AE, Vedder H, Vieta E, Vincent J, Visscher PM, Viswanathan AC, Vukcevic D, Waddington J, Waller M, Walsh D, Walshe M, Walters JTR, Wang D, Wang Q, Wang W, Wang Y, Watson SJ, Webb BT, Weickert TW, Weinberger DR, Weisbrod M, Weiser M, Werge T, Weston P, Whittaker P, Widaa S, Wiersma D, Wildenauer DB, Williams NM, Williams S, Witt SH, Wolen AR, Wong EHM, Wood NW, Wormley BK, Wu JQ, Xi S, Xu W, Young AH, Zai CC, Zandi P, Zhang P, Zheng X, Zimprich F, Zollner S, Corvin A, Fanous AH, Cichon S, Rietschel M, Gershon ES, Schulze TG, Cuellar-Barboza AB, Forstner AJ, Holmans PA, Nurnberger JI, Andreassen OA, Lee SH, O'Donovan MC, Sullivan PF, Ophoff RA, Wray NR, Sklar P, Kendler KS.

Abstract

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

KEYWORDS:

bipolar disorder; polygenic risk; psychosis; schizophrenia; subphenotypes

PMID:
29906448
DOI:
10.1016/j.cell.2018.05.046

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