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Cell. 2019 Dec 12;179(7):1469-1482.e11. doi: 10.1016/j.cell.2019.11.020.

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders.

Collaborators (606)

Lee PH, Anttila V, Won H, Feng YA, Rosenthal J, Zhu Z, Tucker-Drob EM, Nivard MG, Grotzinger AD, Posthuma D, Wang MM, Yu D, Stahl EA, Walters RK, Anney RJL, Duncan LE, Ge T, Adolfsson R, Banaschewski T, Belangero S, Cook EH, Coppola G, Derks EM, Hoekstra PJ, Kaprio J, Keski-Rahkonen A, Kirov G, Kranzler HR, Luykx JJ, Rohde LA, Zai CC, Agerbo E, Arranz MJ, Asherson P, Bækvad-Hansen M, Baldursson G, Bellgrove M, Belliveau RA Jr, Buitelaar J, Burton CL, Bybjerg-Grauholm J, Casas M, Cerrato F, Chambert K, Churchhouse C, Cormand B, Crosbie J, Dalsgaard S, Demontis D, Doyle AE, Dumont A, Elia J, Grove J, Gudmundsson OO, Haavik J, Hakonarson H, Hansen CS, Hartman CA, Hawi Z, Hervás A, Hougaard DM, Howrigan DP, Huang H, Kuntsi J, Langley K, Lesch KP, Leung PWL, Loo SK, Martin J, Martin AR, McGough JJ, Medland SE, Moran JL, Mors O, Mortensen PB, Oades RD, Palmer DS, Pedersen CB, Pedersen MG, Peters T, Poterba T, Poulsen JB, Ramos-Quiroga JA, Reif A, Ribasés M, Rothenberger A, Rovira P, Sánchez-Mora C, Satterstrom FK, Schachar R, Artigas MS, Steinberg S, Stefansson H, Turley P, Walters GB, Werge T, Zayats T, Arking DE, Bettella F, Buxbaum JD, Christensen JH, Collins RL, Coon H, De Rubeis S, Delorme R, Grice DE, Hansen TF, Holmans PA, Hope S, Hultman CM, Klei L, Ladd-Acosta C, Magnusson P, Nærland T, Nyegaard M, Pinto D, Qvist P, Rehnström K, Reichenberg A, Reichert J, Roeder K, Rouleau GA, Saemundsen E, Sanders SJ, Sandin S, St Pourcain B, Stefansson K, Sutcliffe JS, Talkowski ME, Weiss LA, Willsey AJ, Agartz I, Akil H, Albani D, Alda M, Als TD, Anjorin A, Backlund L, Bass N, Bauer M, Baune BT, Bellivier F, Bergen SE, Berrettini WH, Biernacka JM, Blackwood DHR, Bøen E, Budde M, Bunney W, Burmeister M, Byerley W, Byrne EM, Cichon S, Clarke TK, Coleman JRI, Craddock N, Curtis D, Czerski PM, Dale AM, Dalkner N, Dannlowski U, Degenhardt F, Di Florio A, Elvsåshagen T, Etain B, Fischer SB, Forstner AJ, Forty L, Frank J, Frye M, Fullerton JM, Gade K, Gaspar HA, Gershon ES, Gill M, Goes FS, Gordon SD, Gordon-Smith K, Green MJ, Greenwood TA, Grigoroiu-Serbanescu M, Guzman-Parra J, Hauser J, Hautzinger M, Heilbronner U, Herms S, Hoffmann P, Holland D, Jamain S, Jones I, Jones LA, Kandaswamy R, Kelsoe JR, Kennedy JL, Joachim OK, Kittel-Schneider S, Kogevinas M, Koller AC, Lavebratt C, Lewis CM, Li QS, Lissowska J, Loohuis LMO, Lucae S, Maaser A, Malt UF, Martin NG, Martinsson L, McElroy SL, McMahon FJ, McQuillin A, Melle I, Metspalu A, Millischer V, Mitchell PB, Montgomery GW, Morken G, Morris DW, Müller-Myhsok B, Mullins N, Myers RM, Nievergelt CM, Nordentoft M, Adolfsson AN, Nöthen MM, Ophoff RA, Owen MJ, Paciga SA, Pato CN, Pato MT, Perlis RH, Perry A, Potash JB, Reinbold CS, Rietschel M, Rivera M, Roberson M, Schalling M, Schofield PR, Schulze TG, Scott LJ, Serretti A, Sigurdsson E, Smeland OB, Stordal E, Streit F, Strohmaier J, Thorgeirsson TE, Treutlein J, Turecki G, Vaaler AE, Vieta E, Vincent JB, Wang Y, Witt SH, Zandi P, Adan RAH, Alfredsson L, Ando T, Aschauer H, Baker JH, Bencko V, Bergen AW, Birgegård A, Perica VB, Brandt H, Burghardt R, Carlberg L, Cassina M, Clementi M, Courtet P, Crawford S, Crow S, Crowley JJ, Danner UN, Davis OSP, Degortes D, DeSocio JE, Dick DM, Dina C, Docampo E, Egberts K, Ehrlich S, Espeseth T, Fernández-Aranda F, Fichter MM, Foretova L, Forzan M, Gambaro G, Giegling I, Gonidakis F, Gorwood P, Mayora MG, Guo Y, Halmi KA, Hatzikotoulas K, Hebebrand J, Helder SG, Herpertz-Dahlmann B, Herzog W, Hinney A, Imgart H, Jiménez-Murcia S, Johnson C, Jordan J, Julià A, Kaminská D, Karhunen L, Karwautz A, Kas MJH, Kaye WH, Kennedy MA, Kim YR, Klareskog L, Klump KL, Knudsen GPS, Landén M, Le Hellard S, Levitan RD, Li D, Lichtenstein P, Maj M, Marsal S, McDevitt S, Mitchell J, Monteleone P, Monteleone AM, Munn-Chernoff MA, Nacmias B, Navratilova M, O'Toole JK, Padyukov L, Pantel J, Papezova H, Rabionet R, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Roberts M, Rujescu D, Rybakowski F, Scherag A, Schmidt U, Seitz J, Slachtova L, Slof-Op't Landt MCT, Slopien A, Sorbi S, Southam L, Strober M, Tortorella A, Tozzi F, Treasure J, Tziouvas K, van Elburg AA, Wade TD, Wagner G, Walton E, Watson HJ, Wichmann HE, Woodside DB, Zeggini E, Zerwas S, Zipfel S, Adams MJ, Andlauer TFM, Berger K, Binder EB, Boomsma DI, Castelao E, Colodro-Conde L, Direk N, Docherty AR, Domenici E, Domschke K, Dunn EC, Foo JC, de Geus EJC, Grabe HJ, Hamilton SP, Horn C, Hottenga JJ, Howard D, Ising M, Kloiber S, Levinson DF, Lewis G, Magnusson PKE, Mbarek H, Middeldorp CM, Mostafavi S, Nyholt DR, Penninx BW, Peterson RE, Pistis G, Porteous DJ, Preisig M, Quiroz JA, Schaefer C, Schulte EC, Shi J, Smith DJ, Thomson PA, Tiemeier H, Uher R, van der Auwera S, Weissman MM, Alexander M, Begemann M, Bramon E, Buccola NG, Cairns MJ, Campion D, Carr VJ, Cloninger CR, Cohen D, Collier DA, Corvin A, DeLisi LE, Donohoe G, Dudbridge F, Duan J, Freedman R, Gejman PV, Golimbet V, Godard S, Ehrenreich H, Hartmann AM, Henskens FA, Ikeda M, Iwata N, Jablensky AV, Joa I, Jönsson EG, Kelly BJ, Knight J, Konte B, Laurent-Levinson C, Lee J, Lencz T, Lerer B, Loughland CM, Malhotra AK, Mallet J, McDonald C, Mitjans M, Mowry BJ, Murphy KC, Murray RM, O'Neill FA, Oh SY, Palotie A, Pantelis C, Pulver AE, Petryshen TL, Quested DJ, Riley B, Sanders AR, Schall U, Schwab SG, Scott RJ, Sham PC, Silverman JM, Sim K, Steixner AA, Tooney PA, van Os J, Vawter MP, Walsh D, Weiser M, Wildenauer DB, Williams NM, Wormley BK, Zhang F, Androutsos C, Arnold PD, Barr CL, Barta C, Bey K, Bienvenu OJ, Black DW, Brown LW, Budman C, Cath D, Cheon KA, Ciullo V, Coffey BJ, Cusi D, Davis LK, Denys D, Depienne C, Dietrich A, Eapen V, Falkai P, Fernandez TV, Garcia-Delgar B, Geller DA, Gilbert DL, Grados MA, Greenberg E, Grünblatt E, Hagstrøm J, Hanna GL, Hartmann A, Hedderly T, Heiman GA, Heyman I, Hong HJ, Huang A, Huyser C, Ibanez-Gomez L, Khramtsova EA, Kim YK, Kim YS, King RA, Koh YJ, Konstantinidis A, Kook S, Kuperman S, Leventhal BL, Lochner C, Ludolph AG, Madruga-Garrido M, Malaty I, Maras A, McCracken JT, Meijer IA, Mir P, Morer A, Müller-Vahl KR, Münchau A, Murphy TL, Naarden A, Nagy P, Nestadt G, Nestadt PS, Nicolini H, Nurmi EL, Okun MS, Paschou P, Piras F, Piras F, Pittenger C, Plessen KJ, Richter MA, Rizzo R, Robertson M, Roessner V, Ruhrmann S, Samuels JF, Sandor P, Schlögelhofer M, Shin EY, Singer H, Song DH, Song J, Spalletta G, Stein DJ, Stewart SE, Storch EA, Stranger B, Stuhrmann M, Tarnok Z, Tischfield JA, Tübing J, Visscher F, Vulink N, Wagner M, Walitza S, Wanderer S, Woods M, Worbe Y, Zai G, Zinner SH, Sullivan PF, Franke B, Daly MJ, Bulik CM, Lewis CM, McIntosh AM, O'Donovan MC, Zheutlin A, Andreassen OA, Børglum AD, Breen G, Edenberg HJ, Fanous AH, Faraone SV, Gelernter J, Mathews CA, Mattheisen M, Mitchell KS, Neale MC, Nurnberger JI, Ripke S, Santangelo SL, Scharf JM, Stein MB, Thornton LM, Walters JTR, Wray NR, Geschwind DH, Neale BM, Kendler KS, Smoller JW.

Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

KEYWORDS:

GWAS; Psychiatric genetics; cross-disorder genetics; functional genomics; gene expression; genetic architecture; genetic correlation; neurodevelopment; pleiotropy; psychiatric disorders

PMID:
31835028
DOI:
10.1016/j.cell.2019.11.020

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