Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

C O'Dushlaine, L Rossin, PH Lee, L Duncan, NN Parikshak, S Newhouse, S Ripke, BM Neale, SM Purcell, Daniëlle Posthuma, JI Nurnberger, SH Lee, SV Faraone, RH Perlis, BJ Mowry, A Thapar, ME Goddard, JS Witte, D Absher, I AgartzH Akil, F Amin, OA Andreassen, A Anjorin, R Anney, V Anttila, DE Arking, P Asherson, MH Azevedo, L Backlund, JA Badner, AJ Bailey, T Banaschewski, JD Barchas, MR Barnes, TB Barrett, N Bass, A Battaglia, M Bauer, M Bayes, F Bellivier, SE Bergen, W Berrettini, C Betancur, T Bettecken, J Biederman, EB Binder, DW Black, DHR Blackwood, CS Bloss, M Boehnke, DI Boomsma, R Breuer, R Bruggeman, P Cormican, NG Buccola, JK Buitelaar, WE Bunney, JD Buxbaum, WF Byerley, EM Byrne, S Caesar, W Cahn, RM Cantor, Maria Casas Sanahuja, A Chakravarti, K Chambert, K Choudhury, S Cichon, M Mattheisen, CR Cloninger, DA Collier, EH Cook, H Coon, B Cormand, A Corvin, WH Coryell, DW Craig, IW Craig, J Crosbie, ML Cuccaro, D Curtis, D Czamara, S Datta, G Dawson, R Day, EJ de Geus, F Degenhardt, S Djurovic, GJ Donohoe, AE Doyle, J Duan, F Dudbridge, E Duketis, RP Ebstein, HJ Edenberg, J Elia, S Ennis, B Etain, A Fanous, AE Farmer, IN Ferrier, M Flicldnger, E Fombonne, T Foroud, J Frank, B Franke, C Fraser, R Freedman, NB Freimer, CM Freitag, M Friedl, L Frisen, L Gailagher, PV Gejman, L Georgieva, ES Gershon, I Giegling, M Gill, SD Gordon, K Gordon-Smith, EK Green, TA Greenwood, DE Grice, M Gross, D Grozeva, W Guan, H Gurling, L de Haan, JL Haines, H Hakonarson, J Hallmayer, SP Hamilton, ML Hamshere, TF Hansen, AM Hartmann, M Hautzinger, AC Heath, AK Henders, S Herms, IB Hickie, M Hipolito, S Hoefels, F Holsboer, Witte Hoogendijk, JJ (Jouke Jan) Hottenga, CM Hultman, V Hus, A Ingason, M Ising, S Jamain, EG Jones, I Jones, L Jones, JY Tzeng, AK Kahler, RS Kahn, R Kandaswamy, MC Keller, JL Kennedy, E Kenny, L Kent, YJ Kim, GK Kirov, SM Klauck, L Klei, JA Knowles, MA Kohli, DL Koller, B Konte, A Korszun, L Krabbendam, R Krasucki, J Kuntsi, P Kwan, M Landen, N Langstrom, M Lathrop, J Lawrence, WB Lawson, M Leboyer, DH Ledbetter, T Lencz, KP Lesch, DF Levinson, CM Lewis, Juan Li, P Lichtenstein, JA Lieberman, DY Lin, DH Linszen, CY Liu, FW Lohoff, SK Loo, C Lord, JK Lowe, S Lucae, DJ MacIntyre, PAF Madden, E Maestrini, PKE Magnusson, PB Mahon, W Maier, AK Malhotra, SM Mane, CL Martin, NG Martin, K Matthews, M Mattingsdal, SA McCarroll, KA McGhee, JJ McGough, PJ McGrath, P McGuffin, MG McInnis, A McIntosh, R McKinney, AW McLean, FJ McMahon, WM McMahon, A McQuillin, H Medeiros, SE Medland, S Meier, I Melle, F Meng, J Meyer, CM (Christel) Middeldorp, L Middleton, V Milanova, A Miranda, AP Monaco, GW Montgomery, JL Moran, D Moreno-De-Luca, G Morken, DW Morris, EM Morrow, V Moskvina, P Muglia, TW Muhleisen, WJ Muir, B Muller-Myhsok, M Murtha, RM Myers, I Myin-Germeys, MC Neale, SF Nelson, CM Nievergelt, I Nikolov, V Nimgaonkar, WA Nolen, MM Nothen, EA Nwulia, DR Nyholt, RD Oades, A Olincy, G Oliveira, L Olsen, RA Ophoff, U Osby, MJ Owen, A Palotie, JR Parr, AD Paterson, CN Pato, MT Pato, BW Penninx, ML Pergadia, MA Pericak-Vance, BS Pickard, J Pimm, J Piven, JB Potash, F Poustka, P Propping, V Puri, DJ Quested, EM Quinn, JA Ramos-Quiroga, HB Rasmussen, S Raychaudhuri, K Rehnstrom, A Reif, M Ribases, JP Rice, M Rietschel, K Roeder, H Roeyers, A Rothenberger, G Rouleau, D Ruderfer, D Rujescu, AR Sanders, SJ Sanders, SL Santangelo, JA Sergeant, R Schachar, M Schalling, AF Schatzberg, WA Scheftner, GD Schellenberg, SW Scherer, NJ Schork, TG Schulze, J Schumacher, M Schwarz, E Scolnick, LJ Scott, JX Shi, PD Shilling, SI Shyn, JM Silverman, SL Slager, SL Smalley, JH Smit, EN Smith, EJS Sonuga-Barke, DS Cair, M State, M Steffens, HC Steinhausen, JS Strauss, J Strohmaier, TS Stroup, JS Sutdiffe, P Szatmari, S Szelinger, S Thirumalai, RC Thompson, AA Todorov, F Tozzi, J Treutlein, M Uhr, EJCG (Edwin) van den Oord, G Van Grootheest, J van Os, AM Vicente, VJ Vieland, JB Vincent, PM Visscher, CA Walsh, TH Wassink, SJ Watson, MM Weissman, T Werge, TF Wienker, EM Wijsman, G Willemsen, N Williams, AJ Willsey, SH Witt, W Xu, AH Young, TW Yu, S Zammit, PP Zandi, P (Ping) Zhang, FG Zitman, S Zollner, B Devlin, JR Kelsoe, P Sklar, MJ Daly, MC O'Donovan, N Craddock, KS Kendler, LA Weiss, NR Wray, ZM Zhao, DH Geschwind, PF Sullivan, JW Smoller, PA Holmans, G Breen

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498 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
Original languageUndefined/Unknown
Pages (from-to)199-209
Number of pages11
JournalNature Neuroscience
Volume18
Issue number2
DOIs
Publication statusPublished - 2015

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