Using brain cell-type-specific protein interactomes to interpret 
neurodevelopmental genetic signals in schizophrenia

Hsu, Y.-H.H.; Pintacuda, G.; Liu, R.; Nacu, E.; Kim, A.; Tsafou, K.; Petrossian, N.; Crotty, W.; Suh, J.M.; Riseman, J.; Martin, J.M.; Biagini, J.C.; Mena, D.; Ching, J.K.T.; Malolepsza, E.; Li, T.; Singh, T.; Ge, T.; Egri, S.B.; Tanenbaum, B.; Stanclift, C.R.; Apffel, A.M.; Ripke, S.; Neale, B.M.; Corvin, A.; Walters, J.T.R.; Farh, K.-H.; Holmans, P.A.; Lee, P.; Bulik-Sullivan, B.; Collier, D.A.; Huang, H.; Pers, T.H.; Agartz, I.; Agerbo, E.; Albus, M.; Alexander, M.; Amin, F.; Bacanu, S.A.; Begemann, M.; Belliveau, R.A.; Bene, J.; Bergen, S.E.; Bevilacqua, E.; Bigdeli, T.B.; Black, D.W.; Bruggeman, R.; Buccola, N.G.; Buckner, R.L.; Byerley, W.; Cahn, W.; Cai, G.; Campion, D.; Cantor, R.M.; Carr, V.J.; Carrera, N.; Catts, S.V.; Chambert, K.D.; Chan, R.C.K.; Chan, R.Y.L.; Chen, E.Y.H.; Cheng, W.; Cheung, E.F.; Chong, S.A.; Cloninger, C.R.; Cohen, D.; Cohen, N.; Cormican, P.; Craddock, N.; Crowley, J.J.; Curtis, D.; Davidson, M.; Davis, K.L.; Degenhardt, F.; Del Favero, J.; Demontis, D.; Dikeos, D.; Dinan, T.; Djurovic, S.; Donohoe, G.; Drapeau, E.; Duan, J.; Dudbridge, F.; Durmishi, N.; Eichhammer, P.; Eriksson, J.; Escott-Price, V.; Essioux, L.; Fanous, A.H.; Farrell, M.S.; Frank, J.; Franke, L.; Freedman, R.; Freimer, N.B.; Friedl, M.; Friedman, J.I.; Fromer, M.; Genovese, G.; Georgieva, L.; Giegling, I.; Giusti-Rodríguez, P.; Godard, S.; Goldstein, J.I.; Golimbet, V.; Gopal, S.; Gratten, J.; de Haan, L.; Hammer, C.; Hamshere, M.L.; Hansen, M.; Hansen, T.; Haroutunian, V.; Hartmann, A.M.; Henskens, F.A.; Herms, S.; Hirschhorn, J.N.; Hoffmann, P.; Hofman, A.; Hollegaard, M.V.; Hougaard, D.M.; Ikeda, M.; Joa, I.; Julià, A.; Kahn, R.S.; Kalaydjieva, L.; Karachanak-Yankova, S.; Karjalainen, J.; Kavanagh, D.; Keller, M.C.; Kennedy, J.L.; Khrunin, A.; Kim, Y.; Klovins, J.; Knowles, J.A.; Konte, B.; Kucinskas, V.; Kucinskiene, Z.A.; Kuzelova-Ptackova, H.; Kähler, A.K.; Laurent, C.; Lee, J.; Lee, S.H.; Legge, S.E.; Lerer, B.; Li, M.; Li, T.; Liang, K.-Y.; Lieberman, J.; Limborska, S.; Loughland, C.M.; Lubinski, J.; Lönnqvist, J.; Macek, M.; Magnusson, P.K.E.; Maher, B.S.; Maier, W.; Mallet, J.; Marsal, S.; Mattheisen, M.; Mattingsdal, M.; McCarley, R.W.; McDonald, C.; McIntosh, A.M.; Meier, S.; Meijer, C.J.; Melegh, B.; Melle, I.; Mesholam-Gately, R.I.; Metspalu, A.; Michie, P.T.; Milani, L.; Milanova, V.; Mokrab, Y.; Morris, D.W.; Mors, O.; Murphy, K.C.; Murray, R.M.; Myin-Germeys, I.; Müller-Myhsok, B.; Nelis, M.; Nenadic, I.; Nertney, D.A.; Nestadt, G.; Nicodemus, K.K.; Nikitina-Zake, L.; Nisenbaum, L.; Nordin, A.; O'Callaghan, E.; O'Dushlaine, C.; O'Neill, F.A.; Oh, S.-Y.; Olincy, A.; Olsen, L.; Van Os, J.; Pantelis, C.; Papadimitriou, G.N.; Papiol, S.; Parkhomenko, E.; Pato, M.T.; Paunio, T.; Pejovic-Milovancevic, M.; Perkins, D.O.; Pietiläinen, O.; Pimm, J.; Pocklington, A.J.; Powell, J.; Price, A.; Pulver, A.E.; Purcell, S.M.; Quested, D.; Rasmussen, H.B.; Reichenberg, A.; Reimers, M.A.; Richards, A.L.; Roffman, J.L.; Roussos, P.; Ruderfer, D.M.; Salomaa, V.; Sanders, A.R.; Schall, U.; Schubert, C.R.; Schulze, T.G.; Schwab, S.G.; Scolnick, E.M.; Scott, R.J.; Seidman, L.J.; Shi, J.; Sigurdsson, E.; Silagadze, T.; Silverman, J.M.; Sim, K.; Slominsky, P.; Smoller, J.W.; So, H.-C.; Spencer, C.C.A.; Stahl, E.A.; Stefansson, H.; Steinberg, S.; Stogmann, E.; Straub, R.E.; Strengman, E.; Strohmaier, J.; Stroup, T.S.; Subramaniam, M.; Suvisaari, J.; Svrakic, D.M.; Szatkiewicz, J.P.; Söderman, E.; Thirumalai, S.; Toncheva, D.; Tosato, S.; Veijola, J.; Waddington, J.; Walsh, D.; Wang, D.; Wang, Q.; Webb, B.T.; Weiser, M.; Wildenauer, D.B.; Williams, N.M.; Williams, S.; Witt, S.H.; Wolen, A.R.; Wong, E.H.M.; Wormley, B.K.; Xi, H.S.; Zai, C.C.; Zheng, X.; Zimprich, F.; Wray, N.R.; Stefansson, K.; Visscher, P.M.; Adolfsson, R.; Andreassen, O.A.; Blackwood, D.H.R.; Bramon, E.; Buxbaum, J.D.; Børglum, A.D.; Cichon, S.; Darvasi, A.; Domenici, E.; Ehrenreich, Hannelore; Esko, T.; Gejman, P.V.; Gill, M.; Gurling, H.; Hultman, C.M.; Iwata, N.; Jablensky, A.V.; Jönsson, E.G.; Kendler, K.S.; Kirov, G.; Knight, J.; Lencz, T.; Levinson, D.F.; Li, Q.S.; Liu, J.; Malhotra, A.K.; McCarroll, S.A.; McQuillin, A.; Moran, J.L.; Mortensen, P.B.; Mowry, B.J.; Nöthen, M.M.; Ophoff, R.A.; Owen, M.J.; Palotie, A.; Pato, C.N.; Petryshen, T.L.; Posthuma, D.; Rietschel, M.; Riley, B.P.; Rujescu, D.; Sham, P.C.; Sklar, P.; St Clair, D.; Weinberger, D.R.; Wendland, J.R.; Werge, T.; Daly, M.J.; Sullivan, P.F.; O'Donovan, M.C.; Qin, S.; Sawa, A.; Kahn, R.; Hong, K.S.; Shi, W.; Tsuang, M.; Itokawa, M.; Feng, G.; Glatt, S.J.; Ma, X.; Tang, J.; Ruan, Y.; Zhu, F.; Horiuchi, Y.; Lee, B.D.; Joo, E.-J.; Myung, W.; Ha, K.; Won, H.-H.; Baek, J.H.; Chung, Y.C.; Kim, S.-W.; Kusumawardhani, A.; Chen, W.J.; Hwu, H.-G.; Hishimoto, A.; Otsuka, I.; Sora, I.; Toyota, T.; Yoshikawa, T.; Kunugi, H.; Hattori, K.; Ishiwata, S.; Numata, S.; Ohmori, T.; Arai, M.; Ozeki, Y.; Fujii, K.; Kim, S.J.; Lee, H.-J.; Ahn, Y.M.; Kim, S.H.; Akiyama, K.; Shimoda, K.; Kinoshita, M.; Carr, S.A.; Schenone, M.; Jaffe, J.; Fornelos, N.; Eggan, K.C.; Lage, K.

doi:10.1016/j.isci.2023.106701

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Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Hsu, Y.-H., Pintacuda, G., Liu, R., Nacu, E., Kim, A., Tsafou, K., et al. (2023). Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia. iScience, 26(5): 106701. doi:10.1016/j.isci.2023.106701.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-7A3C-8 Version Permalink: https://hdl.handle.net/21.11116/0000-000D-7A3D-7

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Creators:
Hsu, Y.-H.H., Author
Pintacuda, G., Author
Liu, R., Author
Nacu, E., Author
Kim, A., Author
Tsafou, K., Author
Petrossian, N., Author
Crotty, W., Author
Suh, J.M., Author
Riseman, J., Author
Martin, J.M., Author
Biagini, J.C., Author
Mena, D., Author
Ching, J.K.T., Author
Malolepsza, E., Author
Li, T., Author
Singh, T., Author
Ge, T., Author
Egri, S.B., Author
Tanenbaum, B., Author
Stanclift, C.R., AuthorApffel, A.M., AuthorRipke, S., AuthorNeale, B.M., AuthorCorvin, A., AuthorWalters, J.T.R., AuthorFarh, K.-H., AuthorHolmans, P.A., AuthorLee, P., AuthorBulik-Sullivan, B., AuthorCollier, D.A., AuthorHuang, H., AuthorPers, T.H., AuthorAgartz, I., AuthorAgerbo, E., AuthorAlbus, M., AuthorAlexander, M., AuthorAmin, F., AuthorBacanu, S.A., AuthorBegemann, M., AuthorBelliveau, R.A., AuthorBene, J., AuthorBergen, S.E., AuthorBevilacqua, E., AuthorBigdeli, T.B., AuthorBlack, D.W., AuthorBruggeman, R., AuthorBuccola, N.G., AuthorBuckner, R.L., AuthorByerley, W., AuthorCahn, W., AuthorCai, G., AuthorCampion, D., AuthorCantor, R.M., AuthorCarr, V.J., AuthorCarrera, N., AuthorCatts, S.V., AuthorChambert, K.D., AuthorChan, R.C.K., AuthorChan, R.Y.L., AuthorChen, E.Y.H., AuthorCheng, W., AuthorCheung, E.F., AuthorChong, S.A., AuthorCloninger, C.R., AuthorCohen, D., AuthorCohen, N., AuthorCormican, P., AuthorCraddock, N., AuthorCrowley, J.J., AuthorCurtis, D., AuthorDavidson, M., AuthorDavis, K.L., AuthorDegenhardt, F., AuthorDel Favero, J., AuthorDemontis, D., AuthorDikeos, D., AuthorDinan, T., AuthorDjurovic, S., AuthorDonohoe, G., AuthorDrapeau, E., AuthorDuan, J., AuthorDudbridge, F., AuthorDurmishi, N., AuthorEichhammer, P., AuthorEriksson, J., AuthorEscott-Price, V., AuthorEssioux, L., AuthorFanous, A.H., AuthorFarrell, M.S., AuthorFrank, J., AuthorFranke, L., AuthorFreedman, R., AuthorFreimer, N.B., AuthorFriedl, M., AuthorFriedman, J.I., AuthorFromer, M., AuthorGenovese, G., AuthorGeorgieva, L., AuthorGiegling, I., AuthorGiusti-Rodríguez, P., AuthorGodard, S., AuthorGoldstein, J.I., AuthorGolimbet, V., AuthorGopal, S., AuthorGratten, J., Authorde Haan, L., AuthorHammer, C., AuthorHamshere, M.L., AuthorHansen, M., AuthorHansen, T., AuthorHaroutunian, V., AuthorHartmann, A.M., AuthorHenskens, F.A., AuthorHerms, S., AuthorHirschhorn, J.N., AuthorHoffmann, P., AuthorHofman, A., AuthorHollegaard, M.V., AuthorHougaard, D.M., AuthorIkeda, M., AuthorJoa, I., AuthorJulià, A., AuthorKahn, R.S., AuthorKalaydjieva, L., AuthorKarachanak-Yankova, S., AuthorKarjalainen, J., AuthorKavanagh, D., AuthorKeller, M.C., AuthorKennedy, J.L., AuthorKhrunin, A., AuthorKim, Y., AuthorKlovins, J., AuthorKnowles, J.A., AuthorKonte, B., AuthorKucinskas, V., AuthorKucinskiene, Z.A., AuthorKuzelova-Ptackova, H., AuthorKähler, A.K., AuthorLaurent, C., AuthorLee, J., AuthorLee, S.H., AuthorLegge, S.E., AuthorLerer, B., AuthorLi, M., AuthorLi, T., AuthorLiang, K.-Y., AuthorLieberman, J., AuthorLimborska, S., AuthorLoughland, C.M., AuthorLubinski, J., AuthorLönnqvist, J., AuthorMacek, M., AuthorMagnusson, P.K.E., AuthorMaher, B.S., AuthorMaier, W., AuthorMallet, J., AuthorMarsal, S., AuthorMattheisen, M., AuthorMattingsdal, M., AuthorMcCarley, R.W., AuthorMcDonald, C., AuthorMcIntosh, A.M., AuthorMeier, S., AuthorMeijer, C.J., AuthorMelegh, B., AuthorMelle, I., AuthorMesholam-Gately, R.I., AuthorMetspalu, A., AuthorMichie, P.T., AuthorMilani, L., AuthorMilanova, V., AuthorMokrab, Y., AuthorMorris, D.W., AuthorMors, O., AuthorMurphy, K.C., AuthorMurray, R.M., AuthorMyin-Germeys, I., AuthorMüller-Myhsok, B., AuthorNelis, M., AuthorNenadic, I., AuthorNertney, D.A., AuthorNestadt, G., AuthorNicodemus, K.K., AuthorNikitina-Zake, L., AuthorNisenbaum, L., AuthorNordin, A., AuthorO'Callaghan, E., AuthorO'Dushlaine, C., AuthorO'Neill, F.A., AuthorOh, S.-Y., AuthorOlincy, A., AuthorOlsen, L., AuthorVan Os, J., AuthorPantelis, C., AuthorPapadimitriou, G.N., AuthorPapiol, S., AuthorParkhomenko, E., AuthorPato, M.T., AuthorPaunio, T., AuthorPejovic-Milovancevic, M., AuthorPerkins, D.O., AuthorPietiläinen, O., AuthorPimm, J., AuthorPocklington, A.J., AuthorPowell, J., AuthorPrice, A., AuthorPulver, A.E., AuthorPurcell, S.M., AuthorQuested, D., AuthorRasmussen, H.B., AuthorReichenberg, A., AuthorReimers, M.A., AuthorRichards, A.L., AuthorRoffman, J.L., AuthorRoussos, P., AuthorRuderfer, D.M., AuthorSalomaa, V., AuthorSanders, A.R., AuthorSchall, U., AuthorSchubert, C.R., AuthorSchulze, T.G., AuthorSchwab, S.G., AuthorScolnick, E.M., AuthorScott, R.J., AuthorSeidman, L.J., AuthorShi, J., AuthorSigurdsson, E., AuthorSilagadze, T., AuthorSilverman, J.M., AuthorSim, K., AuthorSlominsky, P., AuthorSmoller, J.W., AuthorSo, H.-C., AuthorSpencer, C.C.A., AuthorStahl, E.A., AuthorStefansson, H., AuthorSteinberg, S., AuthorStogmann, E., AuthorStraub, R.E., AuthorStrengman, E., AuthorStrohmaier, J., AuthorStroup, T.S., AuthorSubramaniam, M., AuthorSuvisaari, J., AuthorSvrakic, D.M., AuthorSzatkiewicz, J.P., AuthorSöderman, E., AuthorThirumalai, S., AuthorToncheva, D., AuthorTosato, S., AuthorVeijola, J., AuthorWaddington, J., AuthorWalsh, D., AuthorWang, D., AuthorWang, Q., AuthorWebb, B.T., AuthorWeiser, M., AuthorWildenauer, D.B., AuthorWilliams, N.M., AuthorWilliams, S., AuthorWitt, S.H., AuthorWolen, A.R., AuthorWong, E.H.M., AuthorWormley, B.K., AuthorXi, H.S., AuthorZai, C.C., AuthorZheng, X., AuthorZimprich, F., AuthorWray, N.R., AuthorStefansson, K., AuthorVisscher, P.M., AuthorAdolfsson, R., AuthorAndreassen, O.A., AuthorBlackwood, D.H.R., AuthorBramon, E., AuthorBuxbaum, J.D., AuthorBørglum, A.D., AuthorCichon, S., AuthorDarvasi, A., AuthorDomenici, E., AuthorEhrenreich, Hannelore¹, Author Esko, T., AuthorGejman, P.V., AuthorGill, M., AuthorGurling, H., AuthorHultman, C.M., AuthorIwata, N., AuthorJablensky, A.V., AuthorJönsson, E.G., AuthorKendler, K.S., AuthorKirov, G., AuthorKnight, J., AuthorLencz, T., AuthorLevinson, D.F., AuthorLi, Q.S., AuthorLiu, J., AuthorMalhotra, A.K., AuthorMcCarroll, S.A., AuthorMcQuillin, A., AuthorMoran, J.L., AuthorMortensen, P.B., AuthorMowry, B.J., AuthorNöthen, M.M., AuthorOphoff, R.A., AuthorOwen, M.J., AuthorPalotie, A., AuthorPato, C.N., AuthorPetryshen, T.L., AuthorPosthuma, D., AuthorRietschel, M., AuthorRiley, B.P., AuthorRujescu, D., AuthorSham, P.C., AuthorSklar, P., AuthorSt Clair, D., AuthorWeinberger, D.R., AuthorWendland, J.R., AuthorWerge, T., AuthorDaly, M.J., AuthorSullivan, P.F., AuthorO'Donovan, M.C., AuthorQin, S., AuthorSawa, A., AuthorKahn, R., AuthorHong, K.S., AuthorShi, W., AuthorTsuang, M., AuthorItokawa, M., AuthorFeng, G., AuthorGlatt, S.J., AuthorMa, X., AuthorTang, J., AuthorRuan, Y., AuthorZhu, F., AuthorHoriuchi, Y., AuthorLee, B.D., AuthorJoo, E.-J., AuthorMyung, W., AuthorHa, K., AuthorWon, H.-H., AuthorBaek, J.H., AuthorChung, Y.C., AuthorKim, S.-W., AuthorKusumawardhani, A., AuthorChen, W.J., AuthorHwu, H.-G., AuthorHishimoto, A., AuthorOtsuka, I., AuthorSora, I., AuthorToyota, T., AuthorYoshikawa, T., AuthorKunugi, H., AuthorHattori, K., AuthorIshiwata, S., AuthorNumata, S., AuthorOhmori, T., AuthorArai, M., AuthorOzeki, Y., AuthorFujii, K., AuthorKim, S.J., AuthorLee, H.-J., AuthorAhn, Y.M., AuthorKim, S.H., AuthorAkiyama, K., AuthorShimoda, K., AuthorKinoshita, M., AuthorCarr, S.A., AuthorSchenone, M., AuthorJaffe, J., AuthorFornelos, N., AuthorEggan, K.C., AuthorLage, K., Author more..

Affiliations:
1Research Group of Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350303

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Abstract: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

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Language(s): eng - English

Dates: Published Online: 2023-04-18Date issued: 2023-05-08

Publication Status: Issued

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Rev. Type: Peer

Identifiers: DOI: 10.1016/j.isci.2023.106701

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Project name : This work was supported by grants from the Stanley Center for Psychiatric Research, the US National Institute of Mental Health (R01 MH109903 and U01 MH121499), the Simons Foundation Autism Research Initiative (awards 515064 and 735604), the Lundbeck Foundation (R223-2016-721 and R350-2020-963), the Novo Nordisk Foundation (NNF21SA0072102), the Augustinus Foundation, the Knud Højgaard Foundation, the Reinholdt W. Jorck og Hustrus Foundation, the US National Institute of Diabetes and Digestive and Kidney Diseases (U01 DK078616 and T32 DK110919), and a Broad Next10 grant.

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Title: iScience

Source Genre: Journal

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Publ. Info: Amsterdam ; Bosten ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis : Elsevier

Pages: - Volume / Issue: 26 (5) Sequence Number: 106701 Start / End Page: - Identifier: ISSN: 2589-0042
CoNE: https://pure.mpg.de/cone/journals/resource/2589-0042