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

Schizophrenia Working Group of the Psychiatric Genomics Consortium; Stanley Global Asia Initiatives; Psychosis Endophenotypes International Consortium; Wellcome Trust Case Control Consortium; Yu-Han H. Hsu; Greta Pintacuda; Ruize Liu; Eugeniu Nacu; April Kim; Kalliopi Tsafou; Natalie Petrossian; William Crotty; Jung Min Suh; Jackson Riseman; Jacqueline M. Martin; Julia C. Biagini; Daya Mena; Joshua K.T. Ching; Edyta Malolepsza; Taibo Li; Tarjinder Singh; Tian Ge; Shawn B. Egri; Benjamin Tanenbaum; Caroline R. Stanclift; Annie M. Apffel; Hailiang Huang; Steven A. Carr; Monica Schenone; Jake Jaffe; Nadine Fornelos; Kevin C. Eggan; Kasper Lage

doi:10.1016/j.isci.2023.106701

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

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo LiTarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Hailiang Huang, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Kevin C. Eggan^*, Kasper Lage^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	106701
Journal	iScience
Volume	26
Issue number	5
Early online date	18 Apr 2023
DOIs	https://doi.org/10.1016/j.isci.2023.106701
Publication status	Published - 19 May 2023

Keywords / Materials (for Non-textual outputs)

Cellular neuroscience
Developmental neuroscience
Molecular interaction
Proteomics

Access to Document

10.1016/j.isci.2023.106701Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

PIIS2589004223007782Final published version, 5.39 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Cite this

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, 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., ... Lage, K. (2023). Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia. iScience, 26(5), Article 106701. https://doi.org/10.1016/j.isci.2023.106701

@article{277be058e09b43489501287a92960dd0,

title = "Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia",

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.",

keywords = "Cellular neuroscience, Developmental neuroscience, Molecular interaction, Proteomics",

author = "{Schizophrenia Working Group of the Psychiatric Genomics Consortium} and {Stanley Global Asia Initiatives} and {Psychosis Endophenotypes International Consortium} and {Wellcome Trust Case Control Consortium} and Hsu, {Yu-Han H.} and Greta Pintacuda and Ruize Liu and Eugeniu Nacu and April Kim and Kalliopi Tsafou and Natalie Petrossian and William Crotty and Suh, {Jung Min} and Jackson Riseman and Martin, {Jacqueline M.} and Biagini, {Julia C.} and Daya Mena and Ching, {Joshua K.T.} and Edyta Malolepsza and Taibo Li and Tarjinder Singh and Tian Ge and Egri, {Shawn B.} and Benjamin Tanenbaum and Stanclift, {Caroline R.} and Apffel, {Annie M.} and Stephan Ripke and Neale, {Benjamin M.} and Aiden Corvin and Walters, {James T.R.} and Farh, {Kai How} and Holmans, {Peter A.} and Phil Lee and Brendan Bulik-Sullivan and Collier, {David A.} and Hailiang Huang and Pers, {Tune H.} and Ingrid Agartz and Esben Agerbo and Margot Albus and Madeline Alexander and Farooq Amin and Bacanu, {Silviu A.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and William Byerley and Wiepke Cahn and Guiqing Cai and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Catts, {Stanley V.} and Chambert, {Kimberley D.} and Chan, {Raymond C.K.} and Chan, {Ronald Y.L.} and Chen, {Eric Y.H.} and Wei Cheng and Cheung, {Eric FC} and Chong, {Siow Ann} and Cloninger, {C. Robert} and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and Crowley, {James J.} and David Curtis and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and {Del Favero}, Jurgen and Ditte Demontis and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Naser Durmishi and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Laurent Essioux and Fanous, {Ayman H.} and Farrell, {Martilias S.} and Josef Frank and Lude Franke and Robert Freedman and Freimer, {Nelson B.} and Marion Friedl and Friedman, {Joseph I.} and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Ina Giegling and Paola Giusti-Rodr{\'i}guez and Stephanie Godard and Goldstein, {Jacqueline I.} and Vera Golimbet and Srihari Gopal and Jacob Gratten and {de Haan}, Lieuwe and Christian Hammer and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian and Hartmann, {Annette M.} and Henskens, {Frans A.} and Stefan Herms and Hirschhorn, {Joel N.} and Per Hoffmann and Andrea Hofman and Hollegaard, {Mads V.} and Hougaard, {David M.} and Masashi Ikeda and Inge Joa and Antonio Juli{\`a} and Kahn, {Ren{\'e} S.} and Luba Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kennedy, {James L.} and Andrey Khrunin and Yunjung Kim and Janis Klovins and Knowles, {James A.} and Bettina Konte and Vaidutis Kucinskas and Kucinskiene, {Zita Ausrele} and Hana Kuzelova-Ptackova and K{\"a}hler, {Anna K.} and Claudine Laurent and Jimmy Lee and Lee, {S. Hong} and Legge, {Sophie E.} and Bernard Lerer and Miaoxin Li and Tao Li and Liang, {Kung Yee} and Jeffrey Lieberman and Svetlana Limborska and Loughland, {Carmel M.} and Jan Lubinski and Jouko L{\"o}nnqvist and Milan Macek and Magnusson, {Patrik K.E.} and Maher, {Brion S.} and Wolfgang Maier and Jacques Mallet and Sara Marsal and Manuel Mattheisen and Morten Mattingsdal and McCarley, {Robert W.} and Colm McDonald and McIntosh, {Andrew M.} and Sandra Meier and Meijer, {Carin J.} and Bela Melegh and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Younes Mokrab and Morris, {Derek W.} and Ole Mors and Murphy, {Kieran C.} and Murray, {Robin M.} and Inez Myin-Germeys and Bertram M{\"u}ller-Myhsok and Mari Nelis and Igor Nenadic and Nertney, {Deborah A.} and Gerald Nestadt and Nicodemus, {Kristin K.} and Liene Nikitina-Zake and Laura Nisenbaum and Annelie Nordin and Eadbhard O'Callaghan and Colm O'Dushlaine and O'Neill, {F. Anthony} and Oh, {Sang Yun} and Ann Olincy and Line Olsen and {Van Os}, Jim and Christos Pantelis and Papadimitriou, {George N.} and Sergi Papiol and Elena Parkhomenko and Pato, {Michele T.} and Tiina Paunio and Milica Pejovic-Milovancevic and Perkins, {Diana O.} and Olli Pietil{\"a}inen and Jonathan Pimm and Pocklington, {Andrew J.} and John Powell and Alkes Price and Pulver, {Ann E.} and Purcell, {Shaun M.} and Digby Quested and Rasmussen, {Henrik B.} and Abraham Reichenberg and Reimers, {Mark A.} and Richards, {Alexander L.} and Roffman, {Joshua L.} and Panos Roussos and Ruderfer, {Douglas M.} and Veikko Salomaa and Sanders, {Alan R.} and Ulrich Schall and Schubert, {Christian R.} and Schulze, {Thomas G.} and Schwab, {Sibylle G.} and Scolnick, {Edward M.} and Scott, {Rodney J.} and Seidman, {Larry J.} and Jianxin Shi and Engilbert Sigurdsson and Teimuraz Silagadze and Silverman, {Jeremy M.} and Kang Sim and Petr Slominsky and Smoller, {Jordan W.} and So, {Hon Cheong} and Spencer, {Chris C.A.} and Stahl, {Eli A.} and Hreinn Stefansson and Stacy Steinberg and Elisabeth Stogmann and Straub, {Richard E.} and Eric Strengman and Jana Strohmaier and Stroup, {T. Scott} and Mythily Subramaniam and Jaana Suvisaari and Svrakic, {Dragan M.} and Szatkiewicz, {Jin P.} and Erik S{\"o}derman and Srinivas Thirumalai and Draga Toncheva and Sarah Tosato and Juha Veijola and John Waddington and Dermot Walsh and Dai Wang and Qiang Wang and Webb, {Bradley T.} and Mark Weiser and Wildenauer, {Dieter B.} and Williams, {Nigel M.} and Stephanie Williams and Witt, {Stephanie H.} and Wolen, {Aaron R.} and Wong, {Emily H.M.} and Wormley, {Brandon K.} and Xi, {Hualin Simon} and Zai, {Clement C.} and Xuebin Zheng and Fritz Zimprich and Wray, {Naomi R.} and Kari Stefansson and Visscher, {Peter M.} and Rolf Adolfsson and Andreassen, {Ole A.} and Blackwood, {Douglas H.R.} and Elvira Bramon and Buxbaum, {Joseph D.} and B{\o}rglum, {Anders D.} and Sven Cichon and Ariel Darvasi and Enrico Domenici and Hannelore Ehrenreich and T{\~o}nu Esko and Gejman, {Pablo V.} and Michael Gill and Hugh Gurling and Hultman, {Christina M.} and Nakao Iwata and Jablensky, {Assen V.} and J{\"o}nsson, {Erik G.} and Kendler, {Kenneth S.} and George Kirov and Jo Knight and Todd Lencz and Levinson, {Douglas F.} and Li, {Qingqin S.} and Jianjun Liu and Malhotra, {Anil K.} and McCarroll, {Steven A.} and Andrew McQuillin and Moran, {Jennifer L.} and Mortensen, {Preben B.} and Mowry, {Bryan J.} and N{\"o}then, {Markus M.} and Ophoff, {Roel A.} and Owen, {Michael J.} and Aarno Palotie and Pato, {Carlos N.} and Petryshen, {Tracey L.} and Danielle Posthuma and Marcella Rietschel and Riley, {Brien P.} and Dan Rujescu and Sham, {Pak C.} and Pamela Sklar and {St Clair}, David and Weinberger, {Daniel R.} and Wendland, {Jens R.} and Thomas Werge and Daly, {Mark J.} and Sullivan, {Patrick F.} and O'Donovan, {Michael C.} and Shengying Qin and Akira Sawa and Rene Kahn and Hong, {Kyung Sue} and Wenzhao Shi and Ming Tsuang and Masanari Itokawa and Gang Feng and Glatt, {Stephen J.} and Xiancang Ma and Jinsong Tang and Yunfeng Ruan and Feng Zhu and Yasue Horiuchi and Lee, {Byung Dae} and Joo, {Eun Jeong} and Woojae Myung and Kyooseob Ha and Won, {Hong Hee} and Baek, {Ji Hyung} and Chung, {Young Chul} and Kim, {Sung Wan} and Agung Kusumawardhani and Chen, {Wei J.} and Hwu, {Hai Gwo} and Akitoyo Hishimoto and Ikuo Otsuka and Ichiro Sora and Tomoko Toyota and Takeo Yoshikawa and Hiroshi Kunugi and Kotaro Hattori and Sayuri Ishiwata and Shusuke Numata and Tetsuro Ohmori and Makoto Arai and Yuji Ozeki and Kumiko Fujii and Kim, {Se Joo} and Lee, {Heon Jeong} and Ahn, {Yong Min} and Kim, {Se Hyun} and Kazufumi Akiyama and Kazutaka Shimoda and Makoto Kinoshita and Carr, {Steven A.} and Monica Schenone and Jake Jaffe and Nadine Fornelos and Eggan, {Kevin C.} and Kasper Lage",

note = "Funding Information: We thank Carole Manneville, Matthias Mueller, Katie Worringer, and Ajamete Kaykas at Novartis for sharing the hDFn cell line; Ellen Beauchamp, Andrew Guirguis, Rebecca Gorelov, and Zuzana Tothova for sharing cancer cell lines; Karl Clauser for managing and uploading the proteomics data; and Steve Hyman, Mark Daly, and Ben Neale for insightful scientific discussions. 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 H{\o}jgaard 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. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = may,

day = "19",

doi = "10.1016/j.isci.2023.106701",

language = "English",

volume = "26",

journal = "iScience",

issn = "2589-0042",

publisher = "Cell Press",

number = "5",

}

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, Hsu, Y-HH, Pintacuda, G, Liu, R, Nacu, E, Kim, A, Tsafou, K, Petrossian, N, Crotty, W, Suh, JM, Riseman, J, Martin, JM, Biagini, JC, Mena, D, Ching, JKT, Malolepsza, E, Li, T, Singh, T, Ge, T, Egri, SB, Tanenbaum, B, Stanclift, CR, Apffel, AM, Huang, H, Carr, SA, Schenone, M, Jaffe, J, Fornelos, N, Eggan, KC & Lage, K 2023, 'Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia', iScience, vol. 26, no. 5, 106701. https://doi.org/10.1016/j.isci.2023.106701

Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia. / Schizophrenia Working Group of the Psychiatric Genomics Consortium; Stanley Global Asia Initiatives; Psychosis Endophenotypes International Consortium et al.
In: iScience, Vol. 26, No. 5, 106701, 19.05.2023.

Research output: Contribution to journal › Article › peer-review

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T1 - Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Stanley Global Asia Initiatives

AU - Psychosis Endophenotypes International Consortium

AU - Wellcome Trust Case Control Consortium

AU - Hsu, Yu-Han H.

AU - Pintacuda, Greta

AU - Liu, Ruize

AU - Nacu, Eugeniu

AU - Kim, April

AU - Tsafou, Kalliopi

AU - Petrossian, Natalie

AU - Crotty, William

AU - Suh, Jung Min

AU - Riseman, Jackson

AU - Martin, Jacqueline M.

AU - Biagini, Julia C.

AU - Mena, Daya

AU - Ching, Joshua K.T.

AU - Malolepsza, Edyta

AU - Li, Taibo

AU - Singh, Tarjinder

AU - Ge, Tian

AU - Egri, Shawn B.

AU - Tanenbaum, Benjamin

AU - Stanclift, Caroline R.

AU - Apffel, Annie M.

AU - Ripke, Stephan

AU - Neale, Benjamin M.

AU - Corvin, Aiden

AU - Walters, James T.R.

AU - Farh, Kai How

AU - Holmans, Peter A.

AU - Lee, Phil

AU - Bulik-Sullivan, Brendan

AU - Collier, David A.

AU - Huang, Hailiang

AU - Pers, Tune H.

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Bergen, Sarah E.

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AU - Cantor, Rita M.

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AU - Chambert, Kimberley D.

AU - Chan, Raymond C.K.

AU - Chan, Ronald Y.L.

AU - Chen, Eric Y.H.

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AU - Cheung, Eric FC

AU - Chong, Siow Ann

AU - Cloninger, C. Robert

AU - Cohen, David

AU - Cohen, Nadine

AU - Cormican, Paul

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AU - Dinan, Timothy

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AU - Duan, Jubao

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AU - Durmishi, Naser

AU - Eichhammer, Peter

AU - Eriksson, Johan

AU - Escott-Price, Valentina

AU - Essioux, Laurent

AU - Fanous, Ayman H.

AU - Farrell, Martilias S.

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AU - Franke, Lude

AU - Freedman, Robert

AU - Freimer, Nelson B.

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AU - Friedman, Joseph I.

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AU - Giegling, Ina

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AU - Roussos, Panos

AU - Ruderfer, Douglas M.

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AU - Sanders, Alan R.

AU - Schall, Ulrich

AU - Schubert, Christian R.

AU - Schulze, Thomas G.

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AU - Scott, Rodney J.

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AU - Zheng, Xuebin

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AU - Wray, Naomi R.

AU - Stefansson, Kari

AU - Visscher, Peter M.

AU - Adolfsson, Rolf

AU - Andreassen, Ole A.

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AU - Bramon, Elvira

AU - Buxbaum, Joseph D.

AU - Børglum, Anders D.

AU - Cichon, Sven

AU - Darvasi, Ariel

AU - Domenici, Enrico

AU - Ehrenreich, Hannelore

AU - Esko, Tõnu

AU - Gejman, Pablo V.

AU - Gill, Michael

AU - Gurling, Hugh

AU - Hultman, Christina M.

AU - Iwata, Nakao

AU - Jablensky, Assen V.

AU - Jönsson, Erik G.

AU - Kendler, Kenneth S.

AU - Kirov, George

AU - Knight, Jo

AU - Lencz, Todd

AU - Levinson, Douglas F.

AU - Li, Qingqin S.

AU - Liu, Jianjun

AU - Malhotra, Anil K.

AU - McCarroll, Steven A.

AU - McQuillin, Andrew

AU - Moran, Jennifer L.

AU - Mortensen, Preben B.

AU - Mowry, Bryan J.

AU - Nöthen, Markus M.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Pato, Carlos N.

AU - Petryshen, Tracey L.

AU - Posthuma, Danielle

AU - Rietschel, Marcella

AU - Riley, Brien P.

AU - Rujescu, Dan

AU - Sham, Pak C.

AU - Sklar, Pamela

AU - St Clair, David

AU - Weinberger, Daniel R.

AU - Wendland, Jens R.

AU - Werge, Thomas

AU - Daly, Mark J.

AU - Sullivan, Patrick F.

AU - O'Donovan, Michael C.

AU - Qin, Shengying

AU - Sawa, Akira

AU - Kahn, Rene

AU - Hong, Kyung Sue

AU - Shi, Wenzhao

AU - Tsuang, Ming

AU - Itokawa, Masanari

AU - Feng, Gang

AU - Glatt, Stephen J.

AU - Ma, Xiancang

AU - Tang, Jinsong

AU - Ruan, Yunfeng

AU - Zhu, Feng

AU - Horiuchi, Yasue

AU - Lee, Byung Dae

AU - Joo, Eun Jeong

AU - Myung, Woojae

AU - Ha, Kyooseob

AU - Won, Hong Hee

AU - Baek, Ji Hyung

AU - Chung, Young Chul

AU - Kim, Sung Wan

AU - Kusumawardhani, Agung

AU - Chen, Wei J.

AU - Hwu, Hai Gwo

AU - Hishimoto, Akitoyo

AU - Otsuka, Ikuo

AU - Sora, Ichiro

AU - Toyota, Tomoko

AU - Yoshikawa, Takeo

AU - Kunugi, Hiroshi

AU - Hattori, Kotaro

AU - Ishiwata, Sayuri

AU - Numata, Shusuke

AU - Ohmori, Tetsuro

AU - Arai, Makoto

AU - Ozeki, Yuji

AU - Fujii, Kumiko

AU - Kim, Se Joo

AU - Lee, Heon Jeong

AU - Ahn, Yong Min

AU - Kim, Se Hyun

AU - Akiyama, Kazufumi

AU - Shimoda, Kazutaka

AU - Kinoshita, Makoto

AU - Carr, Steven A.

AU - Schenone, Monica

AU - Jaffe, Jake

AU - Fornelos, Nadine

AU - Eggan, Kevin C.

AU - Lage, Kasper

N1 - Funding Information: We thank Carole Manneville, Matthias Mueller, Katie Worringer, and Ajamete Kaykas at Novartis for sharing the hDFn cell line; Ellen Beauchamp, Andrew Guirguis, Rebecca Gorelov, and Zuzana Tothova for sharing cancer cell lines; Karl Clauser for managing and uploading the proteomics data; and Steve Hyman, Mark Daly, and Ben Neale for insightful scientific discussions. 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. Publisher Copyright: © 2023 The Authors

PY - 2023/5/19

Y1 - 2023/5/19

N2 - 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.

AB - 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.

KW - Cellular neuroscience

KW - Developmental neuroscience

KW - Molecular interaction

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=85158169608&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2023.106701

DO - 10.1016/j.isci.2023.106701

M3 - Article

AN - SCOPUS:85158169608

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 5

M1 - 106701

ER -

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, Hsu YHH, Pintacuda G et al. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia. iScience. 2023 May 19;26(5):106701. Epub 2023 Apr 18. doi: 10.1016/j.isci.2023.106701

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

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