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; C. Robert Cloninger; Dragan M. Svrakic

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, C. Robert Cloninger, Dragan M. Svrakic

Division of Adult Acute Clinical

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

2 Scopus citations

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
DOIs	https://doi.org/10.1016/j.isci.2023.106701
State	Published - May 19 2023

Keywords

Cellular neuroscience
Developmental neuroscience
Molecular interaction
Proteomics

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10.1016/j.isci.2023.106701

Cite this

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, Cloninger, C. R., & Svrakic, D. M. (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{c0568f7de60343a9aecce2bd83c3bd9f,

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 Svrakic, {Dragan M.}",

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",

number = "5",

}

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, Cloninger, CR & Svrakic, DM 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

TY - JOUR

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.

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cai, Guiqing

AU - Campion, Dominique

AU - Cantor, Rita M.

AU - Carr, Vaughan J.

AU - Carrera, Noa

AU - Catts, Stanley V.

AU - Chambert, Kimberley D.

AU - Chan, Raymond C.K.

AU - Chan, Ronald Y.L.

AU - Chen, Eric Y.H.

AU - Cheng, Wei

AU - Cheung, Eric FC

AU - Chong, Siow Ann

AU - Cloninger, C. Robert

AU - Cohen, David

AU - Cohen, Nadine

AU - Cormican, Paul

AU - Craddock, Nick

AU - Crowley, James J.

AU - Curtis, David

AU - Davidson, Michael

AU - Davis, Kenneth L.

AU - Degenhardt, Franziska

AU - Del Favero, Jurgen

AU - Demontis, Ditte

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

AU - Duan, Jubao

AU - Dudbridge, Frank

AU - Durmishi, Naser

AU - Eichhammer, Peter

AU - Eriksson, Johan

AU - Escott-Price, Valentina

AU - Essioux, Laurent

AU - Fanous, Ayman H.

AU - Farrell, Martilias S.

AU - Frank, Josef

AU - Franke, Lude

AU - Freedman, Robert

AU - Freimer, Nelson B.

AU - Friedl, Marion

AU - Friedman, Joseph I.

AU - Fromer, Menachem

AU - Genovese, Giulio

AU - Georgieva, Lyudmila

AU - Giegling, Ina

AU - Giusti-Rodríguez, Paola

AU - Godard, Stephanie

AU - Goldstein, Jacqueline I.

AU - Golimbet, Vera

AU - Gopal, Srihari

AU - Gratten, Jacob

AU - de Haan, Lieuwe

AU - Hammer, Christian

AU - Hamshere, Marian L.

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Haroutunian, Vahram

AU - Hartmann, Annette M.

AU - Henskens, Frans A.

AU - Herms, Stefan

AU - Hirschhorn, Joel N.

AU - Hoffmann, Per

AU - Hofman, Andrea

AU - Hollegaard, Mads V.

AU - Hougaard, David M.

AU - Ikeda, Masashi

AU - Joa, Inge

AU - Julià, Antonio

AU - Kahn, René S.

AU - Kalaydjieva, Luba

AU - Karachanak-Yankova, Sena

AU - Karjalainen, Juha

AU - Kavanagh, David

AU - Keller, Matthew C.

AU - Kennedy, James L.

AU - Khrunin, Andrey

AU - Kim, Yunjung

AU - Klovins, Janis

AU - Knowles, James A.

AU - Konte, Bettina

AU - Kucinskas, Vaidutis

AU - Kucinskiene, Zita Ausrele

AU - Kuzelova-Ptackova, Hana

AU - Kähler, Anna K.

AU - Laurent, Claudine

AU - Lee, Jimmy

AU - Lee, S. Hong

AU - Legge, Sophie E.

AU - Lerer, Bernard

AU - Li, Miaoxin

AU - Li, Tao

AU - Liang, Kung Yee

AU - Lieberman, Jeffrey

AU - Limborska, Svetlana

AU - Loughland, Carmel M.

AU - Lubinski, Jan

AU - Lönnqvist, Jouko

AU - Macek, Milan

AU - Magnusson, Patrik K.E.

AU - Maher, Brion S.

AU - Maier, Wolfgang

AU - Mallet, Jacques

AU - Marsal, Sara

AU - Mattheisen, Manuel

AU - Mattingsdal, Morten

AU - McCarley, Robert W.

AU - McDonald, Colm

AU - McIntosh, Andrew M.

AU - Meier, Sandra

AU - Meijer, Carin J.

AU - Melegh, Bela

AU - Melle, Ingrid

AU - Mesholam-Gately, Raquelle I.

AU - Metspalu, Andres

AU - Michie, Patricia T.

AU - Milani, Lili

AU - Milanova, Vihra

AU - Mokrab, Younes

AU - Morris, Derek W.

AU - Mors, Ole

AU - Murphy, Kieran C.

AU - Murray, Robin M.

AU - Myin-Germeys, Inez

AU - Müller-Myhsok, Bertram

AU - Nelis, Mari

AU - Nenadic, Igor

AU - Nertney, Deborah A.

AU - Nestadt, Gerald

AU - Nicodemus, Kristin K.

AU - Nikitina-Zake, Liene

AU - Nisenbaum, Laura

AU - Nordin, Annelie

AU - O'Callaghan, Eadbhard

AU - O'Dushlaine, Colm

AU - O'Neill, F. Anthony

AU - Oh, Sang Yun

AU - Olincy, Ann

AU - Olsen, Line

AU - Van Os, Jim

AU - Pantelis, Christos

AU - Papadimitriou, George N.

AU - Papiol, Sergi

AU - Parkhomenko, Elena

AU - Pato, Michele T.

AU - Svrakic, Dragan M.

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

C2 - 37207277

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, Cloninger CR, Svrakic DM. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia. iScience. 2023 May 19;26(5):106701. 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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