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

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

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 - 19 May 2023

Funding

Funders	Funder number
National Institute of Mental Health	U01 MH121499, R01 MH109903
National Institute of Mental Health
National Institute of Diabetes and Digestive and Kidney Diseases	T32 DK110919, U01 DK078616
National Institute of Diabetes and Digestive and Kidney Diseases
Simons Foundation Autism Research Initiative	735604, 515064
Simons Foundation Autism Research Initiative
Lundbeckfonden	R350-2020-963, R223-2016-721
Lundbeckfonden
Augustinus Fonden
Reinholdt W. Jorck og Hustrus Fond
Novo Nordisk Fonden	NNF21SA0072102
Novo Nordisk Fonden
Knud Højgaards Fond

Keywords

Cellular neuroscience
Developmental neuroscience
Molecular interaction
Proteomics

Access to Document

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 (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

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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 Michael Davidson and Mark Weiser",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = may,

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

language = "אנגלית",

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journal = "iScience",

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Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium & Wellcome Trust Case-Control Consortium 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 - Davidson, Michael

AU - Weiser, Mark

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

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U2 - 10.1016/j.isci.2023.106701

DO - 10.1016/j.isci.2023.106701

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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. 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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