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

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; 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

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 TanenbaumCaroline R. Stanclift, Annie M. Apffel, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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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.

Originalsprog	Engelsk
Artikelnummer	106701
Tidsskrift	iScience
Vol/bind	26
Nummer	5
ISSN	2589-0042
DOI	https://doi.org/10.1016/j.isci.2023.106701
Status	Udgivet - 19 maj 2023

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10.1016/j.isci.2023.106701Licens: CC BY-NC-ND

1-s2.0-S2589004223007782-mainForlagets udgivne version, 5,39 MBLicens: CC BY-NC-ND

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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., ... Wellcome Trust Case Control Consortium (2023). Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia. iScience, 26(5), Artikel 106701. https://doi.org/10.1016/j.isci.2023.106701

@article{316277bfad7946d187ccfc9b81844c04,

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 = "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 Ditte Demontis and Hollegaard, {Mads V.} and Manuel Mattheisen and Sandra Meier and Ole Mors and Rasmussen, {Henrik B.} and Qiang Wang and B{\o}rglum, {Anders D.} and Mortensen, {Preben B.} and Gang Feng and Chen, {Wei J.} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and {Stanley Global Asia Initiatives} and {Psychosis Endophenotypes International Consortium} and {Wellcome Trust Case Control Consortium}",

note = "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 = "Elsevier Inc.",

number = "5",

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Hsu, YHH, 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, 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, bind 26, nr. 5, 106701. https://doi.org/10.1016/j.isci.2023.106701

TY - JOUR

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

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 - Demontis, Ditte

AU - Hollegaard, Mads V.

AU - Mattheisen, Manuel

AU - Meier, Sandra

AU - Mors, Ole

AU - Rasmussen, Henrik B.

AU - Wang, Qiang

AU - Børglum, Anders D.

AU - Mortensen, Preben B.

AU - Feng, Gang

AU - Chen, Wei J.

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

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 - Journal article

C2 - 37207277

AN - SCOPUS:85158169608

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 5

M1 - 106701

ER -

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

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