@article{0f7d0064c5524268a4b4821873895325,
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 Farooq Amin and Bacanu, {Silviu A.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Wiepke Cahn and Kahn, {Ren{\'e} S.} and {Van Os}, Jim and Ophoff, {Roel A.} and Weinberger, {Daniel R.} and Kahn, {Ren{\'e} S.}",
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",
number = "5",
}