TY - JOUR
T1 - Consensus molecular environment of schizophrenia risk genes in coexpression networks shifting across age and brain regions
AU - Pergola, Giulio
AU - Parihar, Madhur
AU - Sportelli, Leonardo
AU - Bharadwaj, Rahul
AU - Borcuk, Christopher
AU - Radulescu, Eugenia
AU - Bellantuono, Loredana
AU - Blasi, Giuseppe
AU - Chen, Qiang
AU - Kleinman, Joel E.
AU - Wang, Yanhong
AU - Sripathy, Srinidhi Rao
AU - Maher, Brady
AU - Monaco, Alfonso
AU - Rossi, Fabiana
AU - Shin, Joo Heon
AU - Hyde, Thomas
AU - Bertolino, Alessandro
AU - Weinberger, Daniel
N1 - Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 798181 awarded to G.P. (PI), and A.B., D.R.W. M.P., L.S., R.B. were partially supported by NIH grant 5R21MH117432-02 awarded to D.R.W. (PI), G.P., R.B., and A.B. This research has been partially supported by the project “Dopamine - dysbindin genetic interaction: a multidisciplinary approach to characterize cognitive phenotypes of schizophrenia and develop personalized treatments” (PRIN: Progetti di Ricerca di Rilevante Interesse Nazionale–Bando 2017 Prot. 2017K2NEF4) awarded to G.P., the funding initiative Horizon Europe Seeds 2021 (Next Generation EU-MUR D.M. 737/2021) for the project S68 to G.P., EXPRIVIA for the research program: “Artificial intelligence, genetics and transcriptomics” to G.P., and the Apulian regional government for the project: “Early Identification of Psychosis Risk” to A.B. G.P. and L.B. have also obtained funding for this work under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.4- Call for tender no. 3138 of 16 December 2021 of Italian Ministry of University and Research funded by the European Union–NextGenerationEU, award number: Project code: CN00000013, Concession Decree No. 1031 of 17 February 2022 adopted by the Italian Ministry of University and Research, CUP: D93C22000430001, Project title: “National Centre for HPC, Big Data and Quantum Computing”. The LIBD supported tissue collection and maintenance, analysis, infrastructure, and personnel.
Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023/4
Y1 - 2023/4
N2 - Schizophrenia is a neurodevelopmental brain disorder whose genetic risk is associated with shifting clinical phenomena across the life span. We investigated the convergence of putative schizophrenia risk genes in brain coexpression networks in postmortem human prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and dentate gyrus granule cells, parsed by specific age periods (total N = 833). The results support an early prefrontal involvement in the biology underlying schizophrenia and reveal a dynamic interplay of regions in which age parsing explains more variance in schizophrenia risk compared to lumping all age periods together. Across multiple data sources and publications, we identify 28 genes that are the most consistently found partners in modules enriched for schizophrenia risk genes in DLPFC; twenty-three are previously unidentified associations with schizophrenia. In iPSC-derived neurons, the relationship of these genes with schizophrenia risk genes is maintained. The genetic architecture of schizophrenia is embedded in shifting coexpression patterns across brain regions and time, potentially underwriting its shifting clinical presentation.
AB - Schizophrenia is a neurodevelopmental brain disorder whose genetic risk is associated with shifting clinical phenomena across the life span. We investigated the convergence of putative schizophrenia risk genes in brain coexpression networks in postmortem human prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and dentate gyrus granule cells, parsed by specific age periods (total N = 833). The results support an early prefrontal involvement in the biology underlying schizophrenia and reveal a dynamic interplay of regions in which age parsing explains more variance in schizophrenia risk compared to lumping all age periods together. Across multiple data sources and publications, we identify 28 genes that are the most consistently found partners in modules enriched for schizophrenia risk genes in DLPFC; twenty-three are previously unidentified associations with schizophrenia. In iPSC-derived neurons, the relationship of these genes with schizophrenia risk genes is maintained. The genetic architecture of schizophrenia is embedded in shifting coexpression patterns across brain regions and time, potentially underwriting its shifting clinical presentation.
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U2 - 10.1126/sciadv.ade2812
DO - 10.1126/sciadv.ade2812
M3 - Article
C2 - 37058565
AN - SCOPUS:85152546689
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 15
M1 - eade2812
ER -