a1a84dd8dd521f08485e4a6820b6f86d pmc_9267632.pdf 8d4f32b5a37b78657dc73d5e37a83af92f0d7a11 pmc_9267632.pdf b7e0e2d526219ca1c4d36e451e69ef7e80668fc5ef55ec31c1211a7e536d79a1 pmc_9267632.pdf Title: NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches Subject: Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset 18 years) and 71 adult-onset (AO) trios) and an independent case–control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180–rs10484320–rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ. Keywords: schizophrenia-spectrum disorders; NRN1; age at onset; working memory; functional magnetic resonance imaging (fMRI) Author: Carmen Almodóvar-Payá, Maria Guardiola-Ripoll, Maria Giralt-López, Carme Gallego, Pilar Salgado-Pineda, Salvador Miret, Raymond Salvador, María J. Muñoz, Luisa Lázaro, Amalia Guerrero-Pedraza, Mara Parellada, María I. Carrión, Manuel J. Cuesta, Teresa Maristany, Salvador Sarró, Lourdes Fañanás, Luis F. Callado, Bárbara Arias, Edith Pomarol-Clotet and Mar Fatjó-Vilas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jul 5 12:12:50 2022 CEST ModDate: Tue Jul 5 13:18:17 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1072934 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EKVCZD+VnURWPalladioL Type 1 Custom yes yes no 10 0 LJKORS+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 BZAXWY+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 MJTAOK+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 OALITY+URWPalladioL-BoldItal Type 1 Custom yes yes no 28 0 COGLGI+CMSY10 Type 1 Builtin yes yes no 32 0 PRJKGQ+VnURWPalladioL-Bold Type 1 Custom yes yes no 36 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 54 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 57 0 RHAWTP+EURM10 Type 1 Builtin yes yes no 88 0 GOBLJB+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 95 0 GOBLKC+PalatinoLinotype CID TrueType Identity-H yes yes yes 98 0 GOBLKD+PalatinoLinotype TrueType WinAnsi yes yes no 104 0 GOBLKF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 107 0 GOBLJB+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 117 0 GOBLKD+PalatinoLinotype TrueType WinAnsi yes yes no 120 0 GOBLKF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 123 0 NPWAER+EURM7 Type 1 Builtin yes yes no 139 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-03-20 02:41:11 CET RepresentationInformation: pmc_9267632.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-10-25 02:19:16 CEST Size: 1072934 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 455 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Genetic Association Analyses Destination: subsection.2.1 Children: Item: Title: Family-Based Destination: subsubsection.2.1.1 Item: Title: Case Control Destination: subsubsection.2.1.2 Item: Title: Neuroimaging Genetic Association Analyses Destination: subsection.2.2 Children: Item: Title: N-Back Functional Response Destination: subsubsection.2.2.1 Item: Title: N-Back Behavioural Response Destination: subsubsection.2.2.2 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Sample Destination: subsection.4.1 Item: Title: Genotyping Destination: subsection.4.2 Item: Title: fMRI Task Description and Acquisition Parameters Destination: subsection.4.3 Children: Item: Title: N-Back Task Destination: subsubsection.4.3.1 Item: Title: N-Back Performance Data Destination: subsubsection.4.3.2 Item: Title: fMRI Acquisition Parameters Destination: subsubsection.4.3.3 Item: Title: Statistical Analyses Destination: subsection.4.4 Children: Item: Title: Design Destination: subsubsection.4.4.1 Item: Title: Genetic Association Analyses Destination: subsubsection.4.4.2 Item: Title: Neuroimaging Association Study Destination: subsubsection.4.4.3 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches Author: Carmen Almodóvar-Payá, Maria Guardiola-Ripoll, Maria Giralt-López, Carme Gallego, Pilar Salgado-Pineda, Salvador Miret, Raymond Salvador, María J. Muñoz, Luisa Lázaro, Amalia Guerrero-Pedraza, Mara Parellada, María I. Carrión, Manuel J. Cuesta, Teresa Maristany, Salvador Sarró, Lourdes Fañanás, Luis F. Callado, Bárbara Arias, Edith Pomarol-Clotet and Mar Fatjó-Vilas Subject: Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset 18 years) and 71 adult-onset (AO) trios) and an independent case control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180 rs10484320 rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ. 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