De Novo Variants Found in Three Distinct Schizophrenia Populations Hit a Common Core Gene Network Related to Microtubule and Actin Cytoskeleton Gene Ontology Classes

• Published in: Life (Basel, Switzerland) Vol. 14; no. 2; p. 244
• Main Authors: Loe-Mie, Yann, Plançon, Christine, Dubertret, Caroline, Yoshikawa, Takeo, Yalcin, Binnaz, Collins, Stephan C, Boland, Anne, Deleuze, Jean-François, Gorwood, Philip, Benmessaoud, Dalila, Simonneau, Michel, Lepagnol-Bestel, Aude-Marie
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-02-2024; MDPI
• Subjects: Actin; Algorithms; Bayesian analysis; Binding; Bioinformatics; Brain; cohorts; Corpus callosum; Cytoskeleton; Disease; gene ontology; Genes; Genetic aspects; Genetic variation; Genetics; Genome-wide association studies; Genomes; Genomics; Genotype & phenotype; Haploinsufficiency; Health risk assessment; Human genetics; Life Sciences; Mental disorders; microtubule; Microtubules; mRNA; Mutation; Protein transport; Proteins; Psychiatric research; Risk factors; Schizophrenia; schizophrenia trios; Software; France; United States > US; Japan; microtubule; gene ontology; mutation; schizophrenia trios; cytoskeleton; Coro1c gene; Coro1c mouse; cohorts
• ISSN: 2075-1729; 2075-1729
• DOI: 10.3390/life14020244

Schizophrenia (SZ) is a heterogeneous and debilitating psychiatric disorder with a strong genetic component. To elucidate functional networks perturbed in schizophrenia, we analysed a large dataset of whole-genome studies that identified SNVs, CNVs, and a multi-stage schizophrenia genome-wide association study. Our analysis identified three subclusters that are interrelated and with small overlaps: GO:0007017~Microtubule-Based Process, GO:00015629~Actin Cytoskeleton, and GO:0007268~SynapticTransmission. We next analysed three distinct trio cohorts of 75 SZ Algerian, 45 SZ French, and 61 SZ Japanese patients. We performed Illumina HiSeq whole-exome sequencing and identified de novo mutations using a Bayesian approach. We validated 88 de novo mutations by Sanger sequencing: 35 in French, 21 in Algerian, and 32 in Japanese SZ patients. These 88 de novo mutations exhibited an enrichment in genes encoding proteins related to GO:0051015~actin filament binding (
= 0.0011) using David, and enrichments in GO: 0003774~transport (
= 0.019) and GO:0003729~mRNA binding (
= 0.010) using Amigo. One of these de novo variant was found in
coding sequence. We studied Coro1c haploinsufficiency in a
mouse and found defects in the corpus callosum. These results could motivate future studies of the mechanisms surrounding genes encoding proteins involved in transport and the cytoskeleton, with the goal of developing therapeutic intervention strategies for a subset of SZ cases.