De novo mutations disturb early brain development more frequently than common variants in schizophrenia.

Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101235742 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-485X (Electronic) Linking ISSN: 15524841 NLM ISO Abbreviation: Am J Med Genet B Neuropsychiatr Genet Subsets: MEDLINE

Publication: Hoboken, N.J. : Wiley-Blackwell
Original Publication: Hoboken, N.J. : Wiley-Liss, c2003-

Schizophrenia*/genetics ; Schizophrenia*/pathology ; Schizophrenia*/physiopathology ; Mutation* ; Brain*/cytology ; Brain*/embryology ; Brain*/growth & development ; Brain*/pathology; Animals ; Mice ; Fetus/cytology ; Fetus/embryology ; Neurons/metabolism ; Loss of Function Mutation ; Mutation, Missense ; Humans ; Organ Specificity

Investigating functional, temporal, and cell-type expression features of mutations is important for understanding a complex disease. Here, we collected and analyzed common variants and de novo mutations (DNMs) in schizophrenia (SCZ). We collected 2,636 missense and loss-of-function (LoF) DNMs in 2,263 genes across 3,477 SCZ patients (SCZ-DNMs). We curated three gene lists: (a) SCZ-neuroGenes (159 genes), which are intolerant to LoF and missense DNMs and are neurologically important, (b) SCZ-moduleGenes (52 genes), which were derived from network analyses of SCZ-DNMs, and (c) SCZ-commonGenes (120 genes) from a recent GWAS as reference. To compare temporal gene expression, we used the BrainSpan dataset. We defined a fetal effect score (FES) to quantify the involvement of each gene in prenatal brain development. We further employed the specificity indexes (SIs) to evaluate cell-type expression specificity from single-cell expression data in cerebral cortices of humans and mice. Compared with SCZ-commonGenes, SCZ-neuroGenes and SCZ-moduleGenes were highly expressed in the prenatal stage, had higher FESs, and had higher SIs in fetal replicating cells and undifferentiated cell types. Our results suggested that gene expression patterns in specific cell types in early fetal stages might have impacts on the risk of SCZ during adulthood.
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P20 GM121325 United States GM NIGMS NIH HHS; U54 GM104944 United States GM NIGMS NIH HHS; R01MH101054 United States NH NIH HHS; R01LM012806 United States NH NIH HHS

Keywords: cell-type-specific enrichment analysis; common variant; de novo mutation; prenatal and postnatal comparison; schizophrenia; single-cell RNA-sequencing

Date Created: 20230302 Date Completed: 20230318 Latest Revision: 20240525

20240525

10.1002/ajmg.b.32932

36863698