Support for the N-methyl-d-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families

Andrew E. Timms, Michael O. Dorschner, Jeremy Wechsler, Kyu Yeong Choi, Robert Kirkwood, Santhosh Girirajan, Carl Baker, Evan E. Eichler, Olena Korvatska, Katherine W. Roche, Marshall S. Horwitz, Debby W. Tsuang

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Importance: Schizophrenia is a complex genetic disorder demonstrating considerable heritability. Genetic studies have implicated many different genes and pathways, but much of the genetic liability remains unaccounted for. Investigation of genetic forms of schizophrenia will lead to a better understanding of the underlying molecular pathways, which will then enable targeted approaches for disease prevention and treatment. Objective: To identify new genetic factors strongly predisposing to schizophrenia in families with multiple affected individuals with schizophrenia. Design: We performed genome-wide array comparative genomic hybridization, linkage analysis, and exome sequencing in multiplex families with schizophrenia. Setting: Probands and their family members were recruited from academic medical centers. Participants: We intended to identify rare disease-causing mutations in 5 large families where schizophrenia transmission appears consistent with single-gene inheritance. Intervention: Array comparative genomic hybridization was used to identify copy number variants, while exome sequencing was used to identify variants shared in all affected individuals and linkage analysis was used to further filter shared variants of interest. Analysis of select variants was performed in cultured cells to assess their functional consequences. Main Outcome Measures: Rare inherited disease-related genetic mutations. Results: No segregating rare copy number variants were detected by array comparative genomic hybridization. However, in all 5 families, exome sequencing detected rare protein-altering variants in 1 of 3 genes associated with the N-methyl-D-aspartate (NMDA) receptor. One pedigree shared a missense and frameshift substitution of GRM5, encoding the metabotropic glutamate receptor subtype 5 (mGluR5), which is coupled to the NMDA receptor and potentiates its signaling; the frameshift disrupts binding to the scaffolding protein tamalin and increases mGluR5 internalization. Another pedigree transmitted a missense substitution in PPEF2 , encoding a calmodulin-binding protein phosphatase, which we show influences mGluR5 levels. Three pedigrees demonstrated different missense substitutions within LRP1B, encoding a low-density lipoprotein receptor-related protein tied to both the NMDA receptor and located in a chromosome 2q22 region previously strongly linked to schizophrenia. Conclusions and Relevance: Exome sequencing of multiplex pedigrees uncovers new genes associated with risk for developing schizophrenia and suggests potential novel therapeutic targets.

Original languageEnglish (US)
Pages (from-to)582-590
Number of pages9
JournalJAMA Psychiatry
Volume70
Issue number6
DOIs
StatePublished - Jun 2013

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

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