Exome sequence data from multigenerational families implicate AMPA receptor trafficking in neurocognitive impairment and schizophrenia risk

Mark Z. Kos, Melanie A Carless, Juan Peralta, August Blackburn, Marcio Almeida, David Roalf, Michael F. Pogue-Geile, Konasale Prasad, Ruben C. Gur, Vishwajit Nimgaonkar, Joanne E Curran, Ravi Duggirala, David C. Glahn, John C Blangero, Raquel E. Gur, Laura A Almasy

    Research output: Contribution to journalArticlepeer-review

    13 Scopus citations

    Abstract

    Schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32-35.3, we analyzed 407 protein- Altering variants for association with ABF and schizophrenia status. For replication, significant, Bonferroni-corrected findings were tested against cognitive traits in Mexican American families (n = 959), as well as interrogated for schizophrenia risk using GWAS results from the Psychiatric Genomics Consortium (PGC). From the gene SYNPO, rs6579797 (MAF = 0.032) shows significant associations with ABF (P = .015) and schizophrenia (P = .040), as well as jointly (P = .0027). In the Mexican American pedigrees, rs6579797 exhibits significant associations with IQ (P = .011), indicating more global effects on neurocognition. From the PGC results, other SYNPO variants were identified with near significant effects on schizophrenia risk, with a local linkage disequilibrium block displaying signatures of positive selection. A second missense variant within the QTL, rs17551608 (MAF = 0.19) in the gene WWC1, also displays a significant effect on schizophrenia in our exome sequences (P = .038). Remarkably, the protein products of SYNPO and WWC1 are interaction partners involved in AMPA receptor trafficking, a brain process implicated in synaptic plasticity. Our study reveals variants in these genes with significant effects on neurocognition and schizophrenia risk, identifying a potential pathogenic mechanism for schizophrenia spectrum disorders.

    Original languageEnglish (US)
    Pages (from-to)288-300
    Number of pages13
    JournalSchizophrenia bulletin
    Volume42
    Issue number2
    DOIs
    StatePublished - Mar 2016

    Keywords

    • Cognition
    • SYNPO
    • Schizophrenia
    • Synaptic plasticity
    • WWC1

    ASJC Scopus subject areas

    • Psychiatry and Mental health

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