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 Blangero, Raquel E. Gur, Laura Almasy

Research output: Contribution to journalArticlepeer-review

11 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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