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Schizophr Bull. 2016 Mar;42(2):288-300. doi: 10.1093/schbul/sbv135. Epub 2015 Sep 24.

Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk.

Author information

1
South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX; mark.kos@utrgv.edu.
2
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX;
3
South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
4
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
5
Department of Psychology, University of Pittsburgh, Pittsburgh, PA;
6
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA;
7
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA;
8
Department of Psychiatry, Olin Neuropsychiatric Research Center, Yale School of Medicine, Hartford, CT.

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.

KEYWORDS:

SYNPO; WWC1; cognition; schizophrenia; synaptic plasticity

PMID:
26405221
PMCID:
PMC4753604
[Available on 2017-03-01]
DOI:
10.1093/schbul/sbv135
[Indexed for MEDLINE]
Free PMC Article

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