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

Authors

Mark Kos, The University of Texas Rio Grande Valley
Melanie A. Carless, The University of Texas at San Antonio
Juan M. Peralta, The University of Texas Rio Grande Valley
August N. Blackburn, The University of Texas Rio Grande Valley
Marcio Almeida, The University of Texas Rio Grande Valley
David Roalf
Michael F. Pogue-Geile
Joanne E. Curran, The University of Texas Rio Grande Valley
Ravi Duggirala, The University of Texas Rio Grande Valley
John Blangero, The University of Texas Rio Grande Valley
Laura Almasy, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

9-2015

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.

Comments

© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Recommended Citation

Kos, M. Z., Carless, M. A., Peralta, J., Blackburn, A., Almeida, M., Roalf, D., Pogue-Geile, M. F., Prasad, K., Gur, R. C., Nimgaonkar, V., Curran, J. E., Duggirala, R., Glahn, D. C., Blangero, J., Gur, R. E., & Almasy, L. (2016). Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk. Schizophrenia bulletin, 42(2), 288–300. https://doi.org/10.1093/schbul/sbv135

Publication Title

Schizophrenia bulletin

DOI

10.1093/schbul/sbv135

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics