title: Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk.
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.
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX; mark.kos@utrgv.edu.
authors.forename: Mark Z
authors.initials: MZ
authors.lastname: Kos
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX;
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
authors.forename: Juan
authors.initials: J
authors.lastname: Peralta
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX;
authors.forename: August
authors.initials: A
authors.lastname: Blackburn
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
authors.forename: Marcio
authors.initials: M
authors.lastname: Almeida
authors.affiliation: Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: David
authors.initials: D
authors.lastname: Roalf
authors.affiliation: Department of Psychology, University of Pittsburgh, Pittsburgh, PA;
authors.forename: Michael F
authors.initials: MF
authors.lastname: Pogue-Geile
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA;
authors.forename: Konasale
authors.initials: K
authors.lastname: Prasad
authors.affiliation: Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA;
authors.forename: Vishwajit
authors.initials: V
authors.lastname: Nimgaonkar
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
authors.forename: Ravi
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: Department of Psychiatry, Olin Neuropsychiatric Research Center, Yale School of Medicine, Hartford, CT.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX;
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
mesh_terms: D003072:Cognition Disorders / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci; D017470:Receptors, Glutamate / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017470:Receptors, Glutamate; C503967:SYNPO protein, human; C513637:WWC1 protein, human; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human
keywords: SYNPO; WWC1; cognition; schizophrenia; synaptic plasticity