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Schizophrenia Bulletin vol. 42 no. 2 pp. 288–300, 2016 doi:10.1093/schbul/sbv135 Advance Access publication September 24, 2015 Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk Mark Z. Kos*,1, Melanie A. Carless2, Juan Peralta1, August Blackburn2, Marcio Almeida1, David Roalf3, Michael F. Pogue-Geile4, Konasale Prasad5, Ruben C. Gur3, Vishwajit Nimgaonkar6, Joanne E. Curran1, Ravi Duggirala1, David C. Glahn7, John Blangero1, Raquel E. Gur3, and Laura Almasy1 1South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX; 2Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX; 3Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 4Department of Psychology, University of Pittsburgh, Pittsburgh, PA; 5Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA; 6Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA; 7Department of Psychiatry, Olin Neuropsychiatric Research Center, Yale School of Medicine, Hartford, CT *To whom correspondence should be addressed; South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, San Antonio, TX 78229, US; tel: 210-585-9772, fax: 210-582-5836, e-mail: [email protected] Schizophrenia is a mental disorder characterized by effects on neurocognition and schizophrenia risk, identify- impairments in behavior, thought, and neurocognitive per- ing a potential pathogenic mechanism for schizophrenia formance. We searched for susceptibility loci at a quantita- spectrum disorders. tive trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often Key words: schizophrenia/cognition/SYNPO/WWC1/ compromised in schizophrenia patients and their unaf- synaptic plasticity fected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original Introduction linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32–35.3, we Schizophrenia is a complex, highly heritable brain disor- analyzed 407 protein-altering variants for association with der characterized by disturbances in behavior, thought, ABF and schizophrenia status. For replication, significant, and emotion.1 Although a number of genes and neuro- Bonferroni-corrected findings were tested against cognitive biological pathways have been implicated in linkage and traits in Mexican American families (n = 959), as well as genome-wide association studies, much of the genetic interrogated for schizophrenia risk using GWAS results liability of schizophrenia remains to be explained,2,3 sug- from the Psychiatric Genomics Consortium (PGC). From gesting a polygenic architecture,4 likely confounded by the gene SYNPO, rs6579797 (MAF = 0.032) shows signifi- the clinical heterogeneity of the disorder.5 cant associations with ABF (P = .015) and schizophrenia Deficits in cognitive functions have been commonly (P = .040), as well as jointly (P = .0027). In the Mexican observed in schizophrenia patients, and in smaller mag- American pedigrees, rs6579797 exhibits significant associ- nitude in unaffected family members, especially for execu- ations with IQ (P = .011), indicating more global effects on tive function, learning, and memory,6–10 which may reflect neurocognition. From the PGC results, other SYNPO vari- innate, underlying differences that mediate the familial ants were identified with near significant effects on schizo- risk of schizophrenia. Analysis of such endophenotypes phrenia risk, with a local linkage disequilibrium block can delineate the psychiatric phenome and allow for iden- displaying signatures of positive selection. A second mis- tification of etiological mechanisms that are more proxi- sense variant within the QTL, rs17551608 (MAF = 0.19) mate to gene action than disease endpoints.11 Thus, genes in the gene WWC1, also displays a significant effect that moderately influence the risk of schizophrenia may on schizophrenia in our exome sequences (P = .038). exhibit substantially stronger effects on cognition, making Remarkably, the protein products of SYNPO and WWC1 them easier to detect at genome-wide significance levels. are interaction partners involved in AMPA receptor traf- This approach was employed by Almasy et al12 who ficking, a brain process implicated in synaptic plasticity. conducted a genome-wide linkage screen of schizo- Our study reveals variants in these genes with significant phrenia and cognitive performance in affected families, © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected] 288 Exome Data Implicate AMPA Trafficking in SCZ Risk discovering a quantitative trait locus (QTL) for abstrac- Phenotyping tion and mental flexibility (ABF) on chromosome 5q DSM-IV diagnoses were determined from: (1) the (log of odds [LOD] = 3.43; P = .011), with effects on Diagnostic Interview for Genetics Studies, version 2.040; schizophrenia risk revealed through bivariate analysis. (2) the Family Interview for Genetics Studies41; and (3) Although several linkage studies of schizophrenia have reviews of medical records. Lifetime best-estimate diag- 13–20 implicated chromosome 5q, these findings provide noses were arrived at by 2 investigators, each blind to the insight into the potential neuropathology of the region, familial relationships among participants (kappa > 0.8). as the neural underpinnings for ABF have been localized In total, 106 individuals were diagnosed with schizophre- 21 primarily to the prefrontal brain circuitry, including the nia or SAD, with 75% undergoing treatment at the time 22 dorsolateral and superior prefrontal cortices, whose of assessment. Effects of medication on neurocognitive anatomical abnormalities and activity levels have been measures have been shown to be negligible or subtle.42–44 23–27 strongly associated with schizophrenia. In addition to schizophrenia, other psychiatric conditions The specific genetic variants contributing to this broad identified included schizotypal personality disorder, psy- linkage region have yet to be determined. Previous endo- chotic disorder, and different forms of bipolar disorder. phenotype studies that have targeted schizophrenia Participants completed a computerized test battery45,46 candidate genes have been successful in identifying risk designed to evaluate 9 neurocognitive domains.39 ABF 28–38 variants, including ones for cognitive traits. In this was assessed using the Penn Conditional Exclusion Test article, we investigate the QTL at chromosome 5q, focus- (PCET),47 for which participants are required to select ing on nonsynonymous variation from 238 local genes. one of 4 shapes for exclusion based on a sorting principle. Exome sequencing was conducted on 134 samples from An efficiency score was calculated as the averagez score 8 European American families drawn from the original for performance accuracy and speed. linkage study, including 25 diagnosed with schizophrenia or schizoaffective disorder. Significant SNP associations for ABF and schizophrenia were followed up in indepen- Exome Sequencing dent Mexican American families for select neurocognitive We used the Illumina TruSeq platform (Illumina) for sam- measurements, as well as examined among the GWAS ple preparation, exome enrichment, and sequencing on results from the Psychiatric Genomics Consortium the Illumina HiSeq 2000 instrument. In total, 62 Mb were (PGC). We identify a number of potential risk loci, with sequenced, yielding uniform coverage of 201 121 exons implications for the neurobiological basis of cognitive from 20 794 genes. FASTQ files of demultiplexed paired impairment as observed in schizophrenia patients. sequencing reads of 100 bp were produced by CASAVA 1.8 suite and mapped to the UCSC human genome reference Methods assembly 19 (hg19) using BWA (v. 0.6.1).48 Mapped reads were analyzed with SAMtools (v. 0.1.12a)49 and Picard (v. Family Samples 1.56) (http://picard.sourceforge.net) to mark likely PCR The Multiplex-Multigenerational Genetic Investigation duplicates and ensure consistency of the mapped data, of Schizophrenia (MGI) has been described previ- with the output processed with the GATK (v. 1.6) pack- ously.12,39 Families were recruited through a European age50 (for more detail, see supplementary methods). American individual with schizophrenia, who had at least We called a total of 380 895 high-quality SNPs, with an 1 first-degree relative with schizophrenia or schizoaffec- average of 35 reads per variant, each functionally anno- tive disorder (SAD), depressed type. From the extended tated with ANNOVAR.51 At the QTL for ABF efficiency families, all the available first-, second- and third-degree at 5q32–35.3, spanning approximately 35 Mb, 6518 SNPs relatives 15 years of age or older were invited to par- were called, encompassing 366 different genes. To focus ticipate. MGI was approved by the Institutional Review on sites of potential functional relevance, sequence data Board of each of the 3 collaborating institutions, with all were filtered for variant quality LOD scores of 4.0 or participants providing informed consent. In the case of greater, have no missing genotype data, and represent minors under age 18 who provided assent,
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