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Strong Synaptic Transmission Impact by Copy Number Variations in Schizophrenia

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Strong Synaptic Transmission Impact by Copy Number Variations in Schizophrenia Strong synaptic transmission impact by copy number variations in schizophrenia Joseph T. Glessnera, Muredach P. Reillyb, Cecilia E. Kima, Nagahide Takahashic, Anthony Albanoa, Cuiping Houa, Jonathan P. Bradfielda, Haitao Zhanga, Patrick M. A. Sleimana, James H. Florya, Marcin Imielinskia, Edward C. Frackeltona, Rosetta Chiavaccia, Kelly A. Thomasa, Maria Garrisa, Frederick G. Otienoa, Michael Davidsond, Mark Weiserd, Abraham Reichenberge, Kenneth L. Davisc,JosephI.Friedmanc, Thomas P. Cappolab, Kenneth B. Marguliesb, Daniel J. Raderb, Struan F. A. Granta,f,g, Joseph D. Buxbaumc, Raquel E. Gurh, and Hakon Hakonarsona,f,g,1 aCenter for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104; bPenn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; cConte Center for the Neuroscience of Mental Disorders and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, 10029; dSheba Medical Center, Tel Hashomer, 52621, Israel; eMount Sinai and Institute of Psychiatry, King’s College, London, SE5 8AF, United Kingdom; fDivision of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104; gDepartment of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and hSchizophrenia Center, Neuropsychiatry Division, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104 Edited by James R. Lupski, Baylor College of Medicine, Houston, TX, and accepted by the Editorial Board April 13, 2010 (received for review January 7, 2010) Schizophrenia is a psychiatric disorder with onset in late adoles- contribute to the complex etiology underlying various psychiatric cence and unclear etiology characterized by both positive and ne- and neurodevelopmental disorders (13, 14). Whereas rare recurrent gative symptoms, as well as cognitive deficits. To identify copy CNVs have been reported in patients with schizophrenia, these number variations (CNVs) that increase the risk of schizophrenia, explain only a small fraction of the genetic risk of this common we performed a whole-genome CNV analysis on a cohort of 977 complex disease (15, 16). Accordingly, we have applied approaches schizophrenia cases and 2,000 healthy adults of European ancestry with the objective of discovering variations and biological pathways fi who were genotyped with 1.7 million probes. Positive ndings contributing to the pathobiology of schizophrenia. were evaluated in an independent cohort of 758 schizophrenia Our study cohort included 1,206 schizophrenia cases and 1,378 GENETICS cases and 1,485 controls. The Gene Ontology synaptic transmission neurologically normal controls from the Genetic Association In- P × family of genes was notably enriched for CNVs in the cases ( = 1.5 formation Network (GAIN), genotyped on the Affymetrix 6.0 −7 CACNA1B DOC2A 10 ). Among these, and , both calcium-signaling array (17). We downloaded the data files from the database of genes responsible for neuronal excitation, were deleted in 16 cases Genotype and Phenotype (dbGaP) (ncbi.nlm.nih.gov/gap; study and duplicated in 10 cases, respectively. In addition, RET and RIT2, phs000021.v2.p1) and analyzed them for CNV associations. This both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive GAIN project, also known as Molecular Genetics of Schizophre- to seven cases, and RIT2 deletions were overrepresented common nia (MGS), previously reported linkage to 8p23.3-p21.2 and variant CNVs in the schizophrenia cases. Our results suggest that 11p13.1-q14.1 (18) and association of FGFR2 and ZNF804A in novel variations involving the processes of synaptic transmission a genome-wide association study (GWAS) (19, 20), but failed to contribute to the genetic susceptibility of schizophrenia. associate previously reported candidate genes (21) and found novel associations of common genotype variants on 6p22.1 (22). genetics | genomics | neurobiology In addition, 351 schizophrenia cases and 2,107 control subjects from the University of Pennsylvania (UPenn) were included, along chizophrenia is a devastating mental disorder characterized with 178 schizophrenia cases from Mount Sinai School of Medi- Sby reality distortion. Common features are positive symptoms cine and Sheba Medical Center. Both cohorts were genotyped on of hallucinations, delusions, disorganized speech, and abnormal the Affymetrix 6.0 array at The Children’s Hospital of Philadel- thought process; negative symptoms of social deficit, lack of mo- phia (CHOP). tivation, anhedonia, and impaired emotion processing; and cog- Control subjects from UPenn were originally recruited in re- nitive deficits with occupational dysfunction. Onset of symptoms lation with cross-sectional case-control studies on HDL choles- typically occurs in late adolescence or early adulthood, with ∼1.5% terol, coronary angiography, and heart transplantation outcomes of the population affected (1). at UPenn. The average age of the control cohort was 62 years, Previous studies have associated various copy number variations and no subjects had any major psychoses or other psychological (CNVs) with schizophrenia including deletions of 22q11.2 (2), symptoms. NRXN1 (3), APBA2 (3), and CNTNAP2 (4). These CNVs are rare, Samples from GAIN and UPenn were subsequently randomly however, and they account for a relatively small proportion of the divided into a discovery cohort of 977 schizophrenia cases and 2,000 overall genetic risk in schizophrenia. Large, rare CNVs affecting controls and an independent replication cohort of 758 schizophre- many different genes enriched in neurodevelopmental pathways nia cases and 1,485 controls, including samples from Mount Sinai – have been reported as well (5 7), with novel deletions and dupli- School of Medicine/Sheba Medical Center. Bias of contribution cations of genes observed in 15% of cases versus 5% of controls in to specific loci among these sample sources was monitored. one study (P = 0.0008) (5). A study of CNVs in Chinese schizo- phrenia patients detected no significant difference in rare CNVs between cases and controls, however (8). Another study of 1,013 fi Author contributions: J.D.B., R.E.G., and H.H. designed research; M.P.R., C.E.K., N.T., A.A., cases and 1,084 controls of European ancestry also failed to nd C.H., J.P.B., H.Z., P.M.A.S., J.H.F., M.I., E.C.F., R.C., K.A.T., M.G., F.G.O., M.D., M.W., A.R., more rare CNVs >100 kb in cases or enrichment for neuro- K.L.D., J.I.F., T.P.C., K.B.M., D.J.R., S.F.A.G., J.D.B., and R.E.G. performed research; J.T.G. developmental pathways (9). Specific loci exhibiting runs of ho- analyzed data; and J.T.G. and H.H. wrote the paper. mozygosity (ROHs) also have been associated with schizophrenia The authors declare no conflict of interest. −4 (10), and association of de novo CNVs (P =7.8× 10 ) was recently This article is a PNAS Direct Submission. J.L. is a guest editor invited by the Editorial Board. reported in sporadic schizophrenia cases compared with controls 1To whom correspondence should be addressed. E-mail: [email protected]. fi (11). Comparison of genomic ndings in schizophrenia and autism This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. has suggested a diametric etiology (12). CNVs have been shown to 1073/pnas.1000274107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1000274107 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 All subjects were diagnosed with schizophrenia based on cri- might overlook bias introduced by certain samples with large teria in the Diagnostic and Statistical Manual of Mental Disorders numbers of CNVs called (typically as a result of sample quality), IV (DSM-IV) (23). Subjects had at least 6 months’ duration of sample age, cell line artifacts, probe resolution, GC content, lack of the “A” criteria for schizophrenia, were at least 18 years old at genotype information, and subphenotype characterization. the time of the interview, and were known by their informant for When using a threshold for CNV calls of 100 kb and larger, we at least 2 years. Additional demographic data for the study replicated the 22q11.2 deletions robustly and detected CNV subjects are presented in Tables S1 and S2. associations with GRID1, CNTNAP2, DISC1, and NRXN1,as Various array technologies, including aCGH, Affymetrix reported previously (2–4). However, further review revealed GeneChip and Illumina BeadChip, have been used to identify multiple smaller CNVs (<100 kb) in these regions in both the CNVs in healthy subjects. Previous studies have revealed signifi- cases and controls, suggesting that large CNVs in these regions cant common variations in the general healthy population (24). and additional environmental and/or genetic factors might be Various algorithms are also being used to call CNVs, most of required for expression of the schizophrenia phenotype. Dele- which use the hidden Markov model (HMM) as implemented in tions of 1q21.1 and 15q13.3 (6) were detected, but were not PennCNV (25). Clustering of all Affymetrix data in one run with significantly associated with schizophrenia (Figs. S1 and S2). Affymetrix Power Tools (APT), which implements BirdSeed, is We next carried out a genome-wide single SNP association essential to minimize the stratification resulting from clustering analysis. We found no loci that were significant genome-wide; bias. Indeed, the genotypes provided by dbGaP in matrix format however, we detected nominally significant associations to several had significant clustering bias among three apparent runs of APT genes that are essential for brain development and function and of on sample subsets based on Eigenstrat analysis. We ran APT with potential relevance to schizophrenia, including, but not limited to, − − all Affymetrix 6.0 samples in a single run, yielding a typical result ASTN2, CNTN5, and GRIK2 (P = 2.29 × 10 6, 6.63 × 10 6, and − showing few African and Asian admixed samples without the 2.53 × 10 5, respectively; Table 1).
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