Psychiatry - Research Publications

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    Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia
    Mostaid, MS ; Lee, TT ; Chana, G ; Sundram, S ; Weickert, CS ; Pantelis, C ; Everall, I ; Bousman, C (FRONTIERS MEDIA SA, 2017-11-06)
    Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini-Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG-ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG-ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.
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    Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis
    Bousman, CA ; Yung, AR ; Pantelis, C ; Ellis, JA ; Chavez, RA ; Nelson, B ; Lin, A ; Wood, SJ ; Amminger, GP ; Velakoulis, D ; McGorry, PD ; Everall, IP ; Foley, DL (NATURE PUBLISHING GROUP, 2013-04)
    Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4-14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37-4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05-2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ∼1.5-fold, with 71.4% of those carrying a combination of 3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis.
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    The impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes
    Wells, R ; Swaminathan, V ; Sundram, S ; Weinberg, D ; Bruggemann, J ; Jacomb, I ; Cropley, V ; Lenroot, R ; Pereira, AM ; Zalesky, A ; Bousman, C ; Pantelis, C ; Weickert, CS ; Weickert, TW (SPRINGERNATURE, 2015)
    BACKGROUND: Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group. METHODS: A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups. RESULTS: A total of 157 patients (29%) classified as 'preserved' performed within one s.d. of control means in all cognitive domains. Patients classified as 'deteriorated' (n=239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as 'compromised,' performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures. CONCLUSIONS: In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group.
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    Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations
    Liu, C ; Bousman, CA ; Pantelis, C ; Skafidas, E ; Zhang, D ; Yue, W ; Everall, IP (SPRINGERNATURE, 2017-02-21)
    Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred the notion that schizophrenia may be better conceptualized as a pathway(s) disorder. Here, we empirically tested this notion by conducting a pathway-wide association study (PWAS) encompassing 255 experimentally validated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways among 5033 individuals diagnosed with schizophrenia and 5332 unrelated healthy controls across three distinct ethnic populations; European-American (EA), African-American (AA) and Han Chinese (CH). We identified 103, 74 and 87 pathways associated with schizophrenia liability in the EA, CH and AA populations, respectively. About half of these pathways were uniquely associated with schizophrenia liability in each of the three populations. Five pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across all three populations and the single-nucleotide polymorphism sets representing these five pathways were enriched for single-nucleotide polymorphisms with regulatory function. Our findings provide empirical support for schizophrenia as a pathway disorder and suggest schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity.
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    Meta-analysis reveals associations between genetic variation in the 5′ and 3′regions of Neuregulin-1 and schizophrenia
    Mostaid, MS ; Mancuso, SG ; Liu, C ; Sundram, S ; Pantelis, C ; Everall, IP ; Bousman, CA (SPRINGERNATURE, 2017-01-17)
    Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5' and 3' regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5'-end and two (rs2954041 and rs10503929) near the 3'-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5' and 3' ends of NRG1 are associated with schizophrenia and provide renewed justification for further investigation of NRG1's role in the pathophysiology of schizophrenia.
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    Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients
    Mostaid, MS ; Lee, TT ; Chana, G ; Sundram, S ; Weickert, CS ; Pantelis, C ; Everall, I ; Bousman, C (NATURE PUBLISHING GROUP, 2017-12-11)
    Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFα (P = 0.0175), EGFβ (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-β1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-β1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFα (P = 0.02) and EGFβ (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.
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    Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group
    Kelly, S ; Jahanshad, N ; Zalesky, A ; Kochunov, P ; Agartz, I ; Alloza, C ; Andreassen, OA ; Arango, C ; Banaj, N ; Bouix, S ; Bousman, CA ; Brouwer, RM ; Bruggemann, J ; Bustillo, J ; Cahn, W ; Calhoun, V ; Cannon, D ; Carr, V ; Catts, S ; Chen, J ; Chen, J-X ; Chen, X ; Chiapponi, C ; Cho, KK ; Ciullo, V ; Corvin, AS ; Crespo-Facorro, B ; Cropley, V ; De Rossi, P ; Diaz-Caneja, CM ; Dickie, EW ; Ehrlich, S ; Fan, F-M ; Faskowitz, J ; Fatouros-Bergman, H ; Flyckt, L ; Ford, JM ; Fouche, J-P ; Fukunaga, M ; Gill, M ; Glahn, DC ; Gollub, R ; Goudzwaard, ED ; Guo, H ; Gur, RE ; Gur, RC ; Gurholt, TP ; Hashimoto, R ; Hatton, SN ; Henskens, FA ; Hibar, DP ; Hickie, IB ; Hong, LE ; Horacek, J ; Howells, FM ; Pol, HEH ; Hyde, CL ; Isaev, D ; Jablensky, A ; Jansen, PR ; Janssen, J ; Jonsson, EG ; Jung, LA ; Kahn, RS ; Kikinis, Z ; Liu, K ; Klauser, P ; Knoechel, C ; Kubicki, M ; Lagopoulos, J ; Langen, C ; Lawrie, S ; Lenroot, RK ; Lim, KO ; Lopez-Jaramillo, C ; Lyall, A ; Magnotta, V ; Mandl, RCW ; Mathalon, DH ; McCarley, RW ; McCarthy-Jones, S ; McDonald, C ; McEwen, S ; McIntosh, A ; Melicher, T ; Mesholam-Gately, R ; Michie, PT ; Mowry, B ; Mueller, BA ; Newell, DT ; O'Donnell, P ; Oertel-Knoechel, V ; Oestreich, L ; Paciga, SA ; Pantelis, C ; Pasternak, O ; Pearlson, G ; Pellicano, GR ; Pereira, A ; Zapata, JP ; Piras, F ; Potkin, SG ; Preda, A ; Rasser, PE ; Roalf, DR ; Roiz, R ; Roos, A ; Rotenberg, D ; Satterthwaite, TD ; Savadjiev, P ; Schall, U ; Scott, RJ ; Seal, ML ; Seidman, LJ ; Weickert, CS ; Whelan, CD ; Shenton, ME ; Kwon, JS ; Spalletta, G ; Spaniel, F ; Sprooten, E ; Stablein, M ; Stein, DJ ; Sundram, S ; Tan, Y ; Tan, S ; Tang, S ; Temmingh, HS ; Westlye, LT ; Tonnesen, S ; Tordesillas-Gutierrez, D ; Doan, NT ; Vaidya, J ; van Haren, NEM ; Vargas, CD ; Vecchio, D ; Velakoulis, D ; Voineskos, A ; Voyvodic, JQ ; Wang, Z ; Wan, P ; Wei, D ; Weickert, TW ; Whalley, H ; White, T ; Whitford, TJ ; Wojcik, JD ; Xiang, H ; Xie, Z ; Yamamori, H ; Yang, F ; Yao, N ; Zhang, G ; Zhao, J ; van Erp, TGM ; Turner, J ; Thompson, PM ; Donohoe, G (SPRINGERNATURE, 2018-05)
    The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
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    Meta-analysis supports GWAS-implicated link between GRM3 and schizophrenia risk
    Saini, SM ; Mancuso, SG ; Mostaid, MS ; Liu, C ; Pantelis, C ; Everall, IP ; Bousman, CA (SPRINGERNATURE, 2017-08-08)
    Genome-wide association study (GWAS) evidence has identified the metabotropic glutamate receptor 3 (GRM3) gene as a potential harbor for schizophrenia risk variants. However, previous meta-analyses have refuted the association between GRM3 single-nucleotide polymorphisms (SNPs) and schizophrenia risk. To reconcile these conflicting findings, we conducted the largest and most comprehensive meta-analysis of 14 SNPs in GRM3 from a total of 11 318 schizophrenia cases, 13 820 controls and 486 parent-proband trios. We found significant associations for three SNPs (rs2237562: odds ratio (OR)=1.06, 95% confidence interval (CI)=1.02-1.11, P=0.017; rs13242038: OR=0.90, 95% CI=0.85-0.96, P=0.016 and rs917071: OR=0.94, 95% CI=0.91-0.97, P=0.003). Two of these SNPs (rs2237562, rs917071) were in strong-to-moderate linkage disequilibrium with the top GRM3 GWAS significant SNP (rs12704290) reported by the Schizophrenia Working Group of the Psychiatric Genomics Consortium. We also found evidence for population stratification related to rs2237562 in that the 'risk' allele was dependent on the population under study. Our findings support the GWAS-implicated link between GRM3 genetic variation and schizophrenia risk as well as the notion that alleles conferring this risk may be population specific.
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    The schizophrenia genetics knowledgebase: a comprehensive update of findings from candidate gene studies
    Liu, C ; Kanazawa, T ; Tian, Y ; Saini, SM ; Mancuso, S ; Mostaid, MS ; Takahashi, A ; Zhang, D ; Zhang, F ; Yu, H ; Shin, HD ; Cheong, HS ; Ikeda, M ; Kubo, M ; Iwata, N ; Woo, S-I ; Yue, W ; Kamatani, Y ; Shi, Y ; Li, Z ; Everall, I ; Pantelis, C ; Bousman, C (NATURE PUBLISHING GROUP, 2019-08-27)
    Over 3000 candidate gene association studies have been performed to elucidate the genetic underpinnings of schizophrenia. However, a comprehensive evaluation of these studies' findings has not been undertaken since the decommissioning of the schizophrenia gene (SzGene) database in 2011. As such, we systematically identified and carried out random-effects meta-analyses for all polymorphisms with four or more independent studies in schizophrenia along with a series of expanded meta-analyses incorporating published and unpublished genome-wide association (GWA) study data. Based on 550 meta-analyses, 11 SNPs in eight linkage disequilibrium (LD) independent loci showed Bonferroni-significant associations with schizophrenia. Expanded meta-analyses identified an additional 10 SNPs, for a total of 21 Bonferroni-significant SNPs in 14 LD-independent loci. Three of these loci (MTHFR, DAOA, ARVCF) had never been implicated by a schizophrenia GWA study. In sum, the present study has provided a comprehensive summary of the current schizophrenia genetics knowledgebase and has made available all the collected data as a resource for the research community.
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    Interrogating the Evolutionary Paradox of Schizophrenia: A Novel Framework and Evidence Supporting Recent Negative Selection of Schizophrenia Risk Alleles
    Liu, C ; Everall, I ; Pantelis, C ; Bousman, C (FRONTIERS MEDIA SA, 2019-04-30)
    Schizophrenia is a psychiatric disorder with a worldwide prevalence of ∼1%. The high heritability and reduced fertility among schizophrenia patients have raised an evolutionary paradox: why has negative selection not eliminated schizophrenia associated alleles during evolution? To address this question, we examined evolutionary markers, known as modern-human-specific (MD) sites and archaic-human-specific sites, using existing genome-wide association study (GWAS) data from 34,241 individuals with schizophrenia and 45,604 healthy controls included in the Psychiatric Genomics Consortium (PGC). By testing the distribution of schizophrenia single nucleotide polymorphisms (SNPs) with risk and protective effects in the human-specific sites, we observed a negative selection of risk alleles for schizophrenia in modern humans relative to archaic humans (e.g., Neanderthal and Denisovans). Such findings indicate that risk alleles of schizophrenia have been gradually removed from the modern human genome due to negative selection pressure. This novel evidence contributes to our understanding of the genetic origins of schizophrenia.