Psychiatry - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 14
  • Item
    Thumbnail Image
    FRONTOSTRIATAL CONNECTIVITY IN TREATMENT-RESISTANT SCHIZOPHRENIA: RELATIONSHIP TO POSITIVE SYMPTOMS AND COGNITIVE FLEXIBILITY
    Cropley, V ; Ganella, E ; Wannan, C ; Zalesky, A ; Van Rheenen, T ; Bousman, C ; Everall, I ; Fornito, A ; Pantelis, C (OXFORD UNIV PRESS, 2018-04)
  • Item
    Thumbnail Image
    Navigating the Labyrinth of Pharmacogenetic Testing: A Guide to Test Selection
    Bousman, CA ; Zierhut, H ; Muller, DJ (WILEY, 2019-08)
  • Item
    Thumbnail Image
    SimPEL: Simulation-based power estimation for sequencing studies of low-prevalence conditions
    Mak, L ; Li, M ; Cao, C ; Gordon, P ; Tarailo-Graovac, M ; Bousman, C ; Wang, P ; Long, Q (WILEY, 2018-07)
    Power estimations are important for optimizing genotype-phenotype association study designs. However, existing frameworks are designed for common disorders, and thus ill-suited for the inherent challenges of studies for low-prevalence conditions such as rare diseases and infrequent adverse drug reactions. These challenges include small sample sizes and the need to leverage genetic annotation resources in association analyses for the purpose of ranking potential causal genes. We present SimPEL, a simulation-based program providing power estimations for the design of low-prevalence condition studies. SimPEL integrates the usage of gene annotation resources for association analyses. Customizable parameters, including the penetrance of the putative causal allele and the employed pathogenic scoring system, allow SimPEL to realistically model a large range of study designs. To demonstrate the effects of various parameters on power, we estimated the power of several simulated designs using SimPEL and captured power trends in agreement with observations from current literature on low-frequency condition studies. SimPEL, as a tool, provides researchers studying low-frequency conditions with an intuitive and highly flexible avenue for statistical power estimation. The platform-independent "batteries included" executable and default input files are available at https://github.com/precisionomics/SimPEL.
  • Item
    Thumbnail Image
    S187. EXPLORING NEURODEVELOPMENTAL AND FAMILIAL ORIGINS OF NEUROLOGICAL SOFT SIGNS IN SCHIZOPHRENIA
    Cooper, R ; Van Rheenen, T ; Zalesky, A ; Wannan, C ; Wang, Y ; Bousman, C ; Everall, I ; Pantelis, C ; Cropley, V (Oxford University Press (OUP), 2020-05-18)
    Abstract Background The neurodevelopmental hypothesis is the most widely regarded framework for understanding the development of schizophrenia. One of the most commonly cited pieces of evidence for this theory is the presence of neurological soft signs (NSS) in individuals prior to the onset of psychosis. Increased NSS is also reported in unaffected individuals with a family history of schizophrenia, suggesting that NSS may also have a familial component. Although much research has implicated reduced grey matter volume (GMV) in association with these signs, a subcomponent of volume, known as gyrification, has been poorly researched. Given that gyrification develops predominantly in prenatal life it may be particularly susceptible to a neurodevelopmental abnormality. The aims of this study were to investigate the neurodevelopmental and familial underpinnings of NSS in schizophrenia. Specifically, we examined the brain structural correlates, at both the level of GMV and gyrification, of NSS in individuals with schizophrenia, their unaffected relatives and healthy controls. We aimed to determine whether gyrification better predicted NSS severity than GMV, and whether the relationship between brain structure and NSS were present in a step-wise manner across the diagnostic groups. Methods The sample consisted of individuals with schizophrenia (N=66), their unaffected relatives (N=27) and healthy controls (N=53). NSS was assessed with the Neurological Evaluation Scale (NES), and GMV and gyrification were extracted from MRI using the FreeSurfer imaging suite. A series of analysis of covariance were used to compare NES scores and brain measures between the groups. Separate linear regression analyses were used to assess whether whole-brain GMV and gyrification predicted NES above a covariate-only model. Moderation analyses were used to assess whether the relationship between NES and brain structure were different between the diagnostic groups. Error control was achieved with a false discovery rate of 5%. Results NES was significantly higher in schizophrenia patients than relatives (p<.0001), who were in turn significantly higher than controls (p=.034). With the groups combined, lower GMV (p<.0001), as well as lower gyrification (p=.004), predicted higher NES above a covariate-only model. GMV predicted greater variance in NSS in comparison to gyrification, explaining an additional 20.3% of the variance in NES, in comparison to the additional 5.5% of variance in NES explained by gyrification. Diagnostic group moderated the association between GMV and NES (p=.019), but not between gyrification and NES (p=.245). Follow-up tests revealed that lower GMV was associated with higher NES in schizophrenia (t=-4.5, p<.0001) and relatives (t=-2.5, p=.015) but not controls (t=-1.9, p=.055). Discussion Our findings indicate that NSS is heritable, being present in patients with established schizophrenia, and to a lesser extent, in unaffected relatives. Consistent with previous research, we revealed that GMV predicted NSS severity, suggesting that abnormalities in volume may underlie these signs. We additionally found that gyrification predicted, although to a lesser extent than volume, NSS severity, providing some support for schizophrenia being of possible neurodevelopmental origin. Evidence for an association between volume and NSS in relatives, whom are not confounded by illness-related factors such as medication and symptom severity, indicates a familial contribution to the neural underpinnings of NSS. Together, our study suggests that there may be various aetiological pathways underlying soft signs across the schizophrenia diathesis, some that may be of familial or neurodevelopmental origin.
  • Item
    No Preview Available
    A Call for Clear and Consistent Communications Regarding the Role of Pharmacogenetics in Antidepressant Pharmacotherapy
    Hicks, JK ; Bishop, JR ; Gammal, RS ; Sangkuhl, K ; Bousman, CA ; Leeder, JS ; Llerena, A ; Mueller, DJ ; Ramsey, LB ; Scott, SA ; Skaar, TC ; Caudle, KE ; Klein, TE ; Gaedigk, A (WILEY, 2020-01)
  • Item
    Thumbnail Image
    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.
  • Item
    Thumbnail Image
    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.
  • Item
    Thumbnail Image
    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.
  • Item
    Thumbnail Image
    "Black box'' pharmacogenetic decision-support tools in psychiatry
    Bousman, CA ; Eyre, HA (ASSOC BRASILEIRA PSIQUIATRIA, 2020-04)
  • Item
    Thumbnail Image
    Genetic associations with clozapine-induced myocarditis in patients with schizophrenia
    Lacaze, P ; Ronaldson, KJ ; Zhang, EJ ; Alfirevic, A ; Shah, H ; Newman, L ; Strahl, M ; Smith, M ; Bousman, C ; Francis, B ; Morris, AP ; Wilson, T ; Rossello, F ; Powell, D ; Vasic, V ; Sebra, R ; McNeil, JJ ; Pirmohamed, M (NATURE PUBLISHING GROUP, 2020-01-27)
    Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10-6), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10-7; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10-5). Combining clinical and genetic factors together increased the proportion of variability accounted for (r2 0.73, P = 9.8 × 10-9). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.