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100 MCQs from Dr. David Browne and Colleagues
Published in David Browne, Selena Morgan Pillay, Guy Molyneaux, Brenda Wright, Bangaru Raju, Ijaz Hussein, Mohamed Ali Ahmed, Michael Reilly, MCQs for the New MRCPsych Paper A, 2017
Dr Karen Fleming, Dr Michael Kenewali, Dr Manas Sarkar, Dr Daniel White
Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. The current evidence implicates specific genes in both disorders. Evidence supports neuregulin 1 (NGR1), dysbindin (DTNBP1), DISC1, D-amino acid oxidase activator (DAOA (G72)), D-amino acid oxidase (DAO) and regulator of G-protein signalling (RGS4) as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA (G72) and brain-derived neurotrophic factor (BDNF). Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification system that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA (G72), DISC1, and NGR1. (1, p 572)
Genetic influences on antisocial behaviour, problem substance use and schizophrenia: evidence from quantitative genetic and molecular genetic studies
Published in John C. Gunn, Pamela J. Taylor, Forensic Psychiatry, 2014
Pamela J Taylor, Marianne BM van den Bree, Nigel Williams, Terrie E Moffitt
Since 2000, molecular studies have revealed that our genomes carry many segments that are susceptible to deletion, duplication or complex rearrangements (Redon et al., 2006). Collectively, these segments are called copy number variants (CNVs) and can encompass none, one or even a large number of contiguous genes. Analysis of schizophrenia cohorts has yielded strong evidence that some CNVs can increase risk of developing schizophrenia. Individuals who carry a small interstitial deletion at chromosome 22q11 have an approximately 20–30-fold increase in risk of psychosis, especially schizophrenia (Murphy et al., 1999; Papolos et al., 1996; Pulver et al., 1994; Shprintzen et al., 1992). Similarly, a balanced reciprocal translocation between the long arms of chromosomes 1 and 11 has been shown to co-segregate with schizophrenia and other psychiatric disorders in a single Scottish family (Blackwood et al., 2001). The breakpoint site on chromosome 1 physically disrupts a gene which, because of its unknown function, was named ‘disrupted in schizophrenia 1’ (DISC1) (Millar et al., 2000). While the pathogenic mechanisms in this family remain unknown, subsequent molecular studies have implicated the DISC1 protein as well as its binding partners in mechanisms important in brain development (Fatemi et al., 2008; Pickard et al., 2007).
Genetics of Depression
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
Wolfgang Maier, Kathleen R. Merikangas
Besides the main stream of linkage and genetic association studies, a few groups used cytogenetic techniques to search for gene loci that implicate the disease through chromosomal abnormalities (particularly translocations and deletions). A series of regions were found which, unfortunately, did not overlap with regions linked to the disease (for overview see Ref. 132). Of particular interest is a Scottish family with several psychoses, bipolar disorder, and unipolar depression with a balanced translocation between two genes (chromosomes 1q42, 11q14.3). A gene in 11q14.3 disrupted in affected family members (DISC1) with up-to-now unknown function was detected and needs further investigation[134].
Impaired response to sleep deprivation in heterozygous Disc1 mutant mice
Published in The World Journal of Biological Psychiatry, 2022
Chih-Yu Tsao, Li-Heng Tuan, Lukas Jyuhn-Hsiarn Lee, Chih-Min Liu, Hai-Gwo Hwu, Li-Jen Lee
One susceptibility gene related to neuropsychiatric diseases is Disrupted-in-Schizophrenia 1 (DISC1). The link between DISC1 deficiency and psychiatric disorders was originally found in a Scottish pedigree (Millar et al. 2001). Most family members carrying a translocation (1;11) (q42.1;q14.3) of the DISC1 gene display various mental disorders, including schizophrenia, bipolar disorders, and major depression. Alterations in the DISC1 gene have also been observed in schizophrenia patients in Taiwan (Hwu et al. 2003; Liu et al. 2006), the United Kingdom (Hamshere et al. 2005), and the United States (Sachs et al. 2005). Although a large meta-analysis failed to find an association between DISC1 and schizophrenia (Mathieson et al. 2012), the link between schizophrenia and DISC1 interactome genes set has been suggested (Facal and Costas 2019). DISC1 and its binding partners regulate a number of cellular functions, such as neuronal migration, axon extension, dendritic differentiation, mitochondrial motility, cargo transport, and synaptic plasticity, and a variety of psychiatric phenotypes may result if the protein is disrupted (Brandon and Sawa 2011; Bradshaw and Porteous 2012; Lipina and Roder 2014; Shao et al. 2017; Tropea et al. 2018).
Voluntary exercise improves cognitive deficits in female dominant-negative DISC1 transgenic mouse model of neuropsychiatric disorders
Published in The World Journal of Biological Psychiatry, 2019
Hadar Segal-Gavish, Ran Barzilay, Ofri Rimoni, Daniel Offen
The disrupted in schizophrenia 1 (DISC1) gene is a candidate gene for major mental illness. DISC1 was initially identified in a unique Scottish pedigree in which a balanced chromosomal translocation t(1;11)(q42.1;q14.3) disrupts this gene and segregates with major psychiatric disorders such as schizophrenia (SCZ) and affective disorders, including bipolar and major depressive disorder (St Clair et al. 1990; Blackwood et al. 2001). Since then, despite the failure of genome-wide association studies to recognise DISC1 as a candidate risk gene associated with SCZ and bipolar disorder (International Schizophrenia Consortium et al. 2009; Stefansson et al. 2009), accumulating studies have shown that genetic variations of DISC1 are linked to aberrant neurodevelopment and synaptic function (Di Giorgio et al. 2008; Carless et al. 2011; Randall et al. 2014), and associated with a variety of neurodevelopmental disorders, such as SCZ (Hodgkinson et al. 2004), and autism spectrum disorders (Kilpinen et al. 2008).
Bioavailability and Neuroprotectivity of 3-(3, 4-dimethoxy phenyl)-1-4 (methoxy phenyl) prop-2-en-1-one against Schizophrenia: an in silico approach
Published in Journal of Receptors and Signal Transduction, 2019
Venkataramaiah Chintha, Rajendra Wudayagiri
Alterations in neurotransmitter systems (dopamine, glutamine, gamma-aminobutyric acid GABAergic, serotonergic, cholinergic, and opioid) provide a conclusive evidence of synaptic involvement in pathophysiological processes leading to symptoms of schizophrenia [8]. Dopamine, glutamate, and GABA are the neurotransmitter systems that have received the most attention. Hyper activation of the dopamine system was the first established hypothesis and hence traditional antipsychotics which are principally dopamine D2 receptor antagonists are being used for the treatment [9]. The hypofunction of the glutamate system in schizophrenia was first inferred from the observations that N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine, phencyclidine, and MK-801) induce schizophrenia-like symptoms in normal individuals [9]. It has therefore been suggested that alterations at various developmental stages could contribute to the development of schizophrenia [10] and that the genetic defects contributing to the disease may affect the timing of gene expression rather than gene coding mutations. There is accumulated evidence of involvement of a small subset of genes such as DTNBP1, DISC1, and NRG1 [11] in schizophrenia. In the present study the effect of bioactive compound and reference drug clozapine (Clz) was studied on selected susceptible targets genes of schizophrenia such as TH (Tyrosine hydroxylase), DDC (DOPA decarboxylase), DBH (Dopamine β-hydroxylase), VMAT2 (Vesicular monoamine transporter), NMDA (SET-1); RGS4 (Regulator of G-protein signaling 4), NRG1 (Neuregulin-1), COMT (Catechol O-methyltransferase), AKT1 (Protein kinase B) and DTNBP1 (SET 2) (Dystrobrevin Binding Protein 1) using in silico approach.