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    • Psychopathology in Genome and Post-Genome Era
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      DGP - 2006
      دانشگاه علوم پزشکی تهران
    • Introduction
      How genes influence Psychopathology?
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      CONTENTS
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • The twenty-first century will see the reconceptualization of medicine and medical diagnoses to include molecular genetic components.
      • For psychopathological disorders to be included in these advances, our nosology needs to become both biologically and genetically meaningful.
      • Many of these issues were discussed at length in the American Psychopathological Association Series book: Defining Psychopathology in the Twenty-First Century: DSM-V and Beyond (Helzer and Hudziak 2002).
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Disorders / Traits
      • Disorders
      • Simple Disorders
      • Complex Disorders
      • Traits
      • Simple Disorders
      • Complex Disorders
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Patterns of Inheritance in Disorders
      • Non-Mendelian (Complex Disorders / Traits)
      • Polygenic
      • Oligogenic
      • Threshold
      • Mendelian (Simple Disorders / Traits)
      • Autosomal
      • Recessive
      • Dominant
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Genes to Behavior pathways are Complex.
      Multiple Gene-Gene Interactions (Epigenesis).
      Multiple G-E Interactions.
      Multiple neural systems are impaired in psychiatric diseases.
      No one-to-one mapping exists between genes and neural system mechanisms, or between mechanisms and behaviour.
    • Numerous single-gene diseases have clearly elucidated causes.
      First such psychiatric disease was phenylketonuria, where the phenolicodor of the urine of two retarded brothers led to the discovery, in 1934, of excess metabolites of phenylalanine in their urine (Folling 1934).
      PKU is a simple inheritance recessive disease.
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • Introduction
      There are known examples of each type of inheritance in common disease.
      True genetic heterogeneity is found in Alzheimer’s disease, in which there are rare single-gene variants located on Chr. 21, 14, and 1.
      A much more frequent susceptibility allele for Alzheimer’s disease than the single-gene forms is APOE4 (allele 4 of the gene for apolipoprotein E), which is part of the oligogenic inheritance of the common form of the illness and was the first risk factor reported for a common neuropsychiatricdisease.
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Strittmatteret al. 1993
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      A single individual’s genotype has little predictive power for the development of illness and yields insufficient power to test genetic hypotheses.
      However, as multiple associations of genes are established with each of the common psychiatric disorders, predictability of illness in individuals would become much more effective.
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • Key Aspects: Pure Phenotype in terms of:
      • Phenotype Definition
      • Symptoms Clusters
      • Subtypes
      • Syndrome / Disorder
      • Spectrum
      • Age at Onset
      • Sex
      • Related / Unrelated
      • …..
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Key Words; Phenotype Definition Problem
      • The search for the solution to the phenotype problem has come a long way.
      • Operational diagnostic criteria coupled with standardized interviews have dramatically improved reliability, even if operational criteria pose some new problems for clinical practice.
      • Modern definitions of psychiatric phenotypes are valid in as much as they describe categories of high heritability.
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Key Words; Phenotype Definition Problem
      • Quantitative genetic studies have led to studies that are now successfully exploring the molecular genetic aetiology of common psychiatric disorders.
      • However, our current classification does not define disorders that are mutually exclusive either phenotypically or etiologically.
      • For example, both the statistical and the molecular genetic evidence suggests that some genes are associated with an increased risk of both SCZ and BD.
      • Part of our difficulty arises from the clinical necessity of applying categories to phenomena whose underlying structure is almost certainly dimensional (e.g., anxiety; NE, GABA, 5-HT).
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Key Words Symptoms Clusters Problem
      • Positive Symptoms / Gene
      • Negative Symptoms / Gene
      • Disorganized Symptoms / Gene
      • Paranoid Symptoms / Gene
      • …..
    • Key Words; Subtypes Problem
      • Paranoid vs. Non-Paranoid
      • With Psychotic Features vs. Without Psychotic Features
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • Key Words; Syndrome / Disorder Problem
      • Major psychiatric disorders have no well-established etiological agents.
      • Hence, most of our diagnoses are syndromatic.
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Key Words; Spectrum Problem
      • SCZ Spectrum Disorders
      • OCD Spectrum Disorders
      • Autistic Spectrum Disorders
      • …..
    • Key Words; Age at Onset Problem
      • First Hospital Admission ?
      • First Biological Markers ?
      • First Endophenotype Formation ?
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • Key Words; Sex Problem
      • X Chromosome Genes; MAO-A
      • Sex Hormones / Genes
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • Key Words; Related / Unrelated
      • Familial Case Research
      • Non-Familial Case Research
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • Stigmatization
      • Based on Symptoms & Signs??!
      • Based on Biological Markers??!
      • Based on Family History??!
      • Based on Endophenotypes??!
      • …..
      Based on All
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Introduction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • There are a host of behavioural traits with evidence for significant heritability, including:
      • Intelligence
      • Reading disability
      • Personality dimensions
      • Memory
      • Attention
      • …..
      McGuffin et al. 2001
    • Introduction
      On the borders between psychopathology and undesirable behavior, there is evidence for heritability of criminal behaviorand alcoholism.
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Hutchings and Mednick 1975; Mednick et al. 1984; Cloninger et al. 1978
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      How genes influence Psychopathology?
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      How genes influence Psychopathology?
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      How genes influence Psychopathology?“An Example”
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Reported associations between polymorphisms in:
      DRD4 and catatonia / delusions
      DRD2 and disorganization / delusions
      CCK and positive symptoms
      5-HT promoter and auditory hallucinations / affective symptoms
      HkCa3 and negative symptoms
      BDNF and DAT1 and negative symptoms
    • How genes influence Psychopathology?
      The years 2002–2003 were a watershed for gene discovery in psychiatric disorders.
      After many years of false starts and unfulfilled promises, association of a series of genes with BD and SCZ was reported.
      Moreover, the speculation based on linkage evidence that the same genes are involved in susceptibility to both disorders was supported for the G72/G30 complex.
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Berrettini2000; Gershon 2000; Wildenauer et al. 1999
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      How genes influence Psychopathology?
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      In a meta-analysis of all published genomewide linkage scans of BD and SCZ, regions 8p (NRG1), 11p (BDNF), 13q (G72/G30) were found to have statistically significant linkage.
      Another region with significant linkage on meta-analysis in both BD and SCZ is the 22q (COMT).
      Other candidates remain, including GRK3 and PRODH2.
      Badnerand Gershon2002; Lohmuelleret al. 2003
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      How genes influence Psychopathology?
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      The association of BDNF with BD is based on a neurobiological candidate gene approach rather than a positional approach.
      These two approaches to disease gene identification in common disorders are both currently valid, although each has its partisans who occasionally disparage the other approach.
      Botstein and Risch, 2003
    • In Adult Psychiatry
      Schizophrenia
      BMD
      UMD
      OCD
      GAD
      Panic D.
      Eating D.
      BP D.
      Substance Dependency
      ………
      In Child Psychiatry
      Schizophrenia
      Autistic Disorder
      Conduct Disorder
      Mood Disorders
      ADHD
      OCD
      MR
      ………
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      How genes influence Psychopathology?
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Schizophrenia (Candidate Genes)
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • Levinson et al. (2003) divided the genome into segments, or “bins,” and used a ranking method to assess the degree of support across studies for linkage within each segment.
      • The study of Badner and Gershon (2002) strongly supported the existence of susceptibility genes on chromosomes 8p, 13q and 22q.
      • Levinson et al. (2003) and Lewis et al. (2003) favored chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p.
      • Thus, the 8p and 22q regions were supported by both meta-analyses, but eight other regions were supported by only one.
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Schizophrenia (Candidate Genes)
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      NRG1 (neuregulin 1; 8p21-p12)
      DTNBP1 (dysbindin; 6p22.3)
      G72 (13q34)
      DAAO (de-amino acid oxidase; 12q24)
      COMT (catechol-O-methyl transferase; 22q11.21)
      PRODH2 (prolinedehydrogenase; 22q11.21)
      DRD2 (dopamine receptor type 2; 11q23.2)
      CHRNA7 (alpha7 neuronal nicotinic acetylcholine receptor; 15q13-15
      BDNF
      PPP3CC (8p21.3)
      DISC1 (disturbed in schizophrenia1; 1q42)
      G30
      RGS4 (regulator of G-protein signalling-4; Chr.1)
      GRM3 (7q21.1–q21.2)
      5-HTT (human serotonin transporter gene; SLC6A4; 17q11.1-q12)
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      BD – Candidate Genes
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      BMD (Candidate Genes)
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      Chromosomal Regions
      Chr. 6q21–q25
      Chr. 9p22.3–21.1
      Chr. 10q11.21–22.1
      Chr. 11p13
      Chr. 12q23–q24
      Chr. 13q
      Chr. 14q24.1–32.12
      Chr. 18
      Genes
      5-HTTLPR Gene
      G-protein receptor kinase 3 (GRK3, Chr 22)
      Brain derived neurotrophic factor (BDNF)
      COMT
      DAOA
      G72
      G30
      XBP1
      P2X7
    • Chr. 5p13
      دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      ADHD (Candidate Loci and Genes)
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      DAT1
      DRD5
      DRD4
      COMT
      5-HT1D
      5-HT4
      5-HTT
      MAOA
      PRKCG
      CHRNA4
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Autistic Disorders (Candidate Loci and Genes)
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      2q24 – q33
      2q37
      7q22
      7q36
      15q11–q13
      16p
      17q11
      Xp22.3
      Xq13
      Mitochondrial aspartate/glutamate carrier SLC25A12 gene & CMYA3 genes
      CENTG2 gene
      Reelin (RELN) gene
      Engrailed 2 gene (EN2)
      GABAa (GABRB3; GABRA5; GABRG3)
      Neuroligin 3 (NLGN3)
      Neuroligin 4 (NLGN4)
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Future Direction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • Two areas of future research that are particularly promising for informing phenotypic validity include:
      Genetic epidemiologic strategies and prospective longitudinal studies for phenotype refinement
      Greater integration of genetics with basic neuroscience and behavioural sciences to elucidate potentially heritable components of psychiatric phenotypes.
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      Future Direction
      دانشگاه علوم پزشکی تهران
      DGP - 2006
      • Five major applications of genetic epidemiology are needed to advance our understanding of mental disorders:
      Establishment of population-based registries of mental disorders (numerous genetic tests).
      Identification of more homogenous subtypes of mental disorders.
      Investigation of familial patterns among affected and unaffected probandsto estimate mode of genetic transmission.
      Quantification of risk at the levels of the individual and population (i.e., absolute risk, relative risk, attributable risk).
      Development of a richer conceptualization of environmental factors (important mediators of expression of genetic risk).
      Yang et al. 2000
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      دانشگاه علوم پزشکی تهران
      DGP - 2006
    • دپارتمان روانپزشکی ژنومیکی - بیمارستان روزبه –1385
      Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006
      دانشگاه علوم پزشکی تهران
      DGP - 2006