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  1. 1. Psychopathology in Genome and Post- Genome Era ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  2. 2. CONTENTS • Introduction • How genes influence Psychopathology? ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  3. 3. Introduction 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). ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  4. 4. Introduction Disorders / Traits Disorders Simple Disorders Complex Disorders Traits Simple Disorders Complex Disorders ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  5. 5. Introduction Mendelian (Simple Disorders / Traits)  Autosomal  Recessive  Dominant Non-Mendelian (Complex Disorders / Traits)  Polygenic  Oligogenic  Threshold ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Patterns of Inheritance in Disorders
  6. 6. Introduction • 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  7. 7. Introduction • Numerous single-gene diseases have clearly elucidated causes. • First such psychiatric disease was phenylketonuria, where the phenolic odor 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  8. 8. 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 neuropsychiatric disease. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Strittmatter et al. 1993
  9. 9. Introduction • 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  10. 10. Introduction Key Aspects: Pure Phenotype in terms of: Phenotype Definition Symptoms Clusters Subtypes Syndrome / Disorder Spectrum Age at Onset Sex Related / Unrelated ….. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  11. 11. Introduction 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  12. 12. Introduction 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). ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  13. 13. Introduction Key Words Symptoms Clusters Problem Positive Symptoms / Gene Negative Symptoms / Gene Disorganized Symptoms / Gene Paranoid Symptoms / Gene ….. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  14. 14. Introduction Key Words; Subtypes Problem Paranoid vs. Non-Paranoid With Psychotic Features vs. Without Psychotic Features ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  15. 15. Introduction Key Words; Syndrome / Disorder Problem Major psychiatric disorders have no well- established etiological agents. Hence, most of our diagnoses are syndromatic. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  16. 16. Introduction Key Words; Spectrum Problem SCZ Spectrum Disorders OCD Spectrum Disorders Autistic Spectrum Disorders ….. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  17. 17. Introduction Key Words; Age at Onset Problem First Hospital Admission ? First Biological Markers ? First Endophenotype Formation ? ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  18. 18. Introduction Key Words; Sex Problem X Chromosome Genes; MAO-A Sex Hormones / Genes ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  19. 19. Introduction Key Words; Related / Unrelated Familial Case Research Non-Familial Case Research ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  20. 20. Introduction Stigmatization Based on Symptoms & Signs??! Based on Biological Markers??! Based on Family History??! Based on Endophenotypes??! ….. Based on All ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  21. 21. Introduction There are a host of behavioural traits with evidence for significant heritability, including: Intelligence Reading disability Personality dimensions Memory Attention ….. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 McGuffin et al. 2001
  22. 22. Introduction • On the borders between psychopathology and undesirable behavior, there is evidence for heritability of criminal behavior and alcoholism. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Hutchings and Mednick 1975; Mednick et al. 1984; Cloninger et al. 1978
  23. 23. How genes influence Psychopathology? ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  24. 24. How genes influence Psychopathology? ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  25. 25. How genes influence Psychopathology? “An Example” • Reported associations between polymorphisms in: 1. DRD4 and catatonia / delusions 2. DRD2 and disorganization / delusions 3. CCK and positive symptoms 4. 5-HT promoter and auditory hallucinations / affective symptoms 5. HkCa3 and negative symptoms 6. BDNF and DAT1 and negative symptoms ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  26. 26. 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Berrettini 2000; Gershon 2000; Wildenauer et al. 1999
  27. 27. How genes influence Psychopathology? • 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Badner and Gershon 2002; Lohmueller et al. 2003
  28. 28. How genes influence Psychopathology? • 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Botstein and Risch, 2003
  29. 29. How genes influence Psychopathology? 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 • ……… ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  30. 30. Schizophrenia (Candidate Genes) 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. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  31. 31. Schizophrenia (Candidate Genes) • 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 (proline dehydrogenase; 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) ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  32. 32. BD – Candidate Genes ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  33. 33. BMD (Candidate Genes) • Chromosomal Regions 1. Chr. 6q21–q25 2. Chr. 9p22.3–21.1 3. Chr. 10q11.21–22.1 4. Chr. 11p13 5. Chr. 12q23–q24 6. Chr. 13q 7. Chr. 14q24.1–32.12 8. Chr. 18 • Genes 1. 5-HTTLPR Gene 2. G-protein receptor kinase 3 (GRK3, Chr 22) 3. Brain derived neurotrophic factor (BDNF) 4. COMT 5. DAOA 6. G72 7. G30 8. XBP1 9. P2X7 ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  34. 34. ADHD (Candidate Loci and Genes) • DAT1 • DRD5 • DRD4 • COMT • 5-HT1D • 5-HT4 • 5-HTT • MAOA • PRKCG • CHRNA4 • Chr. 5p13 ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  35. 35. Autistic Disorders (Candidate Loci and Genes) • 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) ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  36. 36. Future Direction Two areas of future research that are particularly promising for informing phenotypic validity include: 1. Genetic epidemiologic strategies and prospective longitudinal studies for phenotype refinement 2. Greater integration of genetics with basic neuroscience and behavioural sciences to elucidate potentially heritable components of psychiatric phenotypes. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  37. 37. Future Direction  Five major applications of genetic epidemiology are needed to advance our understanding of mental disorders: 1. Establishment of population-based registries of mental disorders (numerous genetic tests). 2. Identification of more homogenous subtypes of mental disorders. 3. Investigation of familial patterns among affected and unaffected probands to estimate mode of genetic transmission. 4. Quantification of risk at the levels of the individual and population (i.e., absolute risk, relative risk, attributable risk). 5. Development of a richer conceptualization of environmental factors (important mediators of expression of genetic risk). ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006 Yang et al. 2000
  38. 38. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  39. 39. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006
  40. 40. ‫تهران‬ ‫پزشکی‬ ‫علوم‬ ‫دانشگاه‬ ‫ژنومیکی‬ ‫روانپزشکی‬ ‫دپارتمان‬-‫روز‬ ‫بیمارستان‬‫به‬– 1385 Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006 DGP - 2006

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