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Psychopathology in Genome and Post-

Genome Era

دانشگاه علوم پزشکی تهران

دپارتمان روانپزشکی ژنومیکی - 1385 بیمارستان روزبه –

Department of Genomic Psychiatry (DGP) – Roozbeh Hospital - 2006DGP - 2006

CONTENTS• Introduction• How genes influence Psychopathology?




IntroductionThe 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).




IntroductionDisorders / Traits

DisordersSimple DisordersComplex Disorders

TraitsSimple DisordersComplex Disorders




Introduction

Mendelian (Simple Disorders / Traits)

Autosomal Recessive Dominant

Non-Mendelian (Complex Disorders / Traits)

Polygenic Oligogenic Threshold




Patterns of Inheritance in Disorders

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.




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.




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.




Strittmatter et al. 1993

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.




Introduction

Key Aspects: Pure Phenotype in terms of:

Phenotype DefinitionSymptoms ClustersSubtypes Syndrome / DisorderSpectrum Age at OnsetSex Related / Unrelated…..




IntroductionKey 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.




IntroductionKey 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).




IntroductionKey Words Symptoms Clusters Problem

Positive Symptoms / Gene

Negative Symptoms / Gene

Disorganized Symptoms / Gene

Paranoid Symptoms / Gene

…..




IntroductionKey Words; Subtypes Problem

Paranoid vs. Non-Paranoid

With Psychotic Features vs. Without Psychotic Features




IntroductionKey Words; Syndrome / Disorder Problem

Major psychiatric disorders have no well-

established etiological agents.

Hence, most of our diagnoses are syndromatic.




IntroductionKey Words; Spectrum Problem

SCZ Spectrum Disorders

OCD Spectrum Disorders

Autistic Spectrum Disorders

…..




IntroductionKey Words; Age at Onset Problem

First Hospital Admission ?

First Biological Markers ?

First Endophenotype Formation ?




IntroductionKey Words; Sex Problem

X Chromosome Genes; MAO-A

Sex Hormones / Genes




IntroductionKey Words; Related / Unrelated

Familial Case Research

Non-Familial Case Research




Introduction

StigmatizationBased on Symptoms & Signs??!Based on Biological Markers??!Based on Family History??!Based on Endophenotypes??!…..

Based on All




IntroductionThere are a host of behavioural traits with

evidence for significant heritability, including:IntelligenceReading disabilityPersonality dimensionsMemoryAttention…..




McGuffin et al. 2001

Introduction• On the borders between psychopathology and

undesirable behavior, there is evidence for heritability of criminal behavior and alcoholism.




Hutchings and Mednick 1975; Mednick et al. 1984; Cloninger et al. 1978

How genes influence Psychopathology?




How genes influence Psychopathology? دانشگاه علوم پزشکی تهران



How genes influence Psychopathology?“An Example”

• Reported associations between polymorphisms in:

1. DRD4 and catatonia / delusions2. DRD2 and disorganization / delusions 3. CCK and positive symptoms4. 5-HT promoter and auditory hallucinations /

affective symptoms5. HkCa3 and negative symptoms6. BDNF and DAT1 and negative symptoms





• 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.




Berrettini 2000; Gershon 2000; Wildenauer et al. 1999


• 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.




Badner and Gershon 2002; Lohmueller et al. 2003


• 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• ………




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.




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)




BD – Candidate Genesدانشگاه علوم پزشکی

تهران



BMD (Candidate Genes)• Chromosomal

Regions1. Chr. 6q21–q252. Chr. 9p22.3–21.13. Chr. 10q11.21–22.14. Chr. 11p135. Chr. 12q23–q246. Chr. 13q7. Chr. 14q24.1–32.12 8. Chr. 18

• Genes1. 5-HTTLPR Gene2. G-protein receptor kinase 3

(GRK3, Chr 22)3. Brain derived neurotrophic

factor (BDNF)4. COMT5. DAOA6. G727. G308. XBP19. P2X7




ADHD (Candidate Loci and Genes)

• DAT1• DRD5• DRD4• COMT• 5-HT1D• 5-HT4• 5-HTT• MAOA• PRKCG• CHRNA4

• Chr. 5p13




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)




Future DirectionTwo 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.




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).




Yang et al. 2000

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