Gene and Environmental Interplay and Endophenotypes: And lies between this triad?

1
Gene and Environmental Interplay and
Endophenotypes And lies between this triad?

• Bikash Sharma, MD (PGY III)
• Evaristus Nwulia, MD (Supervisor)
• Howard University Hospital
• Department of Psychiatry
• 09/ 02/ 2010

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Family, Twins and Adoption Studies

• Family Studies Familial liability and prenatal
  exposure to infection in the causation of
  schizophrenia¹ª. Family liability and head injury
  for risk of schizophrenia¹ªb
• Twin studies High genetic risk children who
  experienced maltreatment have 25 increase in
  diagnosable conduct disorder compared to those
  who has low genetic risk have only 2¹b.
  Depression more following a major life stress in
  those with genetic liability ¹bª
• Adoption studies schizophrenia spectrum disorder
  in high risk adoptee if reared in an environment
  with dysfunctional communication than if in a
  better communication²ª. Conduct disorder in
  adoptee with genetic predisposition to antisocial
  personality if reared in adverse family
  environment²ªb.
• 1a Clarke MC et al Am J psychiatry 2009
• 1ab Malaspina D et al Am J Psychiatry 2001
• 1b Jaffee SR et al Dev Psychopathol 2005
• 1ba Kendler KS et al Psychol med 1995
• 2a Tienari P et al Psychol Med 2004
• 2ab Cadoret RJ et al Arch Gen Psychiatry 1995

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We know that

• Psychiatric illness are highly heritable. 80
  heritability in twin study¹ and also high in
  family study².
• Environmental factors are stronger predictors³.
• 1 Sullivan PF et al 2003
• 2 Gottesman I et al 2010
• 3 Rutter M 2005

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Brave New Brain Conquering Mental Illness in the
Era of the Genome 2001 Nancy C. Andreasen

• Scientific studies of mental illness is occurring
  in the era of the genome and the golden age of
  neuroscience.
• The terrain of the brain is being mapped in
  parallel with the mapping of the genome. The
  convergence of these two domains of knowledge is
  one of the exciting things that is happening in
  medicine and mental health at the moment.
• The goal of the twenty first century is to find
  a penicillin for mental illness

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At present.

• Identification of specific genes/ markers and
  chromosomal regions for the various mental
  illnesses ¹ ² ³
• ..low replication etiology involves rather than
  single genes/ loci with the large effect, many
  genes each of which contributes a small risk
  interacting with each other or with environmental
  risk factors to cause¹ ?
• gt1300 Schizophrenia candidate gene" studies in
  last 20 years. gt150 schizophrenia genetic
  association articles/year?.
• 1 Purcell SM et al 2009
• 2 Shi J et al 2009
• 3 Stefansson H et al 2009
• 4 Bertram L 2008
• 5 Dick DM et al 2001

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Difficulties in identifying the underlying
putative gene in Mental Illness

• Diagnostic uncertainty and Phenotypic
  heterogeneity.
• Genetic heterogeneity.
• Absence of disease specific neuropathological
  features/ biomarkers.
• Kennedy JL et al 2003

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Gene X Environment Concept

• Complex diseases disobey Mendelian patterns of
  inheritance¹
• Development of complex disease² depends on
  combination of persons genetic, environment and
  lifestyle.
• By studying gene and environment interactions,
  genetic risk factors may be modified in an
  environment-specific manner³
• 1 Davey SG et al 2003 Hern LM et al 2004
• 2 Hunter DJ et al 2005
• 3 Dempfle CE et al 2008

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Expression of Gene
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(No Transcript)
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Copy Number Variations (CNVs)

• An average of 70 CNVs averaging 250,000
  nucleotides in size in each DNA sample.
• 1,447 different CNVs that collectively covered
  about 12 percent of the human genome and six to
  19 percent of any given chromosome
• Stephen W. Scherer et al 2006 Nature

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• How an environmental factor external to the
  person gets under the skin¹

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Gene- environment Interplay

• Heritability- environment interaction¹
• Gene- environment correlation²
• Epigenetic programming³
• Measured gene- environment interaction
• 1. Rowe DC et al 1999Heath AC et al 1998
  Koopmans JR et al 1999 Turkheimer E et al 2003
• 2. Cameron NM et al 2007 Levenson JM et al 2005
  Prey LA 2004
• 3. Plomin R et al 1977 Rutter M et al 2002

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Epigenetics
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Epigenetics and Schizophrenia

• The origins of Schizophrenia may not lie strictly
  in DNA sequence variations rather, these may be
  coupled with epigenetic dysfunctions as the key
  etiopathogenic factors¹
• Aberrant gene expression (of, e.g., reelin,
  glutamic acid decarboxylase I GAD1 or GAD67,
  vesicular GABA transporter VGAT, GABA
  transporter GAT-1, NMDA receptors NR2s, and
  others) observed in GABAergic neurons of
  Schizophrenia patients is a consequence of
  promoter hypermethylation mediated by the
  overexpression of DNA methyltransferase I?
• 1 Petronis A 2004 Costa E et al 2006
• 2 Benes FM et al, 2007 Huang HS et al 2007
  Guidotti A wt al 2005

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Gene X Environment Interactions
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GXE Interactions ( contd.)

• Polymorphic apolipoprotein gene and head injury
  increases beta amyloid deposition in brain/
  Alzheimers dementia¹
• Farmingham Heart study Polymorphic hepatic
  lipase gene promoter and high dietary fat intake
  for abnormal HDL concentration²
• Apolipoprotein E4 genotype and cigarette smoking
  in CAD³
• Mayeux RM et al 1995 Nicholl JAR et al 1995
• Ordovas JM et al 2002 Tai ES et al 2003
• Humphries SE et al 2001 Talmud PJ et al 2004

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Main Objectives

• To show robust evidence for interaction between
  gene (G) and environment (E) in causation of
  psychiatric disorder (D)
• To show plausible effect of the environmental
  risk (E) on biological systems involved in the
  disorder (D)
• AND
• To show neurobiological link between candidate
  gene (G) and endophenotypes/ Intermediate
  phenotypes (IP) for psychiatric disorder (D)

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Concepts

• I. Measured Environments (E)
• II. Selection of Candidate genes (G)
• III. Selection of Endophenotypes, Intermediate
  phenotypes (IP)/ Biomarkers

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I. Candidate Environments for a Disorder

• Schizophrenia Spectrum disorders¹
• Depression²
• Substance abuse³
• Antisocial disorder?
• ADHD
• Alzheimer dementia
• Autism spectrum disorder
• 1 Tsuang MT et al 2001 Van Os et al 2005
• 2 Kendler KS et al 2002 (Women) and 2006 (Men)
• 3 Heath AC et al 2002
• 4 Loeber R et al 1998

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I. Characters of Environmental Influences

• Cumulative effect of multiple environmental
  pathogens is large
• Chains of related events is powerful
• Extended/ repeated exposure is strong
• Accumulation of multiple negative life events
  interact more strongly with genetic risk than a
  single life event¹ even if the single event is
  extremely traumatic²
• 1 Caspi A et al 2003
• 2 Kendler KS et al 2005

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I. Stress Sensitization Hypothesis

• Association between past-year stressful life
  events and the 12-month prevalence of major
  depression, PTSD, other anxiety disorders, and
  perceived stress varies according to exposure to
  Childhood adversity in a sample from the National
  Epidemiological Survey of Alcohol and Related
  Conditions (NESARC) (n34 653)¹
• 1. McLaughlin KA et al 2010

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I. Nature of a Environmental Risk Factors

• Variability in response among those exposed to
  the same environmental risks
• Evidence that the putative environmental risk is
  true in having causal effect
• Plausible effect of the environmental risk on
  Biological systems involved in the disorder ¹
• 1 Adolphs R 2003 Charney D 2004 de Kloet ER et
  al 2005 Nemeroff CB 2004.

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II. Nature of Candidate Genes

• A (Polymorphic) variant of a gene has high
  prevalence rate.
• Gene involved can be hidden from Natural
  selection in which case odd variant may be
  possible
• Gene whose main effect association with the
  mental illness is replicated.
• Genes effects on phenotype are conditional on
  the environment.

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II. How we hunt for Genes Linkage and
Association Studies
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II. Genome wide Association studies

• National Human Genome Research Institute,
  National Institutes of Health¹
• Genetic Association Information Network (GAIN)?
• The Genes, Environment and Health Initiative
  (GEI)?
• 1.www.genome.gov
• 2.http//fnih.org/index.php?optioncom_contenttas
  kviewid338Itemid454
• 3.www.genesandenvironment.nih.gov
• http//www.nhlbi.nih.gov/new/press/06-02-06.htm
  

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II. Schizophrenia Gene "Top Results" Allen NC et
al 2008 (Current on June 1, 2008)
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www.schizophreniaforum
.org/res/szgene
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In this data base there are(updated august
10, 2010)

• 1660 studies/ 966 schizophrenia gene/ 8525
  polymorphism/ and 274 meta-analysis included.

Gene Polymorphism Race
PGBD1 rs13211507 All
NRGN rs12807809 All
NOTCH4 rs3131296 All
PDE4B rs910694 All
TCF4 rs9960767 All
DAOA rs778293 Asian
TPH1 rs1800532 All
HTR2A rs6311 White
MDGA1 rs11759115 All
CCKAR rs1800857 All
DRD4 rs1800955 Asian
APOE APOE_e2/3/4 White
GWA_11p14.1 rs1602565 White
DISC1 rs3737597 White
PLXNA2 rs841865 White
GABRB2 rs6556547 White
AKT1 rs3803300 White
DRD2 rs1801028 All
SRR rs408067 Asian
PRSS16 rs6932590 All
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Published genome-wide association studies for
schizophrenia all schizophrenia GWA studies
published to date are shown.

• Study SNPs analyzed Supported
  variant Supported gene Samples discovery
  Samples replication/MA
• Mah etal. (2006) 25,000
  rs752016 PLXNA2
  320 cases/325 controls 200 cases/230
  controls (EA)
• Lencz etal. (2007)500,000 rs4129148
  CSF2RA 178
  cases, 144 controls
• Sullivan etal. (2008)500,000 rs4846033
  
  738 cases, 733 controls
• O'Donovan etal. (2008)500,000 rs1344706
  ZNF804A 479 cases,
  2937controls 7308 cases, 12834 controls
• Shifman etal. (2008)500,000 rs7341475
  RELN 745
  cases, 2644 control 2274 cases, 4401 controls
• Kirov etal. (2009b)550,000 rs11064768
  CCDC60 574 trios
• Need etal. (2009)550,000 rs2135551
  ADAMTSL3 871 cases,
  863 controls 1460 cases, 12995 controls
• Shi etal. (2009)600,000
  rs13025591 AGAP1)
  2681 cases, 2653 controls (EA)
• 
  
  1286 cases, 973 controls (AA)
• 
  rs1851196 ERBB4)
• 
  rs9272219 MHC
• 
  rs9272535 MHC
• 
  rs13194053 MHC
  8008 cases 19077 controls (EA)
• International
• Schizophrenia
• Consortium (2009)1,000,000 rs5761163
  MYO18B 3322
  cases, 3587controls 8008 cases, 19077 control
  .
  rs13194053 MHC

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II. Schizophrenia Gene

• The genetics of this disease are perhaps the most
  studied facet of this disorder, but the emphasis
  on linkage and association analyses across the
  entire genome have provided only limited insight
  to explain the underlying etiological factors of
  the disease¹
• 1 Harrison PJ et al 2005

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III. Endophenotypes

• Heritable Neurophysiological, Biochemical,
  Endocrinological, Neuroanatomical,
  Neuropsychological correlate constituents of
  disorders¹
• 1 Gottesman I et al 2003

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III. Endophenotypes
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III. Characters of Endophenotypes

• Associated with illness in the population
• Association with a candidate gene or gene region
• Heritable
• State independent (manifests in an individual
  whether or not disease is active)
• Within families, endophenotype and disorder
  co-segregate.
• Gottesman I et al 2003
• Gershon ES et al 1986
• Leboyer M et al 1998

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III. Selection of strong endophenotypes of the
disorder

• Many endophenotypes emotions, mood (euphoria,
  depression), Affect, thoughts guilt, perceptions,
  memory, cognition etc) are only appreciated in
  humans.
• Many have their counterparts in mammals and thus
  can be modeled in the lab.

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III. Proposed endophenotypes for Bipolar disorder
(Lenox HH et al 2002)

• Circadian sleep/ wake cycle
• Response to sleep deprivation
• Increases in white matter hyper intensities
  (WHIs) on MRI
• P300 delayed response potentials on EEG after
  infrequent auditory stimulus.
• Response to Psycho stimulants eg- Amphetamines,
  cocaine
• Cholinergic sensitivity
• Intracellular signal transduction.

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III. Proposed endophenotype for depression
Genes Neuro Anatomical Neuro Psychiatric Neurochemical Environmental
NMDAR, 5- HTTLPR Increased amagdala activity - decreased amagdala volume - Mood biased towards negative emotions - Impaired learning and memory Serotenergic dysfunction CRH/ HPA Stressful life events
BDNF, MR, bcl-2, CREB -Reduced hippocampal volume -Reduced ACC volume Impaired learning and memory Psychomotor change Impaired executive functions increased stress sensitivity (gender related) - CRH and HPA axis dysfunftions Serotenergic dysfunction CRH/ HPA - REM sleep abnormalities ( not always environmental) - Stressful life events
bcl-2, CREB Reduced ACC volume Impaired reward function (anhedonia) Catacholamine depletion Stressful life events
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III. Endophenotypes Schizophrenia as an example

• Reporting in the Jan. 9 issue of the American
  Journal of Human Genetics, the team describes how
  a variation in the neuregulin 3 gene influences
  delusions associated with schizophrenia.

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III. Possible Endophenotype in Schizophrenia

• Abnormal P50 auditory evoked potentials
• (chromosome 15) Freedman R et al 1997
• Working memory ( COMT) Egan MF et al 2001

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III. Schizophrenia Endophenotypes
Gene/ Polymorphism Neuroanatomical Neurochemical (Neuroimmunological/ Neuroendocrinological) Neurophysiological Neuropsychiatric Environment Author/ Publication
ZNF804A/rs1344706 MRI showing increased total WM, decreased GM Timed visuomotor performance speed (trails A) Lencz T et al, 2010 FDR corrected plt0.05
RELN/rs7341475G No change Tosh L et al 2010
BDNF Val66Met polymorphism 1. MRI-smaller temporal and occipital GM volumes. 2. Optimized voxel-morphometry parietal heteromodal GM defect 2. Visuospatial impairment/poorer verbal memory performance Ho Bc et al 2006
MICB gene rs1051788 Reduced PreFrontalCortex GM HSV-1 seropositivity Prasad KM et 2009
ZNF804A/rs1344706 Differences in episodic and working memory Walters JT et al 2010
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III. Schizophrenia Endophenotypes(contd.)
Gene/ Polymorphism Neuroanatomical Neurochemical (Neuroimmunological/ Neuroendocrinological) Neurophysiological Neuropsychiatric Environment Author/ Publication
RELN -Verbal and visual working memory -Memory and executive functioning Wedenoja J et al 2008
DRD3/ Ser9Gly Worse premorbid social functioning and an earlier age of onset womengtmen Godlewska BR et al 2010
NMDA NR2B Decreased habituation after acoustic stimulus Hokyo A et al 2010
PPP3CC (gamma isoform of CAN)/ 9 SNPs sustained attention (CPT) Executive functioning (WCST) Liu YL et al 2007
AKT1/ 5SNPs Not associated with processing speed, reasoning, verbal memory, working memory, and vigilance Pinherio Ap et al 2007
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Triads of a Gene, an Environmental pathogen and
Behavioral phenotype (disorder) as measured
variables

• Monoamine oxidase A genotype X childhood
  maltreatment conduct disorder/ Antisocial
  personality/ Violent crime¹
• Serotonin Transporter gene X stressful life
  events depression/ suicidality²
• Catechol-O-methyltransferase gene X cannabis
  exposure Psychosis³
• Caspi A et al 2002 Foley DL et al 2004
  Haberstick BC et al 2005 Kim-Cohen J et al 2006
  Nilsson KW et al 2005 Young SE et al 2006
• Caspi A et al 2003 Eley TC et al 2004 Grabe HJ
  et al 2005 Kaufman J et al 2004 Kendler KS et
  al 2005 Wilhelm KA et al 2006 Zalsman G et al
  2006 Jacobs N et al 2006 Mandelli L et al 2006
• Caspi A et al 2005 Semple DM et al 2005

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Triads of a Gene, an Environmental pathogen and
behavioral phenotype ( ADHD) as measured variables

• Dopamine transporter genotype X maternal
  prenatal smoking childhood hyperactive-
  impulsive, inattentive, and oppositional
  behaviors¹
• Polymorphism in dopamine system X maternal use of
  alcohol during pregnancy ADHD¹ª
• COMT gene variant X Low birth weight ADHD²
• 1 Kahn, R et al 2003
• 1a Brookes KJ et al 2005
• 2 Thapar A et al 2005

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Triads of a Gene, an Environmental pathogen and
behavioral phenotype ( PTSD) as measured variables

• Childhood adversity and adult traumatic events
  both ( instead of only one) interact with
  5-HTTLPR genotypes as a predictor for PTSD risk¹
• Polymorphism in Glucocorticoid receptor
  regulating gene (FKBP5) X Acute medical injury
  PTSD related dissocative symptoms²
• Severity of child abuse, and not adult trauma,
  with FKBP5 polymorphism as a predictor for PTSD
  risk²ª
• The risk of PTSD after trauma depends on
  traumatic load and the catechol-o-methyltransferas
  e Val(158)Met polymorphism³
• 1 Xie P et al 2009
• 2 Koenen KC et al 2005
• 2a Binder EB et al 2008
• 3 Kolassa IT et al 2010

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Implications for Basic Neuroscience

• Which neural substrate involved in the disorder?
• Environmental cause of the disorder has effects
  on variables indexing the same neural substrate
• A candidate gene has functional effects on
  variables indexing the same neural substrate

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Basic Neuroscience Research

• Serotonin Gene X Life stress depression
• Early life blockade of 5 HT transporter alters
  emotional behaviors in adult mice1
• Children with the combination of short 5 HTT
  allele and low social support behavioral
  inhibition in middle childhood2
• Short 5 HTT allele is associated with greater
  coupling between amygdala and ventromedial
  prefontal cortex3
• 5-HTTLPR short allele-driven amygdala
  hyperreactivity in healthy male and female
  subjects with no history of psychiatric illness
  or treatment4
• Short 5 HTT allele career have reduced grey
  matter particularly in perigenual cingulate and
  amygdala with relative uncoupeling of an
  amygdala-cingulate feedback circuit implicated in
  the extinction of negative affect/ emotional
  regulation5
• 1 Ansorge MS et al 2004
• 2 Fox N et al 2005
• 3 Heinz a et al 2005
• 4 Hariri A et al 2005
• 5 Pezawas L et al 2005

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Basic Neuroscience Research (contd.)

• Monoamine oxidase A genotype X childhood
  maltreatment conduct disorder/ Antisocial
  personality/ Violent crime
• - Aggressive behavior and altered amounts of
  brain Serotonin and Norepnephrine in a mice
  lacking MAOA¹
• Point mutation at eighth exon of the MAOA
  structural gene that changes a glutamine to a
  termination codon, leading to an isolated
  complete MAOA deficiency is associated with a
  recognizable behavioral phenotype that include
  disturbed emotional regulation and aggressive
  behaviors²
• Allelic variation in the X-linked MAOA gene
  (associated with impulsive aggression in animal
  and human) show pronounced limbic volume
  reductions and hyperresponsive amygdala during
  emotional arousal, with diminished reactivity of
  regulatory prefrontal regions. In male, findings
  include orbitofrontal volume, amygdala and
  hippocampus hyperreactivity during aversive
  recall, and impaired cingulate activation during
  cognitive inhibition³
• 1 Cases O et al 1995
• 2 Brunner HG et al 1993
• 3 Meyer- Lindenberg A et al 2006

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Basic Neuroscience Research (cont.)

• Catechol-O-methyltransferase gene X cannabis
  exposure Psychosis
• COMT valine allele and cannabis use associated
  brain endophenotypes for schizophrenia such as
  frontal/ prefrontal cortex, hippocampus¹
• Individuals carrying two copies of valine allele
  exhibited more cannabis induced memory and
  attention impairments and also psychotic
  experiences
• 1 Egan MF et al 2001 and 2003 Bunney WW et al
  2000 Weinberger DR et al 2001
• 2 Henquet C et al 2009

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Can we find?

• A discrete molecular pathogenesis for mental
  disorder like in Alzheimers disease.

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Schizophrenia Gene Networks and Pathways and
Their Applications for Novel Candidate Gene
Selection Using Interactomics

• Striking correlations between the functions of
  gene products or gene networks and the features
  of the diseases they cause¹
• Global topological features of cancer proteins in
  the human interactome²
• The first comprehensive review of the protein
  interaction network and pathway-based analysis
  characteristics of schizophrenia candidate genes
  has been implemented as an alternative and
  effective approach to investigating the molecular
  mechanisms of schizophrenia³
• 1 Jimenez-Sanchez G et al 2001 Lopez-Bigas N et
  al 2006 Ideker T et al 2008
• 2 Jonsson PF et al 2006
• 3 Sun J et al PLoS One 2010

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Schizophrenia Gene Networks and Pathways and
Their Applications for Novel Candidate Gene
Selection (Contd.)
51
Schizophrenia Gene Networks and Pathways and
Their Applications for Novel Candidate Gene
Selection (Contd.)
52
Schizophrenia Gene Networks and Pathways and
Their Applications for Novel Candidate Gene
Selection (Contd.)
53
Schizophrenia Gene Networks and Pathways and
Their Applications for Novel Candidate Gene
Selection (Contd.)
54
Gene moderates responses to the environment

• Gene predict individual differences in
  physiological responsiveness to stressful
  conditions in knockout mice¹, stressed reared
  rhesus macaques² and human³.
• 1 Murphy DL et al 2003
• 2 Bennett AJ et al 2002 Barr CS et al 2004
  Champoux M et al 2002
• 3 Hariri AR et al 2002 Hutchinson KE et al 2002

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The beginning of the end for the Kraepelinian
dichotomy?

• There is also substantial evidence for an overlap
  between schizophrenia and bipolar disorder genes.
  
• Valles V et al 2000 Cardno AG et al
  2002 Badner JA et al 2002 Maier W et al 2002
• Laursen TM et al 2009 Lichtenstein P et
  al 2009 Van Snellenberg JX et al 2009 Purcell
  SM et al 2009 Williams HJ et al 2010
• Possible relationship between susceptibility
  genes and the clinical picture for disorders in
  the psychosisbipolar spectrum. Recent genetic
  studies suggest that there are genes specific to
  schizophrenia (S), genes specific to bipolar
  disorder (B) and genes that confer risk to
  schizoaffective disorder, schizophrenia and
  bipolar disorder (M). The combination of
  susceptibility genes inherited by an individual,
  together with the environmental exposures,
  determine the key clinical features of the
  illness, positioned on a spectrum from
  prototypical schizophrenia at one end to
  prototypical bipolar disorder at the other. Most
  cases lie somewhere in the central part of the
  spectrum.
• Craddock N et al 2005

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Pharmacogenomics and Personalized Medicine in
Psychiatry

• Pharmacogenomics aims to develop rational means
  to optimize drug therapy with respect to the
  patients' genotype to ensure maximum efficacy
  with minimal adverse effects¹.
• Genotype determining variations in efficacy of
  psychotropic drugs?.
• 1 U.S. Food and Drug Administration 2005
• 2 Basu A et al 2004 Evans W.E et al 2001,
  Goldstein D et al 2003

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Computational Intelligence and Bioinformatics

• A complex system is a system composed of
  interconnected parts that as a whole exhibit one
  or more properties (behavior among the possible
  properties) not obvious from the properties of
  the individual parts. Nervous System is dynamic
  information processing systems at many
  interconnected levels
• Ben Hesper and Paulien Hogeweg,
  Bioinformatics (1978)
• Computational intelligence, has recently become
  the third method of scientific enquiry besides
  theory and experimentation for complex diseases
  in genetic association study.
• International Journal of Computational
  Intelligence in Bioinformatics and Systems
  Biology, Arpad Kelemen et al (March 2009),
  Volume 1, Issue 1  

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What lies ahead

• Psychiatric disorders are a complicated
  subject in human genetics. They are complex
  disorders presenting all the limitations imposed
  by genetic heterogeneity, reduced penetrance and
  the possibility of geneX gene interactions, while
  they have the additional limitation of the lack
  of an objectively measurable phenotype. The
  complexities of psychiatric diseases require
  large samples and genome wide approaches. Genome
  wide linkage screens, dissection of the phenotype
  to reduce heterogeneity, candidate region
  association analyses and candidate gene
  investigations are some of the methods. The
  difficulties associated with psychiatric
  disorders can be overcome through careful
  assessment of the phenotypes and powerful high
  throughput approaches accompanied by utilization
  of the accumulating knowledge on the human
  genome.

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Breaking News

• 
  Thank you.