BEHAVIORAL GENETICS

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BEHAVIORAL GENETICS

• Topic 8
• Schizophrenia

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Outline

• Diagnosis Epidemiology
• Twin and Adoption Studies
• Nature of Genetic Influence
• Nature of Environmental Influence

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Schizophrenia Symptoms

• Thought disorder
• Delusions
• Hallucinations
• Inappropriate affect
• Deterioration of social behavior

Positive Symptoms
Negative Symptoms
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Clinical Course

• Childhood expressions/Initial Symptoms
• Prodromal phase
• Active phase
• Residual phase

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Variable Age of Onset

• Typical onset is in early adulthood (i.e., late
  teens through the 20s), but can have onsets as
  late as middle-age.
• Age of onset is, on average, earlier in affected
  men as compared to affected women. Men are also
  more likely to have a severe form of
  schizophrenia.

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Schizophrenia Frequency Statistics
Based on data from London in the 1970s published
by Wing Fryers (1976)
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Frequency of Schizophrenia

• Incidence -- of individuals who develop the
  disorder in a given period of time.
• Prevalence -- of individuals who have the
  disorder at a given point in time.
• Lifetime prevalence -- of individuals at a
  given point in time who ever had the disorder.
• Lifetime morbid risk -- probability that an
  individual will develop the disorder in his/her
  lifetime.

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Abridged Weinberg Method
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Cross-cultural Distribution

• High prevalence societies
• Yugoslavia, North Swedish, Irish Republic,
  Canadian Catholics, Palau
• Low prevalence societies
• aboriginal tribes in Taiwan, Ghana, Old Order
  Amish

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Social Class

• Sociogenic Hypothesis stressors associated with
  lower social class status precipitate
  schizophrenia
• Downward Drift (social selection) those with a
  predisposition to develop schizophrenia migrate
  to the lower social classes.

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Cantor-Graae et al. (2005). Schizophrenia and
migration A meta-analysis and review. Amer J.
Psychiatry, 16212-24.
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Fitness of Schizophrenics
Data based on Norwegian psychiatric patients for
1936-1955 Ødegaard (1972)
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Epidemiology Summary

• Common -- LMR is about 1
• Variable age of onset
• Sex difference in severity
• Cross-cultural universal
• Associated with social class
• Reduced fertility

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Tienari Finnish Twin Study
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Pollin et al.
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Maudsley Twin Study(Gottesman Shields)

• Maudsley Twin Registry 45,000 consecutive
  admissions
• Probands 57 twins diagnosed with Sz

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Source of Information in a Family/Twin Study

• Family Study Method direct interview
• Family History Method someone other than the
  target reports
• Archival data Medical charts, registry
  diagnoses

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Gottesman Shields (1972)
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Probandwise Twin Concordance for Schizophrenia
in studies published 1996 to 1999
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Risk Ratio for Schizophrenia In Twins(Klaning et
al., 1996)
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Danish Adoption Studies(Rosenthal, Kety, Wender,
Schulsinger, Jacobsen)

• 5,500 non-familial adoptions between 1924 1947
  from Copenhagen.
• Of 10,000 bioparents, 69 judged from records to
  be w/i Sz spectrum
• 42 chronic
• 8 borderline
• 9 doubtful
• 10 acute, schizoaffective

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Danish Adoption Studies(Rosenthal et al., 1968)
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Adoptees Family Study Design(Kety et al., 1968)
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Genetic Models of Schizophrenia

• Diathesis-stress
• Generalized-single-locus (GSL)
• Multifactorial Threshold (MFT)

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Generalized-Single Locus (GSL)

• Schizophrenia is due to a single gene (locus)
  that is incompletely penetrant
• Strength biologically tractable
• Weakness incompatible with familial risk and
  fertility data

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Multifactorial Threshold Model (MFT)

• Underlying the categorical diagnosis of
  schizophrenia is an hypothesized quantitative
  continuum (termed liability). An individual is
  affected if his/her combined liability exceeds a
  fixed threshold value.
• The inheritance of schizophrenia is thus due to
  the inheritance of the quantitative liability.
• Weaknesses
• Biological tractability
• Biological plausibility
• Strengths
• Consistent with family data
• Fertility data

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Gene Identification

• Where to look
• Targeted (e.g, pathophysiology, animal models,
  cytogenetic, linkage results)
• Genome-wide
• How to look
• Linkage analysis
• Association Studies
• Linkage disequilibrium mapping

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Chromosome 5(Bassett et al., 1988)

• Two affected family members with typical
  schizophrenia

Chromosome 1
Chromosome 5
5q11.1 5q13.3
Partial trisomy for 5q11.1 - 5q13.3
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Chromosome 5 Hypothesis

• The 2 schizophrenics had 3 copies of all genes in
  5q11.1 - 5q13.3
• Other individuals may have schizophrenia because
  they inherit a mutation in a key gene in 5q11.1 -
  5q13.3 (cf APP and DS)

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Non-Sz, O-blood type Mother
Sz, A-blood type Dad
s
s
s
S
O
O
O
A
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Mothers Gametes
Fathers Gametes
or
s
s
S
O
O
A
s
s
S
s
O
O
O
A
Non-Sz, O-blood
Sz, A-blood
(50)
(50)
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• Genetic linkage linked loci reside physically
  near each other on the same chromosome. A w/i
  family association between a genetic marker and
  disease status ? linked disease-susceptibility
  locus.
• Genetic marker polymorphic DNA sequence (not
  usually expressed) of known chromosomal location
• Recombination -- rate at which disease status is
  assoc. with different genetic marker status in
  offspring than parents (range is 0 to 50)

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Recombination

• If on same chromosome, there are two types of
  offspring
• Sz, A blood type (50)
• non-Sz, O blood type (50)
• If on different chromosomes, there will be 4
  types of offspring
• Non-Sz, O-blood type (25)
• Non-SZ, A-blood type (25)
• Sz, O-blood type (25)
• Sz, A-blood type (25)

0 Recombination
50 Recombination
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Complications

• Not all matings are informative
• May not have marker in region
• Reduced penetrance
• Crossing-over recombination

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Recombination
(Grand) Maternal 9
s
S
O
A
(Grand) Paternal 9
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Lod Score

• lod log10 (oddslinkageno linkage)
• odds probability linked at (q lt.50)
• probability unlinked (q .50)
• lod is consider significant if gt 3.0 (region
  positive) or lt -2.0 (region excluded)

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Lod Scores
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Sherrington et al. (1988)

• Targeted 5q11-5q13 in 7 pedigrees (104
  individuals with 44 affected)
• Assumed schizophrenia was autosomal dominant with
  86 penetrance.
• Lod score 6.5 at q .08 (odds better than
  3,000,0001).

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Genome-wide Linkage AnalysisA Non-targeted
Alternative

• Limitation of targeted approaches there are too
  few targets
• Genome-wide linkage analysis identify the
  chromosomal location of likely disease-susceptibil
  ity loci.
• Usually 300-400 markers

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Positional Cloning Strategy

• Linkage Analysis to identify genomic region
• Confirmation of region through other linkage
  studies
• Fine-scale mapping to narrow the region to lt 1 Mb
  (cytogenetic, LD)
• Identifying candidate genes in the reduced region
  
• Determine if relevant gene
• Expression pattern
• Effect in other species
• Cytogenetic observations
• Sequence and mutation analysis

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Status of the Chromosome 1 Linkage

• Have other significant linkages been reported in
  the region (1p36)?
• 1q22.1-23 ( 140cM away) (Gurling et al., 2001)
• 1q32-42 ( 90cM away) (Ekelund et al., 2001
  Blackwood et al., 2001)
• 1q21-22 ( 150cM away) (Brzustowicz, 2000)
• Other evidence
• Disruption of genes in 1q42 region due to
  balanced translocation associated with
  schizophrenia (Millar et al., 2001)
• RGS4 (regulator of G protein signalling-4) gene
  association studies

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Owen, M.J. et al. (2005). Trends in Genetics, 21
518-525
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Positive Linkage Findings for Hypertension
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Sanders, A.R. et al. (2008). No significant
association of 14 candidate genes
with Schizophrenia ... American Journal of
Psychiatry, advanced e-pub, 15.1.08
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SzGene Database(http//www.schizophreniaforum.org
/res/sczgene/default.asp)
Allen, N.C. et al. (2008). Systematic
meta-analyses and field synopsis of genetic
association studies in schizophrenia The SzGene
database. Nature Genetics, 40(7) 827-834
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Velo-Cardiofacial Syndrome (VCFS)

• Developmental disorder causing cleft palate,
  cardiovascular abnormalities, and learning
  disabilities.
• Associated with 3 Mb deletion on 22q11( 30
  genes)
• 20-30 have a psychotic disorder--
  schizophrenia, schizoaffective
• Mice deleted for this region have impaired
  learning and sensorimotor gating

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COMT Polymorphism

• COMT metabolizes released dopamine (esp frontal
  cortex) gene maps to 22q11
• Missense mutation that results in a Met for Val
  substitution at amino acid position 108
• Met allele has ¼ as much activity as Val

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Human Studies of COMT

• Val allele has been associated with schizophrenia
  in at least 4 studies (but there are also
  negative studies)
• Val allele has been directly associated with
  reduced performance on neuropsychological
  measures that tap prefrontal functioning (e.g.,
  Wisconsin Card Sort)
• fMRI studies

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Paternal Mutations
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CNVs and Schizophrenia
Xu, B. et al. (2008). Strong association of de
novo copy number mutations With sporadic
schizophrenia. Nature Genetics, 40(7) 880-885.
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Anticipation
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Nature of Diathesis Summary

• Schizophrenia is heritable
• Twin studies
• Adoption studies
• Other observations linkage, paternal age, VCFS
• Multigenic rather than single-gene
• Empiric risk figures
• Fertility
• Multiple linkages
• Positional Cloning strategy
• Linkage
• Confirmation through Replication
• Narrowing of Region
• Candidate Genes 6-10 genomic regions
• Importance of microdeletions
• VCFS
• CNVs

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Nature of Environmental Influence

• Evidence against shared enviro. influence
• Majority of schizophrenics do not have
  schizophrenic sibs
• Being reared by an adoptive schizophrenic parent
  does not increase risk of schizophrenia
• Studies of offspring of discordant schizophrenic
  twins

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Gottesman Bertelsen (1989)
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Non-shared Env. Influence

• Life events (stress)
• Neurodevelopmental insults
• Birth Size
• Maternal Conditions (malnutrition, diabetes,
  influenza)
• Obstetric Complications (hypoxia, placental
  abruption)
• Impaired neuromotor development (later attainment
  of developmental milestones - e.g., walking-,
  diminished motor skills
• Minor physical anomalies
• Enlarged brain ventricles
• Season of birth effect

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Enlarged Ventricles
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Conceptual Paradigm for Schizophrenia

• Diathesis-stress model Schizophrenia is the
  result of an interaction between an inherited
  diathesis and exogenous stress. The diathesis is
  likely necessary but is certainly not sufficient
  to develop the disorder.

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Summary - Diathesis

• Twin and adoption studies consistently support
  importance of genetic factors. Heritability
  80 under MFT
• Linkage has implicated but not confirmed several
  chromosomal regions
• Other hints to the genetics of SZ come from
  studies of VCFS CNVs, anticipation, paternal
  mutation and candidate gene studies

Summary - Stress

• Shared environmental factors do not appear to be
  important to the etiology of SZ
• Non-shared environmental factors are clearly
  important with best evidence for early
  neurodevelopmental insults