Schizophrenia

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Schizophrenia Genetics

• By Lily Nguyen

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OVERVIEW

• Introduction There are many causes...why
  genetic?
• Types of studies done Which one is the most
  useful?
• Common methods used in the studies
• Looking at the studies Are the findings
  similar?
• Neurobiological Markers prefrontal, hippocampus,
  neurobiological soft sign, thalamus, ventricles.
• Molecular Markers genes, chromosomes and loci
• Other Interesting Markers memory and other
  cognitive factors
• Other Underlying Causes Nature vs. Nurture
• Analyzing these studies How valid are they?
• Future Directions What needs to be done?
• Conclusion
• Websites for you to look at

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INTRODUCTION

• 1 worldwide
• 15 in certain families
• Multiple causes
• Single gene model vs.Polygenic Model

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TYPES OF STUDIES

• Twin studies
• Monozygotic (MZshare 100 genes) gt Concordance
  of 30-50
• Dizygotic (DZshare 50 genes) gt Concordance of
  12-18
• Not strictly genetic!
• Adoption Studies
• Affected adopted children of affected biological
  parents17
• Adopted children of normal parents2
• Schizophrenia higher among children whose
  biological parents had schizophrenia BUT some
  adopted children raised in hostile environment
  also develop schizophrenia Nature vs Nurture?!
• Family Studies
• First Degree Relatives Parents6,
  Siblings9, Twins (see above)
• Second Degree Relatives 2-6
• Third Degree Relatives 2
• There is a genetic component!

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METHODS OF STUDY

• Postmortem studies (i.e. neuron counts)
• Eye-tracking methods
• Blood Test
• Imaging studies mainly MRI, fMRI and PET scans
• Memory Tests

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FINDINGS FROM ARTICLES

• Most articles support role of genetic and
  environment
• Main findings were directed towards prefrontal
  and hippocampus
• Animal Models show behavioural response to
  dopaminergic drugs is partly determined by
  genetic factors
• Genetic knock-out mice that lack dopamine
  transporter (DAT) unable to re-uptake release of
  DA
• Genetic removal of DAT leads to decreased DA
  receptors and lengthened re-uptake time
• Another study using selectively bred rats
  (APO-SUSapomorphine induced) show strong gnawing
  response through several generations.
• Apomorpine Amphetamine (DA agonists)
  suseptibility good candidate for genetic model or
  schizophrenia?

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NEUROBIOLOGICAL MARKERS

• Prefrontal Abnormalities
• Working memory deficits Altered performance on
  executive cognition Exaggerated response of
  dopamine neurons to amphetamine
• Enlarged 3rd ventricle
• Gray matter loss in frontal, temporal and
  thalamus
• Abnormal Regional brain volumes
• High-risk subjects has higher left and right
  amydalo-hippocampus and thalamus volumes
• Neurological Soft-Signs (NSS) genetic and
  environment
• Overall, smaller brain in schizophrenic patients

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MOLECULAR MARKERS

• Chromosome loci reported 1p, 3p (D3 receptor
  gene), 6p, 8p, 10p (found in Caucasian Americans
  but not African Americans), 13q (serotonin 5HT2A
  receptor gene), 22qDS, COMT gene (prefrontal
  memory), BDNF gene (cognitive functions),
• Candidate genes usually involve DA and serotonin
  systems.
• Conclusion Its seems unlikely that one major
  locus exist!
• More than one gene involved
• Different people affected differently
• One gene with many effects.
• Environment cues brings out the disease

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OTHER INTERESTING FINDINGS

• Role of memory deficits due to brain
  abnormalities
• Medial Temporal Lobe Long-term memory
• Frontal Lobe Encoding stage (attention and
  organizing info)
• Smaller Left Hippocampus Recall (consolidation
  of into)
• Several memory tests performed schizophrenic
  patients performed significant worse than
  relatives and controls in almost all, while
  relatives performed less well than controls.
• Verbal Declarative Memory (both episodic and
  declarative) is most impaired in schizophrenia
  and seen in encoding stage.
• 1st degree relatives have smaller left hippocampi
  and worse VDM function than controls
• However, in MZ twins, ill twin and unaffected
  twin show different results
• Other causes Psychosocial causes, Amphetamine
  abuse, Schizophrenia-like pyschosis, Brain
  traumas and disorders, Infections in uterus and
  complications of pregnancy
• Environment factors

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CRITICISMS

• Small samples lack convergence validity
• Few studies are replicated
• More robust animal models needed
• Counfounding variables affect results
• Conflicting results For example, one study found
  that hippocampal volume is actually not a genetic
  component.
• Larger hippocampal volume in parents, unaffected
  twin and sibling protection against
  schizophrenia?
• Could environment cause the shrinkage of
  hippocampus size?

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FUTURE DIRECTIONS

• Detection of target features neuropathological
  signs important for determining risk
• Interventions that reduce known environmental
  factors in high-risk children may alter outcome
• Genetic testing for possible genes important for
  prevention and pharmacological interventions
• Better studies needed such as animal studies,
  larger samples, longitudinal studies, etc.
• More studies that look at both environment and
  genetic factors are necessary
• Look for sensitive period

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AFTERWORD

• There is a clear genetic basis!
• Little evidence for environmental factors as
  primary cause
• Schizophrenia is heterogenous!
• Complex interaction between environment and
  genes.
• There still exist many misconceptions about the
  implications of genetic etiology of schizophrenia.

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INTERESTED?

• Overall information on schizophrenia
• http//www.nimh.nih.gov/publicat/schizoph.cfm
• Interesting video on a schizophrenic teen
• http//www.schizophrenia.ca
• A site dedicated to only researches on
  schizophrenia
• http//www.narsad.org/
• Information for family and friends of
  schizophrenic patient
• http//www.mentalhealth.com/book/p40-sc01.html

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The End