Download 15000 individuals - Terri L. Weaver, Ph.D.

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Genomewide investigations have found > 100 loci
associated with common disorders
◦ Inflammatory bowel disease
◦ Type 2 diabetes
◦ Rheumatoid arthritis
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Features of mapped disorders
◦ Objective diagnostic
 Example = Type 2 diabetes
 Blood glucose levels
◦ Low symptom variability
◦ Clear biological basis
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Mental Disorders
◦ Lack biological assays
◦ Phenotypic features assessed by subjective ratings
 Diagnosis based on symptom report
◦ Considerable symptom variability across individuals
 Why are current diagnostic methods and symptom
variability a problem?
 Will a dimensional approach be helpful in respect to
the symptom variability problem?
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Mendelian Disorders
◦ Simple dominant / recessive patterns
 Punnett Squares
 Examples
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Sickle-cell anemia, Tay Sachs disease, Cystic fibrosis, Huntington’s
Laws
◦ Segregation
◦ Independent Assortment
 Linked genes
http://www.youtube.com/watch?v=D1_-mQS_FZ0&feature=related
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More complex
How do we study heritability?
◦ Twin studies
 Monozygotic (MZ) vs. Dizygotic (DZ)
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Example = Bipolar Disorder
◦ MZ = 60-80%
◦ DZ = < 10%
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Involves conducting genetic mapping studies
on “intermediate phenotypes,”
◦ Quantifiable characteristics such as brain structure
or neurocognitive performance that are
hypothesized to be closer to the biology
represented by the actions of risk genes than the
observable manifestations of psychopathology, i.e.,
psychiatric symptoms
 What does this mean?
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Relatives are presumed carriers but do not
meet criteria for the disorder
◦ We currently have no means to identify carriers
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Help to clarify carrier status of family
members of individuals affected with
psychiatric disorders
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No evidence for Schizophenia
◦ Flint & Munafo (2007)
 Problems?
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Candidate gene studies
◦ Must have hypotheses about trait genes
relationship associated with disease
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Disadvantages
◦ Depend on validity of hypotheses
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New classification system for psychiatric
disorders based on pathophysiologic and
etiologic processes rather than on overt symptom
clusters (Charney & Babich 2002, Hyman 2007, Phillips 2007)
◦ Problems?
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How does this relate to the dimensional
approach?
If specific genetic markers are found for many
psychological disorders, how would psychology
change?
◦ What if some disorders could be treated with gene
therapy?
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In addition to genes, what else contributes to
mental disorders?
◦ Diathesis Stress Model
 Genes + Stress = Disorder
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Determining which environmental factors to
investigate remains daunting
◦ Large sample sizes needed
 Schizophrenia = n =1,000,000
 Relates to Power
 How can this be reduced?
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Variants of small effect
◦ Variations in genes that will have a small effect on
traits
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Variants of large effect
◦ Infrequent variants of relatively large effect may
segregate with disease in families; even if nonMendelian
 Studied in small groups
 Amish
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Technique first used
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Variants of large effect
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Identify genetic loci transmitted with a disease
phenotype more often than expected by chance
or that are shared identically by sets of affected
relatives (e.g., siblings) more often than expected
by chance
Linkage methodology
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Unreplicated studies
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Egeland et al. 1987
◦ bipolar disorder localized to chromosome 11p15
among the old order Amish
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Baron et al. 1987
◦ gene to chromosome Xq27-28 among nonAshkenazi Jews
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Advantages
◦ Does not matter if affected individuals share
specified genes with unaffected individuals
 May still exhibit common traits linked to shared genes
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Disadvantages
◦ Power still an issue
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Dysbindin at 6p22.3, and a region on
chromosome 1 containing the genes DISC1
and DISC2 (disrupted in schizophrenia 1 and
2), located on chromosome1q42.1-1q42.2
(Sklar 2002)
◦ Dysbindin = implicated in synaptic structure and
signaling
◦ DISC 1= mutations show impairments in a wide variety of
tests, including learning, memory, and sociability
◦ Dysbindin and Schizophrenia
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Are given genetic variants more frequent in
affected individuals than in controls
More power than linkage
◦ Do not depend on detection or transmission of
genetic variants with a phenotype in a family
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Association Study Methodology
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Unbiased method for the identification of
multiple susceptibility genes for complex
diseases
Advantages
◦ Can scan for common variations across entire genome
 Single-nucleotide Polymorphism (SNP)
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Power is relative
◦ It increases with the effect size of the causative allele
and sample size
 Differs between ethnicities
 Need 2x as many for African population
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Disadvantages
◦ Massive number of statistical tests
 alpha build up = > false-positive results
 Typical p values = .0000001
 Replication required
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Countered with multi-stage experiment
◦ Why would this help?
 Reduce amount of comparisons
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In past 2 year100 loci for approximately 40
common diseases have been identified and
replicated.
◦ Including complex disorders
 Type II diabetes and obesity
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No unequivocally significant or replicated
results
◦ Even with the large sample sizes
 >15,000 individuals
◦ Effect sizes too small
◦ What could be contributing to the hypothesized
weak relationships?
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Genomic variants involving large DNA
segments
◦ Comprise12% of genome
◦ May have impact on complex diseases
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Most studies are non-specific
◦ Look at # of CNV, not specific CNV
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(Walsh et al., 2008)
◦ CNVs associated with schizophrenia in up to 10%
of nonfamilial cases
 Arose spontaneously
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Other studies
◦ Novel deletions and duplications in patients with
schizophrenia and other neuropsychiatric
disorders
 Autism
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Regions for which CNVs have been implicated
in one psychiatric disorder
(e.g.,schizophrenia) may also be involved in
other disorders (e.g., autism)
◦ 16p11 chromosomal
◦ How does this relate to the Wan et. al (2008) article?
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Multiple phenotypes from a single mutation
◦ What are the implications for the DSM classification
system?
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Using transcription levels as phenotypes
◦ Expression quantitative trait loci (eQTL) analysis:
 Genetic mapping techniques used to identify specific
genes affecting a quantitative trait(e.g., neuroticism)
 loci regulating mRNA levels
 Help locate candidate genes or association regions
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Statistical Approaches for rare variant
◦ Collapse genotypes across variants and applying
a univariate test
 Less comparisons = more power
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Rodents
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Non-human primates
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Canines
◦ Large databases in place
◦ Easy to create specific genotypes and phenotypes
through breeding
◦ More similar genetically
◦ Can create colonies that model human diseases
◦ More invasive tests can be conducted
◦ Breeds already contain unique combinations of genetic
material
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Locating genes associated with mental disorders
is much more complicated than locating genes
for diseases
◦ Even those with complex inheritance patterns
 Why is this?
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If specific gene combinations are never found for mental
disorders, what will that mean, was the process worth it?
Implications for treatment
Methodology is improving and our
conceptualization of mental disorders are
evolving
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http://www.youtube.com/watch?v=dQnlrSRES
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http://www.youtube.com/watch?v=wgsBxoJ9
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