methodological issues in molecular genetic studies of mental disorders (bearden et al., 2009)
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Methodological Issues in Molecular Genetic Studies of Mental Disorders (Bearden et al., 2009). Genomewide investigations: When it’s Easy. Genomewide investigations have found > 100 loci associated with common disorders Inflammatory bowel disease Type 2 diabetes Rheumatoid arthritis - PowerPoint PPT PresentationTRANSCRIPT
Genomewide investigations have found > 100 loci associated with common disorders◦ Inflammatory bowel disease◦ Type 2 diabetes◦ Rheumatoid arthritis
Features of mapped disorders◦ Objective diagnostic
Example = Type 2 diabetes Blood glucose levels
◦ Low symptom variability◦ Clear biological basis
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?
Mendelian Disorders◦ Simple dominant / recessive patterns
Punnett Squares Examples
Sickle-cell anemia, Tay Sachs disease, Cystic fibrosis, Huntington’s
Laws◦ Segregation◦ Independent Assortment Linked geneshttp://www.youtube.com/watch?v=D1_-mQS_FZ0&feature=related
More complex How do we study heritability?
◦ Twin studies Monozygotic (MZ) vs. Dizygotic (DZ)
Example = Bipolar Disorder◦ MZ = 60-80%◦ DZ = < 10%
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?
Relatives are presumed carriers but do not meet criteria for the disorder◦ We currently have no means to identify carriers
Help to clarify carrier status of family members of individuals affected with psychiatric disorders
No evidence for Schizophenia◦ Flint & Munafo (2007)
Problems?
Candidate gene studies◦ Must have hypotheses about trait genes
relationship associated with disease
Disadvantages◦ Depend on validity of hypotheses
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?
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?
In addition to genes, what else contributes to mental disorders?
◦ Diathesis Stress Model Genes + Stress = Disorder
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?
Variants of small effect◦ Variations in genes that will have a small effect on
traits
Variants of large effect◦ Infrequent variants of relatively large effect
may segregate with disease in families; even if non-Mendelian Studied in small groups
Amish
Technique first used Variants of large effect 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
Unreplicated studies
Egeland et al. 1987◦ bipolar disorder localized to chromosome 11p15
among the old order Amish
Baron et al. 1987◦ gene to chromosome Xq27-28 among non-
Ashkenazi Jews
Advantages◦ Does not matter if affected individuals share
specified genes with unaffected individuals
May still exhibit common traits linked to shared genes
Disadvantages◦ Power still an issue
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
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
Association Study Methodology
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)
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
Disadvantages◦ Massive number of statistical tests
alpha build up = > false-positive results Typical p values = .0000001 Replication required
Countered with multi-stage experiment◦ Why would this help?
Reduce amount of comparisons
In past 2 year100 loci for approximately 40 common diseases have been identified and replicated.◦ Including complex disorders
Type II diabetes and obesity
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?
Genomic variants involving large DNA segments◦ Comprise12% of genome◦ May have impact on complex diseases
Most studies are non-specific ◦ Look at # of CNV, not specific CNV
(Walsh et al., 2008)◦ CNVs associated with schizophrenia in up to
10% of nonfamilial cases Arose spontaneously
Other studies◦ Novel deletions and duplications in patients
with schizophrenia and other neuropsychiatric disorders Autism
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?
Multiple phenotypes from a single mutation◦ What are the implications for the DSM
classification system?
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
Statistical Approaches for rare variant◦ Collapse genotypes across variants and
applying a univariate test Less comparisons = more power
Rodents◦ Large databases in place◦ Easy to create specific genotypes and phenotypes
through breeding
Non-human primates◦ More similar genetically◦ Can create colonies that model human diseases◦ More invasive tests can be conducted
Canines◦ Breeds already contain unique combinations of genetic
material
Locating genes associated with mental disorders is much more complicated than locating genes for diseases◦ Even those with complex inheritance patterns
Why is this?
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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