methodological issues in molecular genetic studies of mental disorders (bearden et al., 2009)

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

http://www.youtube.com/watch?v=O4bHLkFajhQ

http://www.youtube.com/watch?v=dQnlrSRESJ8

http://www.youtube.com/watch?v=wgsBxoJ9z3Q