The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with...

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The Goal 1. Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler et al., (2005)

Transcript of The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with...

Page 1: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.

The Goal

1. Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components.

Hasler et al., (2005)

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The Problem

1. Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components.

2. Underlying genetic diatheses and environmental, epigenetic and stochastic mechanisms have remained mostly uncharacterized.

Hasler et al., (2005)

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Source(s) of the Problem

1. Heterogeneity of phenotype (DSM Category)2. Diagnostic errors3. Environmental effects4. Multiple genes with small effects5. Gene X Gene interactions6. Gene X Environment interactions7. Epigenetic factors

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How Bad Is The Problem?

p (disease|gene)• Odds ratio =

p (disease|no-gene)

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Odd’s Ratio

Huntington's Smoking/Cancer

Psychiatric0

20

40

60

80

100

120

Kendler, 2005

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Huntington’s

X Y

One-to-one relationship

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Anxiety

•A V

•B W

•X Y

•C Z Many-to-many relationship

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Types of Markers (Need not be Biological)

• Episode – associated only with active symptoms– May or may not be genetic– Not a genetic marker – would miss compensated or ‘at-risk’– May predict treatment outcome in specific subgroup, etc.

• Vulnerability – prone to illness, but not part of pathological genotype (black skin & sickle cell)

• Genetic – associated with the pathological gene– Linkage – non-allelic genes in close proximity are linked to disorder– Direct manifestation of genetic diasthesis

• These are endophenotypes

Iacono, 1988

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Anxiety

•A V

•B W

•X Y

•C Z Many-to-many relationship

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Anxiety

•A V

•B W

•X Y

•C Z Many-to-many relationship

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Endophenotypes ?Fisher

(DysReg)

Associated with disease Yes

Reliable

Genetic

Identify at-risk

State independent

First-degree relatives

Plausible

Segregates with illness

Specificity

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Endophenotypes ?Fisher Vasey

(Dysreg) (RSA)

Associated with disease Yes Yes

Reliable Yes

Genetic Yes

Identify at-risk

State independent

First-degree relatives

Plausible

Segregates with illness

Specificity No

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Endophenotypes ?Fisher Vasey Hajcak

(DysReg) (RSA) (ERN)

Associated with disease Yes Yes Yes

Reliable Yes Yes

Genetic Yes Yes

Identify at-risk Yes

State independent Yes

First-degree relatives Yes

Plausible Yes

Segregates with illness

Specificity No No

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Be Careful What You Ask For

• Flint & Munafo, 2007– COMT polymorphism & schizophrenia• COMT regulates dopamine

– Odds ratio = 1.13

• How about endophenotypes?– Move closer to the genes– Genes should account for more variance– Neuropsychological dysfunction associated with

prefrontal cortex

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This Is What You May Get

• Wisconsin Card Sorting Task– Recognized measure of prefrontal function– Effect size of association = 0.5% of variance

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This Is What You May Get

• Wisconsin Card Sorting Task– Recognized measure of prefrontal function– Effect size of association = 0.5% of variance

• N-Back task– Effect size was the same (0.5% of variance)

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This Is What You May Get

• Wisconsin Card Sorting Task– Recognized measure of prefrontal function– Effect size of association = 0.5% of variance

• N-Back task– Effect size was the same (0.5% of variance)

• P300– Effect size was even worse (0.01% of the variance)

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Schizophrenia

•A V

•B W

•X Y

•C Z

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Conclusions• Odds ratios in psychiatric disorders are very low• Endophenotype strategy is very hot & plausible

-- at least theoretically

• Identifying a good endophenotype is difficult– Pay attention to the criteria– Don’t drop bomblets – do the work

• Current status– Some say only success to date is in schizophrenia– But Flint & Munafo is discomfiting

• Have fun – but “Be careful out there”.