Transcript The Problem - University of Delaware

The Goal
1. Understanding the etiology of disease X
requires a genetic diathesis interacting with
environmental, epigenetic and stochastic
components.
Hasler et al., (2005)
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)
Source(s) of the Problem
1.
2.
3.
4.
5.
6.
7.
Heterogeneity of phenotype (DSM Category)
Diagnostic errors
Environmental effects
Multiple genes with small effects
Gene X Gene interactions
Gene X Environment interactions
Epigenetic factors
How Bad Is The Problem?
p (disease|gene)
•
Odds ratio =
p (disease|no-gene)
Odd’s Ratio
120
100
80
60
40
20
0
Kendler, 2005
Huntington’s
X
Y
One-to-one relationship
Anxiety
•A
V
•B
W
•X
Y
•C
Z
Many-to-many relationship
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
Anxiety
•A
V
•B
W
•X
Y
•C
Z
Many-to-many relationship
Anxiety
•A
V
•B
W
•X
Y
•C
Z
Many-to-many relationship
Endophenotypes ?
Fisher
(DysReg)
Associated with disease
Reliable
Genetic
Identify at-risk
State independent
First-degree relatives
Plausible
Segregates with illness
Specificity
Yes
Endophenotypes ?
Associated with disease
Fisher
Vasey
(Dysreg)
(RSA)
Yes
Yes
Reliable
Yes
Genetic
Yes
Identify at-risk
State independent
First-degree relatives
Plausible
Segregates with illness
Specificity
No
Endophenotypes ?
Fisher
Vasey
Hajcak
(DysReg)
(RSA)
(ERN)
Yes
Yes
Yes
Reliable
Yes
Yes
Genetic
Yes
Yes
Associated with disease
Identify at-risk
Yes
State independent
Yes
First-degree relatives
Yes
Plausible
Yes
Segregates with illness
Specificity
No
No
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
This Is What You May Get
• Wisconsin Card Sorting Task
– Recognized measure of prefrontal function
– Effect size of association = 0.5% of variance
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)
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)
Schizophrenia
•A
V
•B
W
•X
Y
•C
Z
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”.