The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with...
-
Upload
augustine-mathews -
Category
Documents
-
view
213 -
download
1
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.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/1.jpg)
The Goal
1. Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components.
Hasler et al., (2005)
![Page 2: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/2.jpg)
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)
![Page 3: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/3.jpg)
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
![Page 4: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/4.jpg)
How Bad Is The Problem?
p (disease|gene)• Odds ratio =
p (disease|no-gene)
![Page 5: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/5.jpg)
Odd’s Ratio
Huntington's Smoking/Cancer
Psychiatric0
20
40
60
80
100
120
Kendler, 2005
![Page 6: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/6.jpg)
Huntington’s
X Y
One-to-one relationship
![Page 7: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/7.jpg)
Anxiety
•A V
•B W
•X Y
•C Z Many-to-many relationship
![Page 8: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/8.jpg)
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
![Page 9: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/9.jpg)
Anxiety
•A V
•B W
•X Y
•C Z Many-to-many relationship
![Page 10: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/10.jpg)
Anxiety
•A V
•B W
•X Y
•C Z Many-to-many relationship
![Page 11: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/11.jpg)
Endophenotypes ?Fisher
(DysReg)
Associated with disease Yes
Reliable
Genetic
Identify at-risk
State independent
First-degree relatives
Plausible
Segregates with illness
Specificity
![Page 12: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/12.jpg)
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
![Page 13: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/13.jpg)
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
![Page 14: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/14.jpg)
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
![Page 15: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/15.jpg)
This Is What You May Get
• Wisconsin Card Sorting Task– Recognized measure of prefrontal function– Effect size of association = 0.5% of variance
![Page 16: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/16.jpg)
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)
![Page 17: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/17.jpg)
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)
![Page 18: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/18.jpg)
Schizophrenia
•A V
•B W
•X Y
•C Z
![Page 19: The Goal 1.Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler.](https://reader035.fdocuments.us/reader035/viewer/2022072006/56649cff5503460f949d15f7/html5/thumbnails/19.jpg)
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”.