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

2. 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)

3. Source(s) of the Problem 1.Heterogeneity of phenotype (DSM Category) 2.Diagnostic errors 3.Environmental effects 4.Multiple genes with small effects 5.Gene X Gene interactions 6.Gene X Environment interactions 7.Epigenetic factors

4. How Bad Is The Problem? p (disease|gene) Odds ratio = p (disease|no-gene)

5. Odd’s Ratio Kendler, 2005

6. Huntington’s X Y One-to-one relationship

7. Anxiety AV BW XY C Z Many-to-many relationship

8. 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

9. Anxiety AV BW XY C Z Many-to-many relationship

10. Anxiety AV BW XY C Z Many-to-many relationship

11. Endophenotypes ? Fisher (DysReg) Associated with diseaseYes Reliable Genetic Identify at-risk State independent First-degree relatives Plausible Segregates with illness Specificity

12. Endophenotypes ? FisherVasey (Dysreg)(RSA) Associated with diseaseYes ReliableYes GeneticYes Identify at-risk State independent First-degree relatives Plausible Segregates with illness SpecificityNo

13. Endophenotypes ? FisherVaseyHajcak (DysReg)(RSA)(ERN) Associated with diseaseYes ReliableYes GeneticYes Identify at-riskYes State independentYes First-degree relativesYes PlausibleYes Segregates with illness SpecificityNo

14. 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

15. This Is What You May Get Wisconsin Card Sorting Task – Recognized measure of prefrontal function – Effect size of association = 0.5% of variance

16. 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)

17. 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)

18. Schizophrenia AV BW XY C Z

19. 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”.