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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) 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”.