1. The Pie of Schizophrenia (Theoretical: Early Molecular Biology)

2. The Pie of Schizophrenia (Theoretical: Current)

4. Specific Genetic Liability -3-20 1 23 General Genetic Liability -3-20 1 23 Specific Environmental Liability -3-20 1 23 Total Liability -3-20 1 23 Frequency Schizotypal Schizophrenic General Environmental Liability -3-20 1 23

5. -3 -2 012 3 4 Total Liability Frequency Schizotypal Schizophrenic Relatives of Schizophrenics General Population

6. 22.1 22.3 21.1 22.1 23 24 25 21 Schematic of chromosome 6 giving two potential linkage hotspots.

7. Summary of Linkage Results in Schizophrenia From Owen et al., Trends in Genetics (2005), 21, 518-525 Red lines = genome-wide significance Blue lines = significant in more than 1 sample Red arrow = possible chromosomal anomolies Yellow = potential candidate genes

9. Summary of GWAS studies in schizophrenia

10. Lee et al., Neuro & Biobeh Rev (2012) GWAS genes of interest in schizophrenia Replication ? Replication

11. “Whilst GWAS have identified new and novel genes that are associated with SZ and BPD, the extent of phenotypic variance that is explained by these genes is disappointingly low.” Lee et al., Neuro & Biobeh Rev (2012), p. 565

12. Summary of CNV studies in schizophrenia

13. Summary of Results: 22q11 microdeletion --> velocardiofacial syndrome (VCFS) aka DiGeorge syndrome; increased risk for mental retardation, autism, bipolar disorder, and schizophrenia. only 6 good CNV studies as of 2010 but evidence for rare CNV deletions in 1q21.1 and 15q13.3 which affect psychosis and other behavioral problems strong effect, but account for about 1% percent of cases Tam et al. (2009). Biol Psychiatry; Bassett et al. (2010) Am J Psychiat Lee et al., Neuro & Biobeh Rev (2012), p. 565

14. Lee et al., Neuro & Biobeh Rev (2012) GeneRegionCNV Sometimes, CNVs are not gene specific ? Lession: Mucking something up in a region is not good.

15. Example: Lack of specificity for Schizophrenia Often, range of psychopathology is even greater.

16. Summary of Results in Psychiatric Genetics: (oversimplified) No single gene, Mendelian forms detected (exception: mental retardation) Hardly any major loci found Few established phenocopies GWAS data suggest very polygenic Promising early results for CNVs

17. Notable Exceptions: Many Mendelian forms of mental retardation Major Loci: ALD and ALDH & Alcoholism Amphetamine psychosis = phenocopy for schizophrenia

18. Odds ratios for ADHD & 7 repeat allele in DRD4 From 7 meta-analyses on European or mostly European Ancestry

19. “None of these [5] papers reports any associations that are formally genome-wide significant after correction for multiple testing.” Franke, Neale, Faraone (2009). Genome-wide association studies in ADHD. Human Genetics, 126:13-50 But a summary of GWAS studies says:

20. Frontiers: Endophenotypes

21. Endophenotype: (“within” phenotype) A phenotype closer to gene action than the phenotype of study; usually an anatomical, physiological, or biochemical variable.

22. Strategy of Endophenotypes: Detect genes that influence the endophenotype instead of genes for the disorder. Examples for schizophrenia: Ventricular size Abnormal eye tracking

23. Frontiers: Genes and Neuroimaging

24. From Heinz et al. (2004). Nature Neuroscience, 8, 20-21. Legend for the next two figures

25. From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.

27. From Hariri et al. (2005), Arch gen Psychiat 62:146-152 Legend for next Figure

28. From Hariri et al. (2005), Arch gen Psychiat 62:146-152

30. Frontiers: Genes-environment Interaction

31. From Caspi et al., Science 297-851-854

32. From Foley et al., Arch gen Psychiat, 61:738-744

33. From Caspi et al., Science 301, 386-389 Depression as a function of stressful life events and the short-long polymorphism in the serotonin transporter gene

34. Frontiers: Rare variants

35. Paraphrase of Erlenmeyer-Kimling lecture, c. 1972 trying to explain the paradox of high heritability and low fitness in schizophrenia. See Keller (2006) Brain & Behavioral Science. Perhaps there are so many genes involved in schizophrenia that new mutations in several of these genes could replenish the loss from selection.

36. Rare Variant Hypothesis: Could be mutations in a gene or CNVs Rare gene mutations hard to find in GWAS. Need sequencing to find them.

37. Future Thought: Perhaps behavior is the genetics of behavior is so polygenic and complex that the study of genetics is not the best way to proceed.