GENETICS AND SCHIZOPHRENIA: INTRIGUING BUT CONFUSING

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2 GENETICS AND SCHIZOPHRENIA: INTRIGUING BUT CONFUSING Daniel R. Weinberger, MD Director of the Genes, Cognition and Psychosis Program Intramural Research Program National Institute of Mental Health National Institutes of Health Bethesda, MD Professor of Psychiatry George Washington University Washington, DC

3 DANIEL R. WEINBERGER, MD Disclosures Research/Grants: None Speakers Bureau: None Consultant: None Stockholder: None Other Financial Interest: None Advisory Board: None

4 LEARNING OBJECTIVE Explore the genetic risk for schizophrenia, and discuss the biological and environmental interactions that can be implicated in neuropsychiatric disorders.

5 GENES AND MENTAL ILLNESS Why Do We Study Them? Most risk for psychiatric illness is related to inheritance Genes transcend phenomenological diagnosis Genes represent mechanisms of disease Genes clarify the environment Genes identify at-risk individuals Genes will help individualize treatment Genes identify biological pathways for development of new treatments

6 COMPLEX DISORDERS LIKE MENTAL ILLNESS ARE POLYGENIC AND GENETICALLY HETEROGENEOUS Affected Person Unaffected Nonpenetrant Goldman D, et al. Nat Rev Gen. 2005;6(7):

7 SCHIZOPHRENIA SUSCEPTIBILITY GENES Strength of the Evidence 1,2 GAD1 2q Yes +++ ERBB4 2q Yes ++ FEZ1 11q Yes + ZNF804A 2q Not known CACNA1C 12p Not known BDNF 11p Yes 1. Harrison PJ, et al. Mol Psychiatry. 2005;10: Straub RE, et al. Biol Psychiatry. 2006;60:81-83.

8 SZGene (SCHIZOPHRENIA GENE) Field Synopsis of Genetic Association Studies in SZ The SRF meta-analysis top 30: Pick your poison Courtesy of

9 ARE ANY OF THE GENETIC ASSOCIATIONS VALID? NO: there are too many inconsistencies YES: inconsistencies would be expected

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11 THE GWA APPROACH 20,142 Subjects Hmmmm. GWA = genome-wide association O Donovan MC, et al. Nat Genet. 2008;40(12):

12 THE GWA APPROACH 47,536 Subjects What happened to ZNF804a? Stefansson H, et al. Nature. 2009;460(7256):

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14 GWAS The Inconvenient Truth The GWAS strategy in psychiatry actually succeeded precisely as much as should have been expected; the approach could never have lived up to the hype because Psychiatric disorders are syndromal, i.e., not distinct disease entities Biological heterogeneity is the rule Most complex biological processes are not linear GWAS = genome-wide association study

15 THE INCONVENIENT TRUTHS II Moreover, the GWAS strategy using the available SNP chips had to miss most of the heritability because of Heterogeneity Rare variants epigenetics Epistasis GENES DO NOT ENCODE FOR PSYCHIATRIC SYNDROMES

16 THE PATH FROM HERE TO THERE cognition DSM-IV temperament Genes: multiple susceptibility alleles each of small effect Cells: subtle molecular abnormalities Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

17 GENETIC VARIANTS ASSOCIATED WITH Lp(a) LIPOPROTEIN LEVEL AND CORONARY DISEASE Clarke R, et al. N Engl J Med. 2009;361(26):

18 THE PATH FROM HERE TO THERE cognition Psychosis temperament Genes: multiple susceptibility alleles each of small effect Cells: subtle molecular abnormalities Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

19 EXECUTIVE COGNITION IN MZ TWINS DISCORDANT FOR SCHIZOPHRENIA normal mean Wisconsin Card Sort Categories Unaffected Affected Goldberg TE, et al. Arch Gen Psychiatry. 1990;47(11):

20 GENETIC VARIATION IN COGNITION AND RISK FOR SCHIZOPHRENIA SHARE MOST GENETIC COMPONENTS A Large Family and Twin Study (N = 2056) Toulopoulou T, et al. Arch Gen Psychiatry. 2010;67(9): Shared genetic components with schizophrenia

21 ABNORMAL BEHAVIOR REFLECTS ABNORMAL BRAIN FUNCTION cognition Psychiatric Disorder temperament Genes: risk associated genotypes Cells: molecular biology Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena

22 ABNORMAL PREFRONTAL EFFICIENCY AND RESPONSE VARIABILITY A Schizophrenia Intermediate Phenotype fmri Noise Power (μv) Controls (N = 89) Patients > Controls 1 (N = 13) (N = 18) Delta Hz Unaffected Siblings (N = 115) EEG-P300 3 R L Schizophrenia Patients (N = 66) Noise Power (μv) 45.0 Healthy Siblings > Controls 2 (N = 48) (N = 33) Controls (N = 89) Theta Hz Unaffected Siblings (N = 115) Callicott JH, et al. Cereb Cortex. 2000;10(11): Callicott JH, et al. Am J Psychiatry. 2003;160(4): Winterer G, et al. Arch Gen Psychiatry. 2003;60(11): R L Schizophrenia Patients (N = 66)

23 THE SIMPLE TRUTH ABOUT THE GENETIC COMPLEXITY OF SCHIZOPHRENIA Four Key Points 1. The genes for schizophrenia are not for schizophrenia 2. Risk for schizophrenia is critically dependent on context (i.e., interactions of genes and the environment) 3. Variable gene processing is the rule in brain and is the likely molecular basis of genetic association 4. The seeds of risk are sown long before the diagnostic illness is manifest

24 WHOLE-GENOME ASSOCIATION STUDY OF BIOPOLAR DISORDER Plot of CACNA1c Region of Association* Combined STEP-BD and UCL Samples WTCCC * Association results (-log10 p) are plotted for all single nucelotide polymorphisms (SNPs) passing quality control Sklar P, et al. Mol Psychiatry. 2008;13(6):

25 BIPOLAR/SCHIZOPHRENIA RISK ASSOCIATED GENE CACNA1c Modulates Cortical Efficiency During Working Memory in Normal Subjects N = 316, p =.01 FDR corrected Extrapolated to N = 10,000, p < 4.87e- 109 Bigos KL, et al. Arch Gen Psychiatry. 2010;67(9):

26 EVEN RELATIVELY SIMPLE BEHAVIORS ARE SUBSERVED BY DISTRIBUTED, DEGENERATE PROCESSING NETWORKS [1] Mesulam MM. Ann Neurol. 1981;10(4): Mesulam MM. Ann Neurol. 1990;28(5): [2]

27 EFFECT OF GENOME-WIDE SIGNIFICANT ZNF804a RISK ASSOCIATED GENOTYPE ON CORTICAL DYNAMICS Is this a neural system mechanism of the association with schizophrenia? Esslinger C, et al. Science. 2009;324(5927):605.

28 GENETIC ASSOCIATION AND BRAIN FUNCTION Some Caveats Most genes are likely to impact on brain function Genetic association with brain function and neural mechanisms of clinical risk are not necessarily linked This linkage requires demonstration that the neural association is with a heritable, susceptibility-related phenotype (i.e., an intermediate phenotype)

29 PREFRONTAL-HIPPOCAMPAL COUPLING DYNAMICS DURING WORKING MEMORY Evidence for a Schizophrenia-Associated Intermediate Phenotype Difference in negative right PFC-right HF coupling (T contrast) p =.05, FWE p <.01 N s = 78 probands 171 unaffected siblings 151 controls Seeded coupling analysis Significant difference in modulation of the task load on the coupling between right DLPFC and right HF coupling p =.05 p <.05, FWE Psychophysiologic interaction analysis Rasetti R, et al. Arch Gen Psychiatry. In Press.

30 ABNORMAL PREFRONTAL EFFICIENCY A Schizophrenia Intermediate Phenotype fmri The N Back working memory task Prefrontal efficiency and prefrontal connectivity measures show no correlation within healthy siblings, suggesting that they represent independent neural system mechanisms of susceptibility Patients > Controls (N = 13) (N = 18) [1] 1. Callicott JH, et al. Cereb Cortex. 2000;10(11): Callicott JH, et al. Am J Psychiatry. 2003;160(4): Healthy Siblings > Controls (N = 48) (N = 33) [2]

31 THE ORIGINAL SCOTTISH PEDIGREE The DISC1 1q;11q translocation Blackwood DH, et al. Am J Hum Genet. 2001;69(2): Blackwood et al AJHG 2001

32 22Q11 HEMIDELETION SYNDROME Velo-Cardio-Facial Syndrome (VCFS)

33 THE CNVs ASSOCIATED WITH SCHIZOPHRENIA ARE NOT ABOUT SCHIZOPHRENIA Moreno-de-Luca D, et al. Am J Hum Genet. 2010;87(5):

34 THE SIMPLE TRUTH ABOUT THE GENETIC COMPLEXITY OF SCHIZOPHRENIA Four Key Points 1. The genes for schizophrenia are not for schizophrenia 2. Risk for schizophrenia is critically dependent on context (i.e., interactions of genes and the environment) 3. Variable gene processing is the rule in brain and is the likely molecular basis of genetic association 4. The seeds of risk are sown long before the diagnostic illness is manifest

35 GENETIC NETWORK IMPLICATED IN MEDIATING VARIATION IN STARVATION STRESS IN FLIES Ayroles JF, et al. Nat Genet. 2009;41(3):

36 ERBB4 SIGNALING IS A SCHIZOPHRENIA RISK PATHWAY ** * * * Courtesy of:

37 EPISTATIC INTERACTIONS IN NRG1-ERBB4-AKT1 ERBB4 AKT1 NRG1 2-SNP interactions between SNPs selected via 3 Machine Learning Algorithms (random forest, conditional inference forest, Monte Carlo logic regression) interaction SNP1 SNP2 SNP1 risk genotype SNP2 risk genotype interaction OR interaction 95% CI LRT p- value NRG1- NRG1 rs rs G/G A/A , NRG1- NRG1 rs rs G/G T carrier , NRG1- NRG1 rs rs T carrier G carrier , NRG1- ERBB4 rs rs C/C A/A , NRG1 x erbb4 x AKT1 risk genotypes at all three loci: OR (CI ), p <.002. Nicodemus KK, et al. Arch Gen Psychiatry. 2010;67(10):

38 COMPARISONS OF GENOTYPE RISK GROUPS ACROSS THREE GENES (NRG1-ERBB4-AKT1) T scor e ANOVA: 3-way interaction F(1,106) = 4.663, p = Parameter estimates in R-BA Risk NRG1 ErbB4 AKT1 NRG1/ ErbB4/ AKT1 genotype Ref group Nicodemus KK, et al. Arch Gen Psychiatry. 2010;67(10):

39 GENES ALSO INTERACT WITH THE ENVIRONMENT TO MODIFY THE EXPRESSION OF THEIR INDIVIDUAL EFFECTS. THIS CAN LEAD TO EXAGGERATED, COMPENSATED, OR NOVEL EFFECTS.

40 INTERACTION OF SERIOUS OCs WITH RISK SNPs IN GENES ASSOCIATED WITH ANOXIA- ISCHEMIA OC = obstetric complications Nicodemus KK, et al. Mol Psychiatry. 2008;13(9):

41 THE SIMPLE TRUTH ABOUT THE GENETIC COMPLEXITY OF SCHIZOPHRENIA: Four Key Points 1. The genes for schizophrenia are not for schizophrenia 2. Risk for schizophrenia is critically dependent on context (i.e., interactions of genes and the environment) 3. Variable gene processing is the rule in brain and is the likely molecular basis of genetic association 4. The seeds of risk are sown long before the diagnostic illness is manifest

42 THE DISC1 GENE 1,2 * t(1,11)(q42.1;q14.3) 4 DISC UTR 1 1 DISC2 (non-coding, specifically human) L Lv Es S * Four transcripts. Exon 11 alternatively spliced 1 Rhesus monkey has L & Lv but not Es and S 2 1. Millar JK, et al. Genomics. 2000;67(1): Bord L, et al. Neurosci Res. 2006;56(3):

43 DISC1 TRANSCRIPTS (~50) IN HUMAN BRAIN TSNAX DISC1 50 kb a b 9a 10 11a/b RACE from DISC1 exon 3a 5 RACE from DISC1 exon 4 5 RACE from DISC1 exon 9 3 RACE from DISC1 exon 2 3 RACE from DISC1 exon 6 Nakata K, et al. Proc Natl Acad Sci USA. 2009;106(37):

44 SHORT DISC1 TRANSCRIPTS ARE ENRICHED IN THE HIPPOCAMPUS OF PATIENTS WITH SCHIZOPHRENIA Norm Expression % Controls * * 50 Δ3 Δ7Δ8 Esv1 Lv L DISC1 3/4 TSNAX 1/2 TSNAX 3/4 TSNAX 5/6 DISC1_All ** ** Controls Schizophrenia N ~70 N ~30 *, ** ANCOVA, p <.05, p <.01 Nakata K, et al. Proc Natl Acad Sci USA. 2009;106(37):

45 EXPRESSION OF SHORT DISC1 TRANSCRIPTS IS MUCH GREATER IN FETAL LIFE DISC1Δ3 DISC1Δ7Δ8 Fetal age Old age DISC1_Esv1 Fetal age Old age DISC1_Long Fetal age Old age Fetal age Old age Nakata K, et al. Proc Natl Acad Sci USA. 2009;106(37):

46 GCAP INVESTIGATORS Neuroimaging Venkatta Mattay Devon Nixon Morgan Proust Joseph Callicott Fabio Sambatero Eugenia Radulescu Hao-Yang Tan Postmortem brain studies Barbara Lipska Amy Deep-Salobslay Thomas Hyde Tian Ye Kenji Nakata Erin Newburn Amanda Law Joel Kleinman Clinical genetics Jose Apud Stefano Marenco Lewellyn Bigelow Kristin Nicodemus Fengyu Zhang Molecular genetics Bhaskar Kolachana Krishna Vakkalanka Amanda Law Richard Straub

47 CLINICAL CONNECTIONS Most complex behaviors are the result of multiple factors that interact biologically There are many pathways to what we call schizophrenia Most neuropsychiatric disorders are likely the result of epistatic genetic interactions and environmental modification Genetic risk for schizophrenia and for cognitive deficits in affected families share most of their genetic components

48 CLINICAL CONNECTIONS Many genes implicated in risk for schizophrenia show predictable effects and interactions at the level of cortical efficiency and network dynamics even in normal subjects Allelic heterogeneity, epistasis, environmental modification and novel RNA transcripts, typically most abundant during early brain development, will likely be the rule for schizophrenia susceptibility gene Rare cases with the diagnosis of schizophrenia have pathogenic structural chromosomal variations Take-home message: simple models don t work

49 QUESTIONS AND ANSWERS

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