GENES AND SCHIZOPHRENIA

Transcription

1 GENES AND SCHIZOPHRENIA Daniel R. Weinberger, MD National Institute of Mental Health National Institutes of Health George Washington University

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

3 LEARNING OBJECTIVE Translate data related to a genetic role in schizophrenia

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

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

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

7 THE GWA APPROACH 20,142 Subjects Hmmmm! SZ and CON = allele frequency in schizophrenia and controls; ATT(P) = trend test p-value; Adj(P) = genomic control adjusted p-value; CMH(P) = Cochran-Mantel-Henszel p-value; Meta-Adj = genomic control adjusted meta-analysis p-value O Donovan MC, et al. Nat Genet 2008;40:

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

9 POLYGENES AND GENETIC RISK FOR PSYCHOSIS p = 2 x Variance Explained (R 2 ) x x x PT < 0.1 PT < 0.2 PT < 0.3 PT < 0.4 PT < MGS-EA MGS-AA O'Donovan STEP-BD WTCCC CAD CD HT RA T1D T2D Schizophrenia Bipolar Disorder Non-Psychiatric (WTCCC) International Schizophrenia Consortium. Nat Genet 2009.

10 THE SIMPLE TRUTH ABOUT THE GENETIC COMPLEXITY OF SCHIZOPHRENIA Two key points!!validity of genetic association depends on relevant biology!!epistasis (i.e., gene x gene interactions) and environmental modification are critical in understanding genetic association

11 TWO QUESTIONS!!Why have genes for psychiatric disorders been the subject of so much controversy?!!why are the clinical associations so weak? Some answers: Heterogeneity Rare variants Epigenetics Epistasis GENES DO NOT ENCODE FOR PSYCHIATRIC SYNDROMES

12 THE PATH FROM HERE TO THERE! Cognition!"#$%&'()*'&*$+,-.$/ )-0&*1$!,'2 Schizophrenia Temperament Genes multiple susceptibility alleles each of small effect Cells subtle molecular abnormalities Systems abnormal information processing Behavior complex functional interactions and emergent phenomena

13 DIABETES GENES DETERMINE INTERMEDIATE PHENOTYPES RELATED TO CELL IMMUNITY Gregersen PK. Nat Genet 2009;41:

14 ABNORMAL PREFRONTAL EFFICIENCY AND RESPONSE VARIABILITY 1-3 A Schizophrenia Intermediate Phenotype fmri Patients > Controls 1 (n = 13) (n = 18) Healthy Siblings > Controls 2 (n = 48) (n = 33) Noise Power (µv) Delta Hz EEG-P300 R L Noise Power (µv) Theta Hz R L Controls (n = 89) Unaffected Siblings of (n = 115) Schizophrenia Patients (n = 66) Controls (n = 89) 1. Callicott JH, et al. Cereb Cortex 2000;10: Callicott JH, et al. Am J Psychiatry 2003;160: Winterer G, et al. Am J Psychiatry 2004;161: Unaffected Siblings of (n = 115) Schizophrenia Patients (n = 66)

15 ABNORMAL BEHAVIOR REFLECTS ABNORMAL BRAIN FUNCTION Cognition!"#$%&'()*'&*$+,-.$/ )-0&*1$!,'2 Psychiatric Disorder Temperament Genes risk associated genotypes Cells synaptic DA Systems prefrontal cortical tuning" Behavior complex functional interactions and emergent phenomena

16 EFFECT OF GENOME-WIDE SIGNIFICANT ZNF804A RISK ASSOCIATED GENOTYPE ON CORTICAL DYNAMICS Esslinger C, et al. Science 2009;324:605.

17 THE COMT GENE AFFECTS HOW EFFICIENTLY YOUR FRONTAL LOBE WORKS N = 126 healthy individuals p <.0001 Meyer-Lindenberg A, Weinberger DA. Nat Rev Neurosci 2006;7:

18 WHY IS COMT EFFECT NOT MORE PENETRANT AT LEVEL OF DIAGNOSIS? Answer: Maybe other genes matter

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

20 COMT BACKGROUND AFFECTS SCHIZOPHRENIA RISK ASSOCIATED WITH OTHER GENES 1,2 COMT = VV COMT = MM Gene SNP 320 Families 68 Families 54 Families GAD1 rs ns.03* ns GAD1 rs ns.03 ns GAD1 rs ns DAOA (G72) rs ns DISC1 rs ns GRM3 rs ns TDT PHASE results in Caucasian families; * p relates to excessive transmissions to affected offspring with COMT val/val genotype 1. Nicodemus KK, et al. Hum Genet 2007;120: Straub RE, et al. Mol Psychiatry 2007;12:

21 ABNORMAL BEHAVIOR REFLECTS ABNORMAL BRAIN FUNCTION Cognition!"#$%&'()*'&*$+,-.$/ )-0&*1$!,'2 Schizophrenia Temperament COMT val/val GRM3 AA genotype Cells DA modulated glu signaling Systems exaggerated inefficiency Behavior

22 EPISTATIC INTERACTION OF COMT val/met AND GRM3 M4 (rs ) IN DLPFC DURING WM fmri BOLD response: load x COMT x GRM3 F(1,25) = 4.47, p <.05 Parameter Estimates at R Dorsal PFC ( ) back 2-back VV+AA VV+G MM+AA MM+G Genotype Tan H, et al. PNAS 2007;104:

23 CORTICAL DA AND GABA INTERACT IN BRAIN Do They Interact Genetically? Lewis DA, et al. Neuropsychopharm 2008;33:

24 THE PATH FROM HERE TO THERE! Cognition!"#$%&'()*'&*$+,-.$/ )-0&*1$!,'2 Schizophrenia NRG1 Temperament ERBB4 AKT1 Cells synaptic biology Systems exaggerated inefficiency Behavior

25 Genes also interact with the environment to modify the expression of their individual effects. This can lead to exaggerated, compensated, or novel effects.

26 GENE-ENVIRONMENT INTERACTION AND RISK FOR PSYCHOSIS COMT and Adolescent Cannabis Use Cannabis - Cannabis + Percent with Schizophreniform Disorder at Age n = (151) (48) (311) (91) (148) (54) met/met val/met val/val Self-Reports of Hallucination/ Delusion Symptoms at Age n = (151) (48) (311) (91) (148) (54) met/met val/met val/val COMT Genotype COMT Genotype Caspi A, et al. Biol Psychiatry 2005;57:

27 INTERACTION OF OCs WITH RISK SNPs IN GENES ASSOCIATED WITH ANOXIA-ISCHEMIA OC = obstetric complication; a number of families differs for each SNP because only fully genotyped families were used in analysis Nicodemus KK, et al. Mol Psychiatry 2008;13:

28 THE SIMPLE TRUTH ABOUT THE GENETIC COMPLEXITY OF SCHIZOPHRENIA Two other key points!!alternative processing of genes is the rule in the brain!!gene effects related to schizophrenia may involve early developmental mechanisms

29 GENETIC VARIATION AND BIOLOGIC VARIATION The SNPs are not functional Characterization of transcripts and gene regulation is rudimentary

30 FUNCTIONAL VARIANTS AND SCHIZOPHRENIA Genetic Risk Coding Mutations Altered splicing Altered expression Altered regulation "

31 NEUREGULIN1 Hap ice Hashimoto R, et al. Mol Psychiatry 2004;9:

32 NEUREGULIN1 TRANSCRIPTS ARE DIFFERENTIALLY EXPRESSED IN SCHIZOPHRENIA AND REGULATED BY 5 SNPs ASSOCIATED WITH THE DISEASE 1,2 TypeIV/PBGD n = 88 p <.05 0 Non-Risk Hap n = 35 Risk Hap Law AJ, et al. PNAS 2006;103: Tan W, et al. J Biol Chem 2007;282: Relative Light Units Individuals T/T vs. C/C pgl4.snp T pgl4.snp C Promoter-Luciferase Construct/ SNP8NRG Relative Light Units Mutagenesis of Individual T to C pgl4.snp T pgl4.snp T Mutant C Promoter-Luciferase Construct/ SNP8NRG

33 NRG1 TYPE IV IS A UNIQUE BRAIN-SPECIFIC ISOFORM MOST ABUNDANT IN FETAL BRAIN Fold Change in Gene Expression mrna Protein Tissue Tan W, et al. J Biol Chem 2007;282:

34 22Q11 HEMIDELETION SYNDROME Velo-Cardio-Facial Syndrome (VCFS)

35 SPECIFIC RECURRENT CNVs ARE FOUND IN 2-3% OF PATIENTS WITH THE DIAGNOSIS OF SCHIZOPHRENIA 1,2 1. International Schizophrenia Consortium. Nat Genet McCarthy SE, et al. Nat Genet 2009;41:

36 CHROMOSOMAL ANOMALIES AND SCHIZOPHRENIA What Do They Tell Us?!! So far, recurrent CNVs that are found with increased frequency in populations with the diagnosis of schizophrenia characterize about 2-3% of individuals with this diagnosis!! About 5% of the time that one of these CNVs is found, it is found in an individual with the diagnosis of schizophrenia ( penetrance )!! None of these CNVs are specific for this diagnosis or even most commonly associated with this diagnosis!! The most frequent association is mental deficiency!! As with autism, there are multiple pathways to the diagnosis!! Are psychotic individuals with these CNVs! cases of schizophrenia? It is important to remember that schizophrenia is not something someone has; it is a diagnosis someone is given

37 GCAP INVESTIGATORS Neuroimaging!! Venkatta Mattay!! Devon Nixon!! Morgan Proust!! Joseph Callicott!! Andreas Meyer-Lindenberg!! Fabio Sambatero!! Hao-Yang Tan Postmortem brain studies!! Barbara Lipska!! Amy Deep-Salobslay!! Thomas Hyde!! Steven Huffaker!! Joel Kleinman NICHD/NIH!! Weng Fang!! Bai Lu Clinical genetics!! Jose Apud!! Stefano Marenco!! Lewellyn Bigelow!! Kristin Nicodemus!! Fengyu Zhang Molecular genetics!! Bhaskar Kolachana!! Krishna Vakkalanka!! Stephen Huffaker!! Richard Straub Mouse genetics!! Jingshan Chen!! Jackie Crawley!! Francesco Papaleo

38 CLINICAL CONNECTIONS!! The genes tell us what schizophrenia is at a basic cellular level!! The current evidence converges on subtle molecular bottlenecks in diverse aspects of synaptic processing and brain development!! There are many pathways to what we call schizophrenia!! The neural mechanism of association for many putative schizophrenia genes involves tuning of working memory circuitry!! Allelic heterogeneity, epistasis, environmental modification, and novel RNA transcripts will likely be the rule for schizophrenia susceptibility genes!! Rare cases with the diagnosis of schizophrenia have pathogenic structural chromosomal variations!! Take-home message: Simple models don t work

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