Schizophrenia: Biology and Etiology Carlsson and Lindqvist 1963 Daniel R. Weinberger, M.D. Genes, Cognition and Psychosis Program National Institute of Mental Health, NIH Bethesda, Maryland 20892 USA weinberd@mail.nih.gov Schizophrenia: The basics Schizophrenia is a serious, chronic disorder of cognition, perception, and comportment. Its onset is typically in early adulthood and it causes a lifetime of disability for most affected individuals. According to the World Health Organization, it is one of the ten most disabling illnesses of human beings. The estimated economic costs in the USA alone are in excess of 50 Billion Dollars/year. What is schizophrenia? Good Question!! Schizophrenia is a syndrome, i.e. a collection of phenomenological characteristics, likely comprised of multiple etiologies with a common clinical endpoint (e.g. like MR, autism, heart failure) The syndrome is somewhat mutable: Symptoms often appear and alter over time Considerable diversity of symptoms across patients
Schizophrenia: The essentials (ca.. 2000) Genes collectively account for most variance in risk Environmental adversity in early development accounts for a small increase in risk Abnormal function of frontal and temporal cortical circuitry is associated with being ill and with increased genetic risk of being ill Subtle abnormalities in neuronal architecture are associated with being ill Antidopaminergic drugs are therapeutic Cognitive deficits in first-episode patients vs. chronic patients 2.0 Meta-Analytic First Episode 1.5 1.0 0.5 0.0 FSIQ Verbal Memory Visual Memory WCST Digit Span Trails A Trails B Block Design Vocabulary Fluency Effect Size (d) Motor Bilder RM, et al. AJP. 2000;157:549-59. 59. Heinrichs RW, Zakzanis KK. Neuropsychology. 1998;12:426-45. Intrapair differences in cognition account for the variance in social and vocational function in MZ twins concordant for schizophrenia Stepwise regression: Memory quotient+iq+card Sort+ Trails A R 2 = 0.99 GAS (social and vocational functioning) Goldberg TE, et al. Schiz Res. 1997;17:77-84.
The prefrontal response in schizophrenia is abnormal: Either too little or too much Underactive ( hypofrontal( hypofrontal ) Overactive ( inefficient( inefficient ) Meyer-Lindenberg A, et al. Amer J Psychiatry. 2001;158:1809-17. Callicott JH, al. Cerebral Cortex. 2000;10:1078-92. Neuroimaging has helped to localize brain regions implicated in the pathogenesis of schizophrenia Dorsolateral Prefrontal Cortex 1. Clinical symptoms 2. Structural imaging findings 3. Functional imaging findings 4. +/- neuropathology Hippocampus 1. Structural imaging 2. Neuropathology 3. +/- Functional imaging Other Candidates 1. Thalamus 2. Nucleus accumbens 3. Midbrain: dopamine hypothesis 4. Papez circuit: anterior cingulate D 2 receptor binding in vitro predicts clinical doses of antipsychotic drugs Creese I, et al. Science. 1976;192:481-3.
Evidence of upregulated presynaptic striatal dopamine activity in schizophrenia 11 C-Raclopride PET 6-18 F-DOPA PET Before Amphetamine After Laurelle et al, 1997.; Laurelle et al, 2000.; Breier A, et al. PNAS. 1997;94:2569-74.; Abi-Dargham A, et al. J Neurosci. 2002;22:3708-19. Reith J, et al. PNAS. 1994;91:11561-4. Hietala J, et al. Lancet. 1995;346:1130-1. Lindstrom LH, et al. Biol Psych. 1999:46:681-8. Meyer- Lindenberg A, et al. Nature Neuroscience. 2002;5:267-71. What causes schizophrenia?? Schizophrenia is largely heritable with an important environmental component Relative risk of developing schizophrenia * Mental Health: A Report of the Surgeon General (1999) http://www.surgeongeneral.gov/library/mental health/home.html
Age boys learned to stand Developmental antecedents are well established The later boys stand during the first year of life, the greater the risk of schizophrenia Isohanni M, et al. Schiz Res. 2001;52:1-19. Increased frequency of childhood enuresis in adult patients with schizophrenia 25 20 * P<.0001 Frequency of Enuresis 15 10 λ s = 2.6 Series1 5 0 1 2 3 Patients N=211 Healthy Sibs N=234 Controls N=335 Hyde et al Brain (2008) Low SES Immigration Urbanicity Substance abuse Poor cognitive performance Schizophrenia Other psychiatric disorder Social withdrawal Older father Perinatal complications Genetic predisposition
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 individualized treatment Genes identify biological pathways for development of new treatments Complex (i.e.multifactorial) disorders like mental illness are polygenic and genetically heterogeneous affected person unaffected nonpenetrant Goldman D, et al. Nat Rev Gen. 2005;6:521-32.
The genome sequence contains many variations } Single nucleotide polymorphism AATCC AAGCC Genes are found by association A gene is said to be associated with a trait (e.g. an illness) when a variant in the gene is found with increased frequency in a population enriched with that trait A population lacking the BLUE trait aa CC Aa Cc aa Cc aa cc aa cc aa cc Aa CC AA cc genotype male female A population of BLUE people AA CC aa Cc Aa Cc AA cc AA cc Aa cc AA CC Aa cc The A gene is associated with the BLUE trait Schizophrenia susceptibility genes: Strength of the evidence GAD1 2q31.1 ++ ++++ Yes +++ ERBB4 2q34 ++ +++ Yes ++ FEZ1 11q24.2 ++ +++ Yes + MUTED 6p24.3 ++++ ++++ +++ Yes MRDS1 (OFCC1) 6p24.3 ++ ++++ + Not known After: Harrison PH, Weinberger DR. Mol Psych. 2005;10:40-68. Modified by: Straub RE, Weinberger DR. Biol Psych. 2006;60:81-3.
Are the genetic associations valid? NO: there are too many inconsistencies YES: inconsistencies would be expected The GWA approach: 20,142 subjects Hmmmm. O Donovan et al Nat Gen 2008
The Wisconsin Card Sorting Task Two Questions: 1.Why are genes for psychiatric disorders so controversial? 2. Why are the clinical associations so weak? One Answer: Genes do not encode psychiatric phenomena The path from here to there cognition Schizophrenia temperament Genes: Cells: Systems: Behavior: multiple susceptibility alleles each of small effect subtle molecular abnormalities abnormal information processing complex functional interactions and emergent phenomena The path from changes in the score (DNA code) to changes in the music (behavior) ~ ~ ~ Broken synapse orchestra Genes: multiple susceptibility alleles each of small effect Cells: subtle synaptic molecular abnormalities Distributed Neural Systems: abnormal information processing Perturbed Cognition: as an emergent phenomena
The Wisconsin Card Sorting Task The path from here to there cognition Schizophrenia temperament Genes: Cells: Systems: Behavior: multiple susceptibility alleles each of small effect subtle molecular abnormalities abnormal information processing complex functional interactions and emergent phenomena Working memory deficits and genetic risk for schizophrenia N Back Percent Correct 120 100 80 60 40 20.001.001 control sib index n=88 n=130 n=126 0 0 Back 1 Back 2 Back Goldberg TE, et al. Arch Gen Psych. 2003;60:889-96. Abnormal prefrontal efficiency and response variability: A schizophrenia intermediate phenotype fmri Patients > Controls (N=13) (N=18) Callicott et al. Cereb Cortex 2000 Healthy Siblings > Controls (N=48) (N=33) Callicott et al. Am J Psychiatry 2003 Noise Power (µv) 148.5 51.5 Controls (N=89) Delta 0.5-5.5 Hz Unaffected Siblings of (N=115) R L Schizophrenia Patients (N=66) EEG Noise Power (µv) 130.0 45.0 Controls (N=89) Theta 6.0-8.0 Hz Unaffected Siblings of (N=115) Schizophrenia Patients (N=66) R L Winterer G, et al. Am J Psychiatry. 2003;161-490-500.
The Wisconsin Card Sorting Task The path from here to there cognition Schizophrenia temperament Genes: Cells: Systems: Behavior: multiple susceptibility alleles each of small effect subtle molecular abnormalities Inefficient prefrontal engagement during executive cognition complex functional interactions and emergent phenomena Schizophrenia susceptibility genes: Strength of the evidence GAD1 2q31.1 ++ ++++ Yes +++ ERBB4 2q34 ++ +++ Yes ++ FEZ1 11q24.2 ++ +++ Yes + MUTED 6p24.3 ++++ ++++ +++ Yes MRDS1 (OFCC1) 6p24.3 ++ ++++ + Not known After: Harrison PH, Weinberger DR. Mol Psych. 2005;10:40-68. Modified by: Straub RE, Weinberger DR. Biol Psych. 2006;60:81-3. From the lab manual of Julie Axelrod
COMT affects cortical function N=126 healthy individuals p<.0001 Meyer-Lindenberg A, Weinberger DR. Nature Rev Neurosci. 2006;7:818-27. Why does COMT not have a more obvious at the behavioral level? Answer: maybe the environment matters! Genes interact with the environment to modify the expression of their individual effects. This can lead to exaggerated, compensated, or novel effects.
A gene-environment environment interaction and risk for schizophrenia psychosis: COMT and adolescent cannabis use cannabis - cannabis + Caspi et al Biol Psych 2005 No one has only one gene. Genes interact to modify the expression of their individual effects. This can lead to exaggerated, compensated, or novel effects. Genetic association in high risk context fmri 77 high risk offspring of schizophrenic parents followed > 10 years 11 developed schizophrenia Val allele associated with increased risk (p < 0.01), VV odds ratio = 8 McIntosh AM, et al. Biol Psychiatry. 2007;61:1127-34.
COMT background affects schizophrenia risk associated with inheritance of other susceptibility alleles* COMT = VV COMT = MM gene marker 320 families 68 families 54 families GAD1 P3433 ns p= 0.03* ns GAD1 P3023 ns 0.03 ns GAD1 P3248 0.02 0.004 ns DAOA (G72)P2323 0.04 0.04 ns DISC1 P3304 0.01 0.005 ns GRM3 P2878 0.02 0.04 ns 0.07 dysbindin P3762 0.03 dysbindin P2555 TDT PHASE results in Caucasian families; 0.03 dysbindin P1757 * p relates to excessive transmissions to 0.02 dysbindin affected P1578 offspring with COMT val/val genotype 0.005 viz. Nicodemus KK, al. Hum Gen. 2006;120:889-906. Straub RE, et al. Mol Psych. 2007;12:854-69. 22q11 Hemideletion Syndrome: Velo-Cardio Cardio-Facial Syndrome (VCFS) Specific recurrent CNVs are found in 2% of patients with the diagnosis of schizophrenia ISC Nat Genetics 2008
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% of individuals with this diagnosis. 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. Genetics and the Future of Psychiatry Where will genes take us? valid diagnosis? primary prevention? mechanisms of disease? improved outcome? new therapeutic targets? Effect of COMT val/met genotype and cognitive response to clozapine N=86 Woodward et al Schiz Res 2007
GCAP Investigators Neuroimaging Joseph Callicott Venkatta Mattay Hao-Yang Tan Andreas Meyer-Lindenberg Clinical genetics Michael Egan Terry Goldberg Lewellyn Bigelow Jose Apud Thomas Hyde Stefano Marenco Kristin Nicodemus Molecular genetics Richard Straub Bhaskar Kolachana Krishna Vakkalanka Schizophrenia Biology and Genetics: Conclusions Schizophrenia is associated with early developmental antecedents that suggest delayed and potentially deficient brain maturation. Genes tell us what the disorder is at a basic cellular level. The current evidence converges on subtle molecular bottlenecks in diverse aspects of synaptic processing and brain development. Many schizophrenia susceptibility genes, despite their diverse effects at the cellular level, impact on a common pattern of prefrontal cortical function, and most risk alleles are associated with relatively less efficient engagement of prefrontal circuitry (i.e. poorer STN), perhaps in part via altered DA signaling. Schizophrenia Biology and Genetics: Conclusions (Cont.) Rare cases with the diagnosis of schizophrenia have pathogenic structural chromosomal variations. The clinical application of gene discovery will require deep understanding of genetic variation, gene processing, molecular pathways, and the interacting environment.