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Schizophrenia Chapter 10 Psychopathology • Sooner or later, half the population suffers a serious run-in – Reactive or endogenous • Very expensive • Historically, known to run in families Schizophrenia • Lifetime risk ~1% • Long-term thought disorder – Cognitive, emotional, motivational • • • • Chronic and acute forms Late adolescence to early adult onset Earlier onset, the worse the prognosis Very expensive (10% of homelessness) Schizophrenia • Disorganized thinking, hallucinations, delusions, blunted affect, poverty of speech, lack of motivation • Subtypes – Paranoid, Disorganized, Catatonic, Undifferentiated Family Risk • Runs in families • As r-value increases, so does probability of having schizophrenia • But not strictly hereditary – – – – – – Cousins, 4% Siblings, 9% Dizygotic twins, 17% Monozygotic twins, 48% Parents of a schizophrenic, 6% Offspring of schizophrenic parent, 13% Diversity • Risk is heritable, but subtypes (e.g., catatonic vs. paranoid) are not – So, is this one disorder or several? • More severe forms are more heritable • Type-I (hallucinations) have better prognosis; type-II (withdrawal, blunted affect) is more severe and more heritable • Some symptom dimensions (e.g., disorganization) more heritable than others Diathesis-Stress Model • Individual may have genes for schizophrenia, but only phenotypically express them after particular stressful life event • Genes create predisposition Identification of Genes • • • • Very active area of research Numerous candidates genes proposed Highly polygenic So far, primary candidate genes proposed on chromosomes 2, 5, 6, 8, 13, 22 • Results very difficult to interpret, though NOTCH4 • • • • On chromosome 6p (also containing some HLAs) Member of a type 1 transmembrane protein family Receptor for membrane bound ligands Roles in variety of developmental processes by controlling cell fate decisions, including postmitotic differentiation of cortical neurons • Evolutionarily conserved intercellular signaling pathway (e.g., homolog to human gene in Drosophila) NOTCH4 • Wei & Hemmings (2000) • Association of schizophrenia with 4 SNPs in the NOTCH4 gene • Highly significant association results for 3 of the SNPs in a sample of 80 British parent-offspring trios Follow-up Studies • Only two with Caucasians (Prasad et al., 2004; Skol et al., 2003) showed weak to modest associations for 2 of the SNP markers, and • Six studies with Caucasians (e.g., Anttila et al., 2003; Luo et al. 2004) found no associations; • Two studies of African samples found associations (Luo et al. 2004; Skol et al. 2003) • But, these studies focused only on a small portion of the gene (5´ promoter region and first exon); additional sites throughout gene need study Liu et al. (2007) • Scanned entire genomic region of NOTCH4 gene using 14 SNPs, 7 of which were validated (minor allele frequency over 10%) • Used relatively large family sample of schizophrenia (218 families with at least two affected siblings) • Asian sample Results • Evidence of association with distal genomic region of NOTCH4 • Failed to find association with 4 SNPs from 5´ region • Weak to modest association found for a few other previously reported SNPs throughout the gene Why Such Poor Replication • Clinical and genetic heterogeneity of schiz. • Ethnicity – Caucasian and African samples show some evidence for proximal region of NOTCH4 – Asian samples don’t, but show evidence for distal region of NOTCH4 • Could be two or more disease-underlying variants at NOTCH4 locus (see Zhang et al. 2004) SNPs and Ethnicity • Each SNP has its own genetic ancestral heritage • Frequencies of each variant may differ between ethnic populations • Remember, synonymous vs. nonsynonymous SNPs COMT • Catechol-O-methyl transferase • Enzyme degrading dopamine, epinephrine, norepinephrine • A non-synonymous SNP (substituting valine for methionine) affects cognitive tasks (set shifting, set inhibition, abstract thought) by reducing dopamine at four times the regular rate • Neurons with mutation need higher levels of activation to release normal levels of dopamine post-synaptically Interesting Interaction • Caspi et al. (2004) • Cannabis use linked to twofold increase in late onset schizophrenia • Majority of young users do not develop any psychosis • Suggests some individuals vulnerable to its effect • Gene-environment interaction Candidate Gene • COMT gene on chromosome 22q11; region implicated in genome scans for schizophrenia • Dopaminergic function disturbances implicated in schizophrenia (e.g., Kapur 2003) • Valine (V) for methionine (M) substitution • Genotypes: M/M (“wildtype”) has lowest COMT activity, V/V highest, M/V intermediate (co-dominant alleles) % with schizophrenia disorder at age 26 Outcome 20 15 10 5 0 M/M V/M V/V COMT genotype No adolescent cannabis use Adolescent cannabis use And so… • Evidence that adolescent, but not adult, cannabis use is associated with schizophrenia through V-M polymorphism • May be limited to a sensitive period of brain development • Study is not identifying a major cause of schizophrenia • Supports COMT V-M functional polymorphism as having a role in psychosis, but perhaps only in context of exposure to environmental pathogens Estrogen • Sex differences in schizophrenia • Affected females have better course of disease than males • Interestingly, women show a second peak-of-onset post-menopause (not seen in men) • Clinical observations of affected women show increased symptoms when estrogen levels are low (pre-menstrual, post-partum, post-menopause) and remission of symptoms when estrogen high (e.g., pregnancy) Martorell et al. (2008) • Study to evaluate hypothesis that estrogen receptor genes ESR1 and ESR2 are involved in schizophrenia onset • Also genes APOE and COMT, both regulated by estrogen receptors could also be involved Method • Analyzed SNPs – 26 in ESR1, 14 in ESR2, 7 in APOE, 12 in COMT • Allele frequencies evaluated in 585 schizophrenics and 615 controls • Both male and female subjects, but grouped and sex-separated analysis performed Findings • Analysis failed to find any significant associations between each of the candidate genes and the diagnosis of schizophrenia • A little unexpected, as various earlier animal models indicate role of estrogen genes in dopamine function – Also, Shifman et al. (2002) found association between 3 COMT SNPs and schizophrenia in Ashkenazi Jews; ethnic variability? • Worth considering previous study’s findings that exposure to environmental toxins may be relevant factor Zinkstok et al. (2008) • Used MRIs to examine gray and white matter density and volume differences between genotype groups for COMT and another gene, PRODH • 51 schizophrenic patients scanned and genotyped • Hypothesize COMT and PRODH polymorphisms may result in structural and functional brain abnormalities Findings • A SNP in the promoter region of COMT is associated with a gray matter increase in the right superior temporal gurus • Two nonsynonymous SNPs in PRODH gene associated with reductions in white matter density reductions in frontal lobes • Interestingly, evidence for COMT and PRODH epistasis – Only patients with a COMT valine allele and one or two mutated PRODH alleles showed increased white matter density in left inferior frontal lobes So Where Are We? • Lots of suggestions for candidate genes and SNP effects • Inconsistent findings across many studies • Very complicated • Individual effects by genes most likely small and highly variable due to variability of genotype, environmental interactions, epistasis • So far, results not terribly conclusive • Is there another approach? Endophenotype • Psychiatric concept; biomarker – – – – – Associated with illness Heritable Stable over time Within families, endophenotype and illness co-segregate Found in relatives of affected individual at higher rate than in general population • Divide behavioural symptoms into more stable phenotypes with clear genetic connection • Overt symptom is a psychosis; underlying phenotype are endophenotype. e.g., sensory gating and decline in working memory (the endophenotypes) Braff, Schork & Gottesman (2007) • Argue for endophenotype strategy to understand genetic architecture of schizophrenia • The ultimate endophenotypes are perturbed levels of specific proteins or gene expression • But this level of analysis not yet possible for schizophrenia • So, use neurophysiological and neurocognitive measures – Ones that reflect more elementary aspects of the biology than clinical features themselves Gur et al. (2007) • Examines computerized neurocognitive measures as candidate endophenotypic markers • Multiplex multigenerational families – Beneficial because power to detect genes for quantitative traits through linkage analysis increases with family size (better than sibpairs) – 349 European Americans from 35 multiplex multigenerational families (58 patients, 291 relatives) and 154 psychiatrically healthy European Americans (control comparator group) Approach • Heterogeneity of schizophrenia at phenotypic and genotypic levels • Endophenotypes genetically simpler than disease endpoints; an advantage (big one!) • Can measure such quantitative parameters in family members where clinical diagnosis may be absent or difficult to gain • If neurocognitive deficits are associated with genetic liability, they should increase with relation to affected individuals Measures • Diagnostic assessment • Computerized neurocognitive “scan” – – – – – – – – Abstraction and mental flexibility Attention Verbal memory Face memory Spatial memory Spatial processing Sensorimotor dexterity Emotional processing 0.5 Accuracy 0.0 -0.5 -1.0 ** *** ** *** Mean z score -1.5 *** *** *** *** *** *** *** -2.0 0.5 Speed 0.0 -0.5 * ** -1.0 *** *** -1.5 -2.0 Abstraction/ flexibility Attention Comparison subjects (N=154) Verbal memory Face memory Spatial memory Spatial processing Relatives of schizophrenic patient (N=291) Sensorimotor Emotion identification Schizophrenia patients (N=58) *, **, ** p<0.5, p<0.01, p<0.001, respectively, vs. comparison subjects Interpretation • Schizophrenics show deficits on various neurocognitive tasks • Relatives (both 1st and 2nd degree) without schizophrenia also show impairments in specific tasks – Extended family tested; can analyze based on shared genes, but won’t have shared environment – Advantage of the multigenerational design. – Parent-sib and co-sib studies can’t separate out shared environment from certain genetic effects • Supports neurocognitive measures as endophenotypic markers of vulnerability to schizophrenia • Target endophenotypic markers for gene identification Hall et al. (2007) • Event-related potentials as candidate endophenotypes – P300 (reduced amplitude and prolonged latency) – P50 (reduction of inhibitory response) – Mismatch negativity (reduced amplitude) • Objectives – Estimate heritabilities for range of event-related potential indices – Quantify strength of relationship of each index with schizophrenia – Examine genetic and environmental overlap with the illness ERPs • Reliably measured using electroencephalography (EEG) • Deflections in voltage in brain activity after a stimulus presentation • Reflect “higher” cognitive processes – Memory, expectation, attention, etc. • Positive (P), negative (N) – N400: negative voltage deflection 400ms after stimulus – P300: positive deflection, 300ms delay (this one responds to unexpected/novel/cognitively salient stimuli across senory/perceptual domains) Twin Design • • • • 16 MZ twins concordant for schizophrenia 9 MZ twins discordant for schizophrenia 45 normal MZ twins 32 normal DZ twins Results Correlation with Genetic Factors in Schizophrenia 0.6 In MZ twins concordant or discordant for schizophrenia (N = 50) and healthy comparison twins (N=154) 0.4 0.2 0 -0.2 -0.4 -0.6 Mismatch P300 Negativity Amplitude Amplitude P300 Latency P50 Suppression Ratio Breakdown Type of Correlation Mismatch Negativity Amplitude Phenotypic correlation 0.31 -0.35 0.35 0.40 0.24 -0.35 0.18 0.40 Due to shared environmental factors 0.01 0.05 0.13 0.00 Due to unique environmental factors 0.06 -0.05 0.03 -0.01 Due to additive genetic factors P300 Amplitude P300 Latency P50 Suppression Ratio P50 • Attractive ERP endophenotype – Little environmental variance (except measurement error) – Highest phenotypic correlation with schizophrenia – Almost all the correlation explained by genetic factors • Measure of sensory inhibition in brain; individual’s ability to filter out repetitive stimuli to avoid information overload • Linked to alpha-7 nicotinic receptor gene (CHRNA7)