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GENOTIPI ED ENDOFENOTIPI NELLA SCHIZOFRENIA

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Presentazione sul tema: "GENOTIPI ED ENDOFENOTIPI NELLA SCHIZOFRENIA"— Transcript della presentazione:

1 GENOTIPI ED ENDOFENOTIPI NELLA SCHIZOFRENIA
Ragalna, 26 Febbraio - 2 Marzo Massimo Gennarelli Professore Associato, Sezione di Biologia e Genetica, Dipartimento di Scienze Biomediche e Biotecnologiche, Università degli Studi di Brescia Laboratorio di Genetica IRCCS-FBF, Brescia

2 Incidenza di malattia: 1%
SCHIZOFRENIA Incidenza di malattia: 1% (Gottesman, 1991) “A Beautiful Mind” Sintomi Positivi o “psicotici”: deliri, allucinazioni Sintomi Disorganizzati: pensiero e linguaggio confuso, comportamenti senza senso Sintomi Negativi: piattezza emotiva o mancanza di espressione, incapacità di iniziare e portare a termine azioni, lacunosità dei contenuti del discorrere e la sua brevità, mancanza di piacere ed interesse per la vita.

3 Ereditabilità stimata: 80%

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5 Based on 1991 Mortality Statistics, US Public Health Service
Dementia in the General Population 1000 Live Births 163 Dead of Other Causes 3 AD AGE 55: 834 Alive, not Demented 32 AD 156 Alive, not Demented Other Dementia AGE 85: 780 Dead of All Causes Dead with AD Based on 1991 Mortality Statistics, US Public Health Service

6 APOE-e4/e4 and Dementia e 1000 APOE- 4/4 AGE 55: AGE 85: 835
Alive, not Demented 163 Dead 2 Alzheimer's AGE 85: 883 Dead of All Causes Dead with AD 102 AD 13 Alive, not Demented Other Dementia Per modifiche

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8 SNP (Single Nucleotide Polymorphism)
……A G C G G A T T A G T…….. ……A G C G G G T T A T T…….. FARMACOGENETICA E FARMACOGENOMICA DEGLI ANTIDEPRESSIVI 8

9 LAST UPDATE: May 25, 2006 1:38 PM . Organism
Number of Submissions (ss#'s) Number of RefSNP Clusters (rs#'s) ( # validated) Homo sapiens / geneReport 27,846,394 11,961,761 (5,646,244) LAST UPDATE: May 25, :38 PM .

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11 G/A G A

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13 M SL SS LL FARMACOGENETICA E FARMACOGENOMICA DEGLI ANTIDEPRESSIVI 13

14 Individui LL Individui SS/SL INTERAZIONE SIGNFICATIVA FRA NUMERO DI EVENTI STRESSANTI E GENOTIPO SS/SL (P = 0,05) FARMACOGENETICA E FARMACOGENOMICA DEGLI ANTIDEPRESSIVI 14

15 Life events, first depression onset and the serotonin transporter gene
Wilhelm K, Mitchell PB, Niven H, Finch A, Wedgwood L, Scimone A, Blair IP, Parker G, Schofield PR. Br J Psychiatry Mar;188: Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype. The 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events FARMACOGENETICA E FARMACOGENOMICA DEGLI ANTIDEPRESSIVI 15

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17 The Gene for…

18 Strategie per l’identificazione di geni di suscettibilità: 1
Strategie per l’identificazione di geni di suscettibilità: 1.ANOMALIE CROMOSOMICHE: riarrangiamenti strutturali in famiglie selezionate 2. STUDI di LINKAGE: basati su famiglie numerose e multigenerazionali con membri affetti in quasi tutte le generazioni 3. STUDI di ASSOCIAZIONE: - caso-controllo (pazienti e controlli ) - TDT (transmission disequilibrium test: genitori come controlli interni e 1 figlio affetto) - SIB PAIR ANALYSIS (coppie di fratelli/sorelle)

19 Jablensky A. Eur Arch Psychiatry Clin Neurosci. 2000;250(6):274-85.
SCHIZOPHRENIA Epidemiology of schizophrenia: the global burden of disease and disability. Jablensky A. Eur Arch Psychiatry Clin Neurosci. 2000;250(6): Evidence from nearly a century of epidemiological research indicates that schizophrenia occurs in all populations with a prevalence in the range of 1.4 to 4.6 per 1000 and incidence rates in the range of per 1000 population. Multi-centre studies conducted by the World Health Organization have highlighted differences between 'Western' and 'Third World' populations as regards the course and outcome of the disorder, with a significantly better prognosis in the developing countries.

20 Ipotesi eziopatogenetiche
1. NEUROSVILUPPO: geni per fattori neurotrofici e proteine sinaptiche (BDNF, GSK3, GAP-43, SNAP 25,…) 2. INFIAMMATORIA: geni per citochine (TNF, IL-1, IL-1RA, IL-10 cluster,…..) 3. ALTERAZIONI DEI SISTEMI NEUROTRASMETTITORIALI: Sistema serotoninergico : 5-HT2A Sistema dopaminergico: DRD3 Sistema glutammatergico: GRIK3, GRIN1, GRIN2B

21 Strategies for the identification of susceptibility genes: 1
Strategies for the identification of susceptibility genes: 1.CHROMOSOMAL ABERRATION: anomalous rearrangements in selected families 2.LINKAGE STUDIES: based on multigenerational numerous families with affected members in almost all the generations 3.ASSOCIATION STUDIES: - case-control (patients and unrelated controls) - TDT (transmission disequilibrium test: parents as internal controls and 1 affected child) - SIB PAIR ANALYSIS (pairs of brothers/sisters)

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23 Strategies for the identification of susceptibility genes: 1
Strategies for the identification of susceptibility genes: 1.CHROMOSOMAL ABERRATION: anomalous rearrangements in selected families 2.LINKAGE STUDIES: based on multigenerational numerous families with affected members in almost all the generations 3.ASSOCIATION STUDIES: - case-control (patients and unrelated controls) - TDT (transmission disequilibrium test: parents as internal controls and 1 affected child) - SIB PAIR ANALYSIS (pairs of brothers/sisters)

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25 Loci di suscettibilità:
22q11-12 Craddock et al, 2005

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28 CANDIDATE GENES ON FUNCTIONAL BASES
SUSCEPTIBILITY LOCI search for single nucleotide polymorphisms (SNPs) or mutations

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30 Strategies for the identification of susceptibility genes: 1
Strategies for the identification of susceptibility genes: 1.CHROMOSOMAL ABERRATION: anomalous rearrangements in selected families 2.LINKAGE STUDIES: based on multigenerational numerous families with affected members in almost all the generations 3.ASSOCIATION STUDIES: - case-control (patients and unrelated controls) - TDT (transmission disequilibrium test: parents as internal controls and 1 affected child) - SIB PAIR ANALYSIS (pairs of brothers/sisters)

31 Case-control association studies
compare the frequency of alleles or genotypes of a particular variant between disease cases and controls.

32 Number of association studies
To date: october 2006 (from 1993) Number of association studies on schizophrenia: 975 Key words: “schizophrenia, gene, association, case-control, polymorphisms”

33 Allelic associations confirmed in many populations for psychiaric disorders
5HT2A: serotonin receptor 2A DRD3: dopamine receptor D3

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35 Susceptibility genes for schizophrenia
Hashimoto R, Hattori S, Chiba S, et al. Psychiatry Clin Neurosci. 2006, suppl 1:S4-S10. Molecular genetic studies of schizophrenia Riley B, Kendler KS. Eur J Hum Genetcs (6):669-80

36 DEFINIZIONE DI ENDOFENOTIPI
STRATEGIE PER MIGLIORARE GLI STUDI DI ASSOCIAZIONE DEFINIZIONE DI ENDOFENOTIPI a partire da marcatori biologici caratteristiche morfologiche evidenziabili con tecniche di neuroimaging (“hippocampal shape deformations”) parametri neurofisiologici (P50 “auditory evoked potential gating deficit”; “aberrant smooth-pursuit eye movement”) misurabili anche nei parenti di I grado dei pazienti

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40 COMT PRODH

41 Neurotrasmettitoriali
NEUROPLASTICITA’ Sistemi Neurotrasmettitoriali Fattori Neurotrofici Signaling Intracellulare Others

42 NGF, BDNF, NT-3, NT-4/5, GDNF, CNTF
FATTORI NEUROTROFICI NGF, BDNF, NT-3, NT-4/5, GDNF, CNTF Sviluppo, Mantenimento e Differenziazione neuronale, Plasticità sinaptica

43 BDNF (Brain-Derived-Neurotrophic-Factor)
Chromosome 11 11p13 11p14 1 297 468 681 1040 1353 BP Promoter 492 Stop codon G492  A492 Val66  Met66 Stop codon ProBDNF (32 kDa) Il gene di BDNF e’ regolato in maniera complessa sia a livello trascrizionale e posttrascrizionale che a livello posttraduzionale. Recentemente e’ stato dimostrato che un polimorfismo funzionale, che provoca la sostituzione dell’aminoacido valina in posizione 66 con una metionina, e’ significativamente correlato con la funzionalita’ ippocampale e la performance nella memoria episodica. May be extracellularly active at TrkB receptors Cleaved in endoplasmic reticulum Cleaved in trans-golgi network and/or immature vesicles Val66  Met66 Or Val66  Met66 Signal peptide Truncated proBDNF (28 kDa) Signal peptide Mature BDNF (14 kDa) Activity unknown Essential role in development, survival and function of neurons Ncbi, accession # x60201; Shintani, et al. 1992; Murer, et al. 2001; Mowla, et al. 2001

44 BDNF TrkB

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46 D.O.Bi.G. - Università di Genova
Pezewas et al. 2004 D.O.Bi.G. - Università di Genova

47 BDNF: case-control studies
in Schizophrenia References SNPs Cases (n) Controls (n) Results Populations Numata et al 2006 Val66Met 159 yes age at onset Japan Zhang et al 2006 G-712A; C– 270T; Val66Met 84 250 no USA Chen et al 2006 3 SNPS 560 576 also gender China Szczepankiewicz et al 2005 C270T 397 380 Poland Dempster et al 2005 92 114 association with WMS-R scale UK Neves-Pereira et al 2005 Val66Met; (GT)n  321 350 haplotypes Scotland Schumacher et al 2005 rs (GT)n- Val66Met 533 1097 haplotype Germany Gourion et al 2005 210 99 gene^gene interaction was associated with an earlier emergence of psychosis by 3 years. France de Krom et al 2005 C– 270T; Val66Met 273 580 Dutch Galderisi et al 2005 C– 270T 106 111 Italy Skibinska et al 2004 336 375 also stratification gender; age at onset Anttila et al 2005 94 98 Finland  Nanko et al 2003 A758G C-270T 178 332 Szekeres et al 2003 101 68 Hungary Virgos et al 2001 262 278 Spain Sasaki et al 1997 60

48 Frequenze alleliche e genotipiche del polimorfismo Val66Met del gene BDNF in 300 pazienti schizofrenici e 424 controlli ______________________________________________________ Genotipi Pazienti Controlli Val/Val (59,3%) 262 (61,8%) Val/Met (33,7%) 137 (32,3%) Met/Met ( 7,0%) ( 5,9%) Total Alleli Val (76,2%) 661 (77,9%) Met (23,8%) 187 (22,1%) Alleli p=0.43 Genotipi p=0.74

49 Ridotti livelli di espressione di BDNF e del suo recettore trkB in corteccia prefrontale di pazienti schizofrenici Hashimoto et al. (2005) J. Neurosci. 25:

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51 Yun Long Tan, Dong Feng Zhou, Liou Yuan Cao, Xiang Yang Zhang

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54 Genes localization Schizop (n) Controls (n) Results References Populations GRIA1 5q33 yes Magri et al 2006 Italian GRIA4 11q22 372 392 no Guo et al 2004 China 100 Makino et al 2003 Japan GRIK2 6q16.3-q21 Shibata et al 2002 GRIK3 1p34-33 100/106 100/100 Shibata et al 2006 160 Lai et al 2005 99 116 Begni et al 2002 GRIK4 11q22.3 GRIK5 19q13.2 GRIN1 9q34.3 253 140 Qin et al 2005 139 145 Begni et al 2003 91 Martucci et al 2003 Eur-American 120 94 Hung et al 2002 GRIN2A 16p13.2 672 686 Iwayama-Shigeno et al 2005 GRIN2B 12p12 188 156 Di Maria et al 2004 193 176 Chiu et al 2003 Miyatake et al 2002 268 337 Ohtsuki et al 2001 164 171 Nishiguchi et al 2000 GRIN2D 19q13.1-qter Makino et al 2005

55 Glutamate receptors subtypes: case-control studies in Schizophrenia
Genes localization Cases (n) Controls (n) Results References Populations GRM2 3p21.1 213 220 no Joo et al 2001 Japan GRM3 7q21.1-q21.2 674 716 Norton et al 2005 UK, Ireland 752 yes Chen et al 2005 china 100 Fujii et al 2003 265/288 227/162 Marti et al 2002 German GRM4 6p21.3 285 288 Ohtsuki et al 2001 GRM5 11q14.2-q14.3 Devon et al 2001 UK GRM7 3p26.1-p25.1 Bolonna et al 2001 181 182 Bray et al 2000 GRM8 7q31.3-q32.1 Takaki et al 2004

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59 NEUROCOGNITIVE ENDOPHENOTYPES (Gur et al 2007)

60 NEUROPHYSIOLOGICAL ENDOPHENOTYPES (Turetsky et al 2007)

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63 COSA VIENE TESTATO VANTAGGI RISCHI
TEST GENETICI GENETICA DELLA MALATTIA DIAGNOSI/PROGNOSI COSA VIENE TESTATO VANTAGGI RISCHI Malattie mendeliane rare: mutazioni in singoli geni Malattie complesse: geni di suscettibilità MIGLIOR COMPRENSIONE DELLE PATOLOGIE E DELLE POSSIBILI TERAPIE Implicazioni etiche, legali e sociali

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70 Date di introduzione di alcuni farmaci antipsicotici
1950 1960 1970 1980 1990 2000 CLORPROMAZINA ALOPERIDOLO CLOZAPINA OLANZAPINA RISPERIDONE QUETIAPINA TIPICI ATIPICI

71 FARMACOGENETICA E FARMACOGENOMICA DEGLI ANTIDEPRESSIVI
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72 FARMACOCINETICA Enzimi del metabolismo di fase I (reazioni di attivazione): CYPs (famiglia del citocromo P450) Enzimi del metabolismo di fase II (reazioni di coniugazione): UGTs (uridine diphosphate glucuronyl-transferases) SULTs (sulfonyl transferases) NAT2 (N-acetyltransferases type II) TPMTs (thiopurine methyltransferases)

73 CLASSIFICATION OF METABOLIZER GROUPS
Heterozygous with one active allele (*1 or *2) and one deficient allele INTERMEDIATE METABOLIZERS (IM) ULTRARAPID METABOLIZERS (UM) Heterozygous for duplicated *1 or *2 + another active allele POOR METABOLIZERS (PM) Homozygous or compound heterozygous with two deficient alleles (*3,*4,*5,*6) EXTENSIVE METABOLIZERS (EM) Carriers of one duplicated active allele + deficient allele

74 Kirchheiner J. Et al., Molecular Psychiatry 2004;1-32
Impact of the CYP2D6 polymorphisms on the pharmacokinetics of antipsychotic drugs: dosage adaptation according to genotype. PM: poor metabolizer IM: intermediate metabolizer EM: extensive metabolizer UM: ultrarapid metabolizer Kirchheiner J. Et al., Molecular Psychiatry 2004;1-32

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76 Haloperidol Clozapine Quetiapine Sertindole Ziprasidon Olanzapine
Risperidone D1 D2 5-HT2a 5-HT1a M1 a1 a2 H1 FARMACOGENETICA E FARMACOGENOMICA DEGLI ANTIDEPRESSIVI 76

77 Non specificato tipici aloperidolo risperidone clozapina Atipici in generale olanzapina

78 Polimorfismi dei geni 5HT2A, 5HT2C, DRD3 e DRD4 e risposta alla clozapina ( Kirchheiner et al., 2004)

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83 Efficacy of rosiglitazone in a genetically defined population
with mild-to-moderate Alzheimer's disease Pharmacogenomics J Jan 31 Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD. Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE varepsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE varepsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE varepsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE varepsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE varepsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

84 A haplotype map of the human genome
Nature 437, (27 October 2005) A haplotype map of the human genome The International HapMap Consortium

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