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GENOTIPI ED ENDOFENOTIPI NELLA SCHIZOFRENIA

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.

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GENOTIPI ED ENDOFENOTIPI NELLA SCHIZOFRENIA

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  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. 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%

  4. 1000 Live Births AGE 55: 834 163 3 Alive, not Dead of AD Demented Other Causes AGE 85: 32 156 32 780 AD Alive, not Other Dead of All Causes Demented Dementia Dead with AD Dementia in the General Population Based on 1991 Mortality Statistics, US Public Health Service

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

  6. SNP(SingleNucleotide Polymorphism) ……A GCG GAT T AGT…….. ……A GCG GGT T ATT……..

  7. LAST UPDATE:May 25, 2006 1:38 PM .

  8. A G/A • G

  9. M SL SS LL

  10. Individui SS/SL Individui LL INTERAZIONE SIGNFICATIVA FRA NUMERO DI EVENTI STRESSANTI E GENOTIPO SS/SL (P = 0,05)

  11. 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. 2006 Mar;188:210-215 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

  12. The Gene for…

  13. Strategie per l’identificazione di geni di suscettibilità:1.ANOMALIE CROMOSOMICHE: riarrangiamenti strutturali in famiglie selezionate2. 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)

  14. SCHIZOPHRENIA Epidemiology of schizophrenia: the global burden of disease and disability. Jablensky A. Eur Arch Psychiatry Clin Neurosci. 2000;250(6):274-85. • 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 0.16-0.42 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.

  15. 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

  16. Strategies for the identification of susceptibility genes:1.CHROMOSOMAL ABERRATION: anomalous rearrangements in selected families2.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)

  17. Strategies for the identification of susceptibility genes:1.CHROMOSOMAL ABERRATION: anomalous rearrangements in selected families2.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)

  18. 22q11-12 • Loci di suscettibilità: Craddock et al, 2005

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

  20. Strategies for the identification of susceptibility genes:1.CHROMOSOMAL ABERRATION: anomalous rearrangements in selected families2.LINKAGE STUDIES: based on multigenerational numerous families with affected members in almost all the generations3.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)

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

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

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

  24. 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 2006. 14(6):669-80

  25. 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

  26. COMT PRODH

  27. NEUROPLASTICITA’ Sistemi Neurotrasmettitoriali Fattori Neurotrofici Signaling Intracellulare Others

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

  29. BDNF (Brain-Derived-Neurotrophic-Factor) Chromosome 11 11p13 11p14 297 681 1040 1353 BP 1 468 Promoter 492 5´ Stop codon Stop codon G492 A492 Val66 Met66 ProBDNF (32 kDa) May be extracellularly active at TrkB receptors Cleaved in endoplasmicreticulum Cleaved in trans-golgi network and/or immature vesicles Or Val66 Met66 Val66 Met66 Signal peptide Signal peptide Truncated proBDNF (28 kDa) Mature BDNF (14 kDa) Essential role in development,survival and function of neurons Activity unknown Ncbi, accession # x60201; Shintani, et al. 1992; Murer, et al. 2001; Mowla, et al. 2001

  30. BDNF TrkB

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

  32. BDNF: case-control studies in Schizophrenia

  33. Frequenze alleliche e genotipiche del polimorfismo Val66Met del gene BDNF in 300 pazienti schizofrenici e 424 controlli ______________________________________________________ Genotipi Pazienti Controlli Val/Val 178 (59,3%) 262 (61,8%) Val/Met 101 (33,7%) 137 (32,3%) Met/Met 21 ( 7,0%) 25 ( 5,9%) Total 300 424 Alleli Val 457 (76,2%) 661 (77,9%) Met 143 (23,8%) 187 (22,1%) ______________________________________________________ Alleli p=0.43 Genotipi p=0.74

  34. Ridotti livelli di espressione di BDNF e del suo recettore trkB in corteccia prefrontale di pazienti schizofrenici Hashimoto et al. (2005) J. Neurosci. 25:372-383

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