GENETICA Y PSIQUIATRÍA

Presentación del tema: "GENETICA Y PSIQUIATRÍA"— Transcripción de la presentación:

1 GENETICA Y PSIQUIATRÍA
REAL ACADEMIA DE MEDICINA DE VALENCIA Valencia 17 de Mayo 2012 GENETICA Y PSIQUIATRÍA Julio Sanjuan

2 MENU 1-Heredabilidad de las enfermedades psiquaitricas
2.Datos generales genetica molecular -Estudios de todo el genoma amplio -Cambios en expresión génica 3-Interacción genético-ambiental 4- El Futuro - Practica Clinica

3 MENU 1-Heredabilidad de las enfermedades psiquaitricas
2.Datos generales genetica molecular -Estudios de todo el genoma amplio -Cambios en expresión génica 3-Interacción genético-ambiental 4-Futuro- Practica Clinica

4 Genética y Psiquiatría
Preguntas Métodos GENETICA CUANTITATIVA ¿Se trata de una enfermedad familiar? Estudios familiares ¿Cuál es la contribución relativa de los genes? Estudios de gemelos y adopción GENETICA MOLECULAR ¿Dónde se localiza el gen/es? Estudios de ligamento ¿Cual es el gen/es? Estudios de asociación

5 ¿SE TRATA DE UNA ENFERMEDAD FAMILIAR?

6 T. Bipolar Riesgo en Familiares
Riesgo para la enfermedad (%) Fañanás, 2002

7 Prevalencia en familias
Población general Hijos Esposas de pacientes Hermanos Primos hermanos Hermanos con un padre esquizofrénico Tios Gemelos dizigóticos Sobrinos Padres Nietos Gemelos monozigóticos Medios hermanos Hijos de dos padres esquizofrénicos Adaptación de Gottesman (1991)

8 2. ¿Cuál es la contribución relativa de los genes?
ESTUDIOS DE GEMELOS MONOCIGOTOS (100%) DICIGOTOS (50%)

9 Heredabilidad de distintos trastornos mentales
Trastorno de ansiedad generalizada 30 Fobias 35 Depresión mayor 30-40 Trastorno de angustia 40 Suicidio 45 Alcoholismo 60 Esquizofrenia 60-80 Trastorno bipolar 70-80

10 CONCLUSIONES -Hay un claro componente genético -Pero el componente genético explica solo una parte del origen de la enfermedad -Existe una influencia ambiental

11 MENU 1-Heredabilidad de las enfermedades psiquaitricas
2.Datos generales genetica molecular -Estudios de todo el genoma amplio -Cambios en expresión génica 3-Interacción genético-ambiental 4- Futuro- Practica Clinica

12 12

13 Schizophrenia genes at last?
4 years ago many researchers thought that at last we had found the genes for schizophrenia Harrison y Weinberger, Mol Psychiatry 2005

14 Harrison & Owen Lancet 2003; 361: 417–19
This model was entusiatically supported by a very cited paper by Harrison and Owen in 2003 in the Lancet In this paper they suggested that the most relevant candidate genes at that moment PRODH DTNBP1 NRG1 RGS4 G72 All were related with glutamate Harrison & Owen Lancet 2003; 361: 417–19

15 In Spanish sample of 800 patients 800 controls
RESULTS In Spanish sample of 800 patients 800 controls Only significant Association with DTNB1 We were unable to detect any significant gene-gene interaction between SNPs DAO, DAOA, DTNBP1, NRG1, RGS4. We only found a significant association with DTNB1 But we were unable to detect any significant gene-gene interaction Vilella et al J Psychiatry Research January 2008

16 1.900 patients y 2000 controls, 789 SNPs
RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF. NO SIGNIFICANT ASSOCIATION Also in a larger sample including more of these candidate genes most significant association was found Hamilton SP Am J Psychiatry April 2008

17 Utilizes modern genetic technology
THE OPTIMISTIC VIEW SureGene, LLC Utilizes modern genetic technology to discover the underlying genetic basis for psychiatric diseases. Our primary goal is to empower patients and physicians with knowledge to make the best possible healthcare decisions based on individual genetic profiles. SureGene, LLC will accomplish these goals through DNA-based diagnostic tests that predict drug response and aid in the diagnosis and classification of disease, such as the AssureGeneTM Test for Schizophrenia 17

18 SENTENCIA PROVISIONAL
HASTA LA FECHA NO HEMOS ENCONTRADO NINGUN GEN CULPABLE DE LA VULNERABILIDAD EN NINGÚN TRASTORNO MENTAL (Mas allá de una duda razonable)

19 WGS en PSICOSIS 2007 International Schizophrenia Consortium
3.800 casos 4.200 controles SNPs Resultados preliminares: Se ha encontrado alguna asociación con P = 10-8 pero NO en los genes candidatos reconocidos enestudios previos

20 Stefansson et al Nature Vol 460|6 2009

21 New candidate genes are not related with previous candidates
Histocompatibility complex (MHC) 6p Neurogranin gene (NRGN) on 11q24.2 More recently we participate in a wide genome multicentric study with almost patients and controls. Again not one of these candidate genes appear associated with schizophrenia New candidate genes are not related with previous candidates Stefensson et al Nature August 2009

22 MICRODELETIÓN OR FREQUENCY 1Q (N = 7) 14. 80 0.15 15Q11.2 (N = 16) 2.73 0.35 15Q.13.3 (N = 4) 11.54 0.08 Nature vol 455, september 2008

23 CONCLUSIONES (PROVISIONALES)
ESTUDIOS DE GENOMA AMPLIO -Descubrimiento de formas genéticas de esquizofrenia pero muy poco frecuentes. Apaprecen tambien en otros Trastornos Psiquiatricos -Descubrimiento de nuevos Polimorfismos con un alta asociación pero con una OR muy baja. Tambien aparecen en otros Tyrastornos Psiquiatricos. -Necesidad de modelos matematicos que permitan analizar combinaciones de mas de de SNPs

24 1. EXPRESIÓN GENICA EN ESTUDIO POSTMORTEM
EN LA ESQUIZOFRENIA A. EXPRESIÓN DE GENES ESPECIFICOS B. MICRORRAYS: TRANSCRIPTOMICA

25 THE REELIN PATHWAY TO SCHIZOPHRENIA
ABNORMAL GENE EXPRESSION THE REELIN PATHWAY TO SCHIZOPHRENIA Within this model, REELIN promoter hypermethiyation represent one the most consistent finding in the post-mortem studies In the brain of schizophrenic patients.

26 B. MICRORRAYS: TRANSCRIPTOMICA
Mirmics Am J Psychiatry 2001

27 RESULTADOS PRINCIPALES (18 estudios revisados 2001-2011)
B. MICRORRAYS: TRANSCRIPTOMICA RESULTADOS PRINCIPALES (18 estudios revisados ) ALTERACIÓN EN LA EXPRESIÓN DE GENES IMPLICADOS EN: -MECANISMOS SINAPTICOS -PROCESOS DE MIELINIZACIÓN -METABOLISMO MITOCONDRIAL -OLIGODENDROCITOS -SISTEMA GABAERGCIO -SISTEMA GLUTAMATERGICO

28 EXPRESIÓN GENICA CEREBRAL
FACTORES DE CONFUSIÓN -EDAD -SEXO -PH -INTERVALO POSTMORTEM -CALIDAD TEJIDO -MEDICACIÓN PREVIA -ENFERMEDADES MEDICAS-CEREBRALES ASOCIADAS -FORMA DE MUERTE -PSICOPATOLOGÍA PREVIA Although new techniques of gene expression and metabolomic are a great advance in postmorten studies of schizophrenia, -the clinical heterogeneity of this disorder and -the lack of knowledge about specific brain areas related to it make difficult to reach conclusive results.

29 EPIGENETIC CHANGES OF FOXP2 IN SCHIZOPHRENIA
In a collaborative study with T. Crow Amparo Tolosa analyses the possible changes in methylation in FOXP2 in different brain areas In schizophrenia compare with control. In this preliminary study no clear difference was found. Nevertheless as you can see there is a trend towards less methylation in the right parahippocampus gyrus. So further studies in other areas particularly in temporal lobe are needed. Tolosa et al Schizophrenia Research

30 1. BRAIN BANK FROM SAN JOAN DE DEU
NOW 32 BRAINS OF PATIENTS WITH SCHIZOPHRENIA

31 CONCLUSIONES (PROVISIONALES)
ESTUDIOS DE EXPRESIÓN GENICA -Hallazgos prometedores en anormal expresión de algunos genes (Reelina) -Hallazgos sugestivos pero no concluyentes con las tecnicas de micro-rrays -Necesidad de nuevos bancos de cerebros con control de las variables de confusión.

32 MENU 1-Heredabilidad de las enfermedades psiquaitricas
2.Datos generales genetica molecular -Estudios de todo el genoma amplio -Cambios en expresión génica 3-Interacción genético-ambiental 4-Implicaciones Practica Clinica

33 MEDICAL MODEL OF COMPLEX DISEASE
The general medical model explains that there are genetic and environmental risks and protective factors in the aetiology of any complex disease.

34 EXAMPLES OF GENE-ENVIROMENTAL INTERACTION IN COMPLEX MEDICAL DISSEASE
SKIN CANCER HIV COLORECTAL VASCULAR ASPIRINE BENFIT COLESTEROL MYOCARDIAL OBESITY LUNG DISEASE THIOPURINE ASTMA DRUG Here are some examples

35 VULNERABILITY STRESS MODEL

36 5-HTTLPR AND EMOTIONAL RESPONSE
1997 5-HTTLPR AND EMOTIONAL RESPONSE There are several reasons to focus in this gene -First serotonin transporter protein is the key for the regulation of the serotoninergic system -Second, there is a very well studied polymorphism in the promoter region of this gene.This polymorphism have to variants. The short allele implicate lower functional activity -Finally many animal and human studies have shown that this polymorphism is very important in the modulation of the emotional response to environmental stress 5-HTTLPR GENOTIPES: 40% SL 35% SS 25% LL

37 5-HTTLPR: Association Studies Before 2003
The Same Gene –variant relate with many Psychiatric Disorder Anxiety and hostility Brummett BH 2003 Anxiety disorders Ohara K et al. 1998 Anxiety symptoms Evans J et al. 1997 Anxiety traits Murakami F et al. 1999 Anxiety-related temperament Jorm AF et al. 2000 Anxiety-related traits Katsuragi S et al. 1999 Lesch KP et al. 1996 Autism Klauck SM et al. 1997 Alcoholism Ishiguro H et al. 1999 Anorexia nervosa Fumeron F et al. 2001 Personality traits Kumakiri C et al. 1999 Du L et al. 2000 Retz W et al. 2002 Affective disorder Lenzinger E et al. 1999 Major depression Ogilvie AD et al. 1996 Yu YW et al. 2002 Depression Neumeister A et al. 2002 Bipolar affective disorder Heiden A 2000 Bipolar and unipolar disorder Serretti A et al. 2001 Bipolar disorder Mynett-Johnson L 2000 Liu W et al. 1998 Schizophrenia Malhotra AK et al. 1998 Smoking Ishikawa H et al. 1999 Suicide Joiner TE Jr et al. 2002 Baca-Garcia E et al. 2002 Violent suicidal behavior Courtet P et al. 2001 Violent suicide Bondy B et al. 2000 Major and bipolar depressives Pathological gambling Perez de Castro I et al., 1999 Harm avoidance behaviour Ricketts MH et al. 1998 Before Caspi’s study in 2003, we had many genetic association studies about this gene in relation with a lot of psychiatric disorders But with not conclusive results NO CONCLUSIVE RESULTS

38 Number of citations = 2.673 < 9 years)
A. Caspi Nevertheless, without doubt, the most influential paper about gene environmental interaction in psychiatry was the study by Caspi and collegues in 2003 Number of citations = < 9 years)

39 Suicide/ideation/attempt Informant reports of depression
Depression Symptoms Major Depression Suicide/ideation/attempt Informant reports of depression The relevance of the work of Caspi and colleagues was that they found significant results of this polymorphism only in interaction with life events Caspi et al Science, vol 301;

40 Is the “Short” variant always a bad/risk factor?
SS= BAD BOY LL = GOOD BOY

41 2009 ..no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression In meta-analysis concluded that there is no evidence. That serotonin transporter genotype alone or in interaction with life events is associated with elevated risk of depression. Risch et al JAMA 2009; 301, The positive results for the 5-HTTLPR SLE interactions in logistic regression models are compatible with chance findings. Munafo et al Biological psychiatry 2009; 65: “s” allele ¡¡¡ INNOCENT !!! 14 studies included 41

42 2010 54 studies included Kang Arch Gen Psychiatry 2010
Until now the last chapter of this story is the meta-analysis of Karg and collegues who conclude that ….. But it is worth looking carefully to the data of this meta-analysis 54 studies included Kang Arch Gen Psychiatry 2010 42

43 Postpartum Depression Multicentric Genetic Study
So, we made a multicentre project of gene-environmental interaction in postpartum depression . 1804 women were included in this longitudinal study With three clinical evaluations just after delivery, at 8 weeks and at 32 weeks. Sanjuan J et al Brit J Psychiatry Nov 2008 43

44 Sanjuan J et al Brit J Psychiatry Nov 2008
Contrary to what we expect, we found a higher risk for depression of women with high expression (Long allele) serotonin transporter genotype Sanjuan J et al Brit J Psychiatry Nov 2008 44

45 How can we explain this? Well, previous experimental studies inducing tryptophan depletion found more significant mood changes in people with the long allele 45

46 POSTPARTUM A DIFFERENT GENETIC WAY TO DEPRESSION?
ACUTE TRYPTOFAN DEPLECTION LL GENOTYPE INCREASE 5-HTT RE-UPTAKE LOWER SEROTONIN LEVEL As postpartum is a natural experiment of acute tryptophan depletion our explanation was that postpartum depression could have a different genetic vulnerability to depression due to gene-hormone interaction DEPRESSIVE SYMPTOMS Sanjuan J et al Brit J Psychiatry Nov 2008 46

47 SS= BAD BOY LL = GOOD BOY

48 WHEN DOES A LIFE EVENT BECOME A RISK FACTOR FOR DEPRESSION?
BEREAVENT DIVORCE JOB LOSS MALTREATMENT

49 Meaning of Life Events - Adulthood
When you select life event in adulthood as stressor there is no evidence of such relationship. In my opinion it is not difficult to understand this controversial results. Divorce is a clear example of life event , but divorce might be bad news for someone an very good news for another. So definitely we need to have a better assessment of what we call stress BEREAVEMENT = Life Event = 5 points INFIDELITY = Life Event = 5 points TOTAL points ??????? Kang Arch Gen Psychiatry 2010 49

50 CONCLUSIONES (PROVISIONALES)
ESTUDIOS DE INTERACCIÓN G X E -No hay polimorfismos buenos y malos en variantes comunes -Dificultad para definir cuales son los factores de riesgo ambiental -Necesidad de modelos matemáticos que permitan analizar combinaciones de miles de variables

51 MENU 1-Heredabilidad de las enfermedades psiquaitricas
2.Datos generales genetica molecular -Estudios de todo el genoma amplio -Cambios en expresión génica 3-Interacción genético-ambiental 5-Futuro- Practica Clinica

52 SOLAPAMIENTO DE TRASTORNOS MENTALES
Since then Many studies suggested that there is an overlap among many psychiatric disorders But in any case as you can see in this Figure Schizophrenia and Psychosis are the syndromes most close to the Cognitive impairment Burmeister et al Nat Rev Genet 2008, 9:

53 TRASTORNOS PSIQUIÁTRICOS
AMPLIANDO EL FENOTIPO TRASTORNOS PSIQUIÁTRICOS T. Abuso de sustancias T. Neurodesarrollo T. Afectivos T. Ansiedad T.Alimentarios T. Psicóticos 2 Dependencia Abstinencia Alerta Diferenciación neuronal Crecimiento neuronal Metabolismo Recompensa Migración axonal Estrés Ritmo circadiano Plasticicdad neuronal Transmisión adrenérgica Transmisión serotoninérgica Transmisión dopaminérgica 1 GABA receptors NMDA Receptors Glutamate receptors Adrenergic receptors CRH 12q11.2 CCK COMT 15q21 Substance P Acetylcholine Receptors Somnostatin MAO Neurotrophic Factors Leptin Differentiation factors 6p. 5q. 11q. Serotinergic Receptors Opioid receptors Dopaminergic Receptors

54 ¿ES LA ESQUIZOFRENIA UN FACTOR DE
PROTECCIÓN DE ALGUNAS ENFERMEDADES INMUNOLOGICAS ARTRITITIS REUMATOIDE?

55 CANCER Y ESQUIZOFRENIA
55

56 RECORTANDO EL FENOTIPO

57 PHENOMENOLOGY – Frank Laroi COGNITION – Flavie Waters
September 2011. PHENOMENOLOGY – Frank Laroi COGNITION – Flavie Waters EMOTIONS - Andre Aleman ELECTROPHYSIOLOGY – Judith Ford NEUROBIOLOGY – Paul Shotbolt NEUROIMAGING – Paul Allen GENETICS - Julio Sanjuan TREATMENT – Iris Sommer These are the research group involved in the genetics of hallucinations without their help this presentations would’nt be possible. VOCES EN LA CABEZA.COM

58 OUR GENETIC STUDIES OF HALLUCINATIONS IN PSYCHOSES
Author/year Journal Sample Gene/ nº of SNPs RESULTS Sanjuan et al 2004 Eur J. Psychiatry Schizophrneic Auditory Hallucinations CCK-AR 4 SNPs Negative (Positive in persistant) Toirac et al 2007 Psychiatric Genetics Schizophrenic 12 SNPs Positive Sanjuan et al 2005 J. NeuroPsychopharchology HTTLPR Rivero et al 2006 Schizophrenia Research ASPM 6 SNPs Negative FOXP2 3 SNPs Tolosa et al 2008 HAR1 10 SNPs Negative (positive In Auditory Hallucinations) Carrera et al 2008 Am J Med Gen MAOB 50 SNPs POSITIVE Sanjuan et al 2006 Schizohrenic To the best of our knowledge, we are the only group doing a systematic research of the genetics of AH.

59 A.J. Allen et al. Schizophrenia Research 109 (2009) 24–37 (modificado)

60 Effect of 5-HTTLPR on brain structure (VBM)
SLC6A4 gene: 5-HTTLPR and neuroimaging phenotypes Effect of 5-HTTLPR on brain structure (VBM) Controls Patients LL S-carriers LL S-carriers We have only preliminary data on this issue (not yet published) Both are in relation with the serotonin transporter polimorphism As yoi can see ss controls have a reduction of hippocampus and parahipocampus and patients have a reduction of anterior cingulate gyrus Hippocampus (bilateral) Parahippocampal gyrus (left) Anterior cingulate gyrus Rivero et al (under review)

61 GWAS of Drug-induced Liver Injury
due to Flucloxacillin Daly et al. Nature Genetics, 2009

62 FUTURO 1. MEJORAR LA DEFINICIÓN DEL FENOTIPO
2.PROYECTOS COLABORATIVOS INTERNACIONALES 3. MEJORAR INTEGRACIÓN BASICOS-CLINICOS 4. NECESIDAD DE NUEVAS IDEAS HIPOTESIS FISIO-PATOLOGICAS

63 VALENCIA SCHIZOPHRENIA RESEARCH GROUP
Coordinator PI. J. Sanjuan PSYCHIATRY Sanjuan J. F. Medicine Gonzalez JC. Clinic Hospital Leal C “ Aguilar E Sagunto Hosp Brotons O “ Luengo A “ Escarti MJ “ CLINICAL PSYCHOLOGY Lorente E Esteban C “ Herrera N “ Gadea “ Llacer B “ Bobes T “ MOLECULAR GENETICS de Frutos R. F. Biology Nájera C “ Moltó MD “ Toirac I “ Tolosa A “ Rivero O “ Iborra JL “ Gilabert J “ MAGNETIC RESONANCE Marti-Bonmati L. H Peset Moratal D. Garcia G “ de la Iglesia M H. Sagunto SPECTROSCOPY Celda B . F. Chemistry. Granados B “ Martinez MC “ DATA ANALYSIS Carot. JM Univ. Politecnica V. Hernandez Bioengineering Depart. I. Blanquer “