FUNDACION CASTILLA DEL PINO : SEMINARIOS 2006-2007 Cordoba , 15 de Diciembre de 2006 Familia, Genes, Cultura y Enfermedad Mental Lourdes Fañanás Saura U B UNIVERSITAT DE BARCELONA

dañaba de algún modo a los demás. Luego, arrepentidos, Yo vengo de una familia en la que cada miembro dañaba de algún modo a los demás. Luego, arrepentidos, cada uno se dañaba a sí mismo. Carlos Fuentes Todas las familias felices, Alfaguara, 2006

Father Mother

C o n c i e n c i a G e n e s A m b i e n te Conducta “La conciencia existe para que exista ANTICIPACIÓN” Todo lo que ocurre en el cerebro es biología y todo lo que ocurre en la mente ocurre a través del cerebro. Joseph le Doux, 1999 A m b i e n te Conducta G e n e s Funciones cerebrales

The recent origin of Homo sapiens sapiens History of our genes Evolution Biological Factors Genes Velocity Slow Selection Natural Sense Random Results “Hominize” Mutation Origin The recent origin of Homo sapiens sapiens (200.000 years b.p.) Cultural Culture Fast Social Deliberate “Humanize” Invention Origin of Homo (~2.106 y) Origin of Hominids (~5.106 y) Chimpanzees (~6.106 y)

Neocortex Associative capacity, symbolism, creativity... Human Language

Brain development and maturity extended until the youth period. Greater neuronal immaturity in the human newborn than in any other primate species. Paedomorphism Brain development and maturity extended until the youth period. Stability of the breeding couple (child survival) Greater post-breeding longevity than any other species (extended contact among generations) Lahdenpera et al., 2004. Nature, 428 By the sea at Klaises River Mouth in South Africa, 100.000 years ago MODERN HUMANS HISTORY 100.000 years 40.000 years 10.000 years Present PALEOLITHIC NEOLITHIC

Contingencia Fragilidad Complejidad “... los hombres no pueden vivir sin intentar conseguir una descripción y una explicación del universo en que viven; las explicaciones que se dan a sí mismos, determinan las actitudes, valores, fines... y la clase de moral en la que organizan y dan sentido a sus vidas...” I. Berlín (1909-1997)

Vulnerable: Susceptible de ser herido o vulnerado, de recibir un daño o perjuicio o de ser afectado, conmovido, convencido o vencido por algo que se expresa. María Moliner Diccionario del uso del español

Un individuo es un elemento que tiende a mantener su identidad independientemente de la incertidumbre del entorno. (J. Wagensberg)

Life time risk for schizophrenia 1% Life time risk for bipolar disorder 0.8% Life time risk for severe major depression ~5% Life time risk for unipolar depression 15-20% Psychotic symptoms 6%- 23% (Van Os et al., 1999, 2001)

GENE X ENVIRONMENT INTERACTION Environmental risk factors for schizophrenia OCs, MPA, influenza: RR 2.0-2.5 Use of cannabis: RR ~3.0 Ethnicity, social exclusion: RR 2.0-3.0 (Van Os et al., 1998; Fearon et al., 2006) GENE X ENVIRONMENT INTERACTION First degree schizophrenic relative: 10% increased risk

5 - 10 FUNCTIONAL INTERACTIONS x PROTEIN Alternative start/stop of transcription Post-transcriptional mechanisms (Alternative splicing, RNA editing...) Post-traductional mechanisms (Phosphorilation, glycosilation...) 30.000 GENES 500-1000 x103 PROTEINS 5 - 10 FUNCTIONAL INTERACTIONS x PROTEIN ORF (Open Reading Frames) GENOME DYNAMIC PROTEOME E N V I R O N M E N T

THE SEQUENCE OF HUMAN GENOME How many, which and where the genes are. Knowing the variability associated to these genes All we have the same genes but not all of us are genetically identical for them 2001, Science: 291

GENETIC VARIABILITY Nuclear Human Genome: C G A T 3.2OO 106 nucleotides 3% expressed 35,000 genes 0.1% interindividual differences estimated in Homo sapiens (Sachidanandam et al., Nature 2001) 12% interindividual differences!! (CNV’s) (Redon et al., Nature 2006) INDIVIDUAL A GENOME INDIVIDUAL B GENOME Single Nucleotide Polymorphisms (SNPs) 6.000.000 SNPs 93% genes at least one SNP 40% genes ten or more C G T A GENETIC VARIABILITY

< 15.000 tissue specific genes are may be expressed Stress related, neuroprotection MAOA NOTCH4 SYN3 L1CAM RELN G72/G30 DAAO PRODH GRM3 Dysbindin RGS4 NTRK1 BDNF NRG1 IL-1B DRD2 COMT SLC6A4 DISC1 DRD3 DRD4 SLC6A3 HTR1A ADRA1 Neurotransmission Functional synaptic plasticity  50% of the total genes are expressed in brain Early environmental factors and morphological consequences < 15.000 tissue specific genes are may be expressed Candidate genes for mental disorders Genes que interactúan con factores ambientales tempranos/

Partial Family History James Stephen Jane Herbert Leslie James Caroline  Herbert Duckworth George Stella Gerald  Julia Vanessa Thoby Virginia Adrian  Harriet Laura  Bipolar illness Suicide Recurrent depressive illness Cyclothymia Unspeciefied psychosis Virginia Woolf Partial Family History

Multiple and shared genes for functional psychoses ~ 46 % Lifetime risk of developing SZ and BP ~ 8 % ~ 10 % ~3 % ~3 % ~1 % ~0.8 % Genetic epidemiology by means of twin, family and adoption studies have pointed out that the lifetime risk of developing SZ is related with percentage of genes shared with an SZ patient. Whereas the lifetime risk for sz is 1% in the general population. A person who is a second degree relative of a patient with sz (aunt, uncle, cousin...) that share 25% of its genes with a patient, has a risk around 3%. A person who is a 1st degree relative of a patient with sz (parents, siblings, children...) and share 50% of its genes with the patient have a risk of 10% (as I commentend in the previous slide). While identical individuals that are MZ twins that share 100% of their genes have an increased risk situated around the 46%. This evidence seems to discard the possibility of a mendelian inheritance model and the existence of one gene responsible of sz in which case we will find a clear linear trend. However this distribution seems clearly to fit with a model of multiple genes and enviromental factors that could explain the discordance between MZ twins. 2nd degree 25% genes 1st degree 50% genes MZ twins 100% genes % of shared genes Relatives of schizophrenic patients SZ BP General population

GENE CONSEQUENCES Neurotransmission Plasticity Synaptogenesis Adapted from Harrison and Weinberger, 2004 GENE CONSEQUENCES FUNCTIONAL ESTRUCTURAL GRM3 G72 DAAO COMT RGS4 PRODH PPP3CC IL-1B NRG1 Dysbindin DISC1 Neurotransmission Plasticity Synaptogenesis Bipolar disorder Schizoaffective Schizophrenia Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia Schmidt-Kastner R., van Os J., Steinbusch H. and Schmitz C., 2006. Schizophrenia Research 84:253-271

Endophenotypes ENVIRONMENT Cannabis Life events …