Lourdes Fañanás SauraLourdes Fañanás Saura

Familia, Genes, Cultura y

Enfermedad Mental

Familia, Genes, Cultura y

Enfermedad Mental

U

B

UNIVERSITAT DE BARCELONAUNIVERSITAT DE BARCELONA

FUNDACION CASTILLA DEL PINO : SEMINARIOS 2006-

2007

FUNDACION CASTILLA DEL PINO : SEMINARIOS 2006-

2007 Cordoba , 15 de Diciembre de 2006

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

FatherFather MotherMother

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

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

G e n e s

Funciones cerebrales Funciones cerebrales

Con

duct

a

C o n c i e n c i a“La conciencia existe para que exista ANTICIPACIÓN”“La conciencia existe para que exista ANTICIPACIÓN”

The recent origin of Homo sapiens sapiens (200.000 years b.p.)

The recent origin of Homo sapiens sapiens (200.000 years b.p.)

Origin of Hominids (~5.106 y)Origin of Hominids (~5.106 y)

Origin of Homo (~2.106 y)Origin of Homo (~2.106 y)

Chimpanzees Chimpanzees (~6.106 y)(~6.106 y)

History of our genes

EvolutionEvolution BiologicalBiological

Factors Factors Genes Genes VelocityVelocity SlowSlowSelection Selection NaturalNaturalSenseSense RandomRandomResultsResults “Hominize”“Hominize”

MutationMutationOriginOrigin

CulturalCultural

Culture Culture FastFastSocialSocialDeliberateDeliberate“Humanize”“Humanize”

InventionInvention

Human LanguageHuman

Language

Associative capacity, symbolism, creativity...Associative capacity, symbolism, creativity...

Neocortex Neocortex

By the sea at Klaises River Mouth in South Africa, 100.000 years agoBy the sea at Klaises River Mouth in South Africa, 100.000 years ago

MODERN HUMANS HISTORY

Present100.000 years 40.000 years 10.000 yearsPALEOLITHIC NEOLITHIC

• Greater neuronal immaturity in the human newborn than in any other primate species.

• Brain development and maturity extended until the youth period.

• Greater post-breeding longevity than any other species (extended contact among generations)

Lahdenpera et al., 2004. Nature, 428

• Stability of the breeding couple (child survival)

Pae

dom

orp

his

m

FragilidadContingencia

Complejidad

“... los hombres no pueden vivir sin intentar conseguir una descripción y una explicación del universo en que viven;

“... 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

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)

Psychotic symptoms 6%- 23% (Van Os et al., 1999, 2001)Psychotic symptoms 6%- 23% (Van Os et al., 1999, 2001)

Life time risk for schizophrenia 1%Life time risk for schizophrenia 1%Life time risk for bipolar disorder 0.8%Life time risk for bipolar disorder 0.8%

Life time risk for severe major depression ~5%Life time risk for severe major depression ~5%

Life time risk for unipolar depression 15-20%Life time risk for unipolar depression 15-20%

First degree schizophrenic relative: 10% increased risk

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

500-1000 x103

PROTEINS500-1000 x103

PROTEINS5 - 10 FUNCTIONAL INTERACTIONS x

PROTEIN

5 - 10 FUNCTIONAL INTERACTIONS x

PROTEIN

Alternative start/stop of transcriptionPost-transcriptional mechanisms (Alternative splicing, RNA editing...) Post-traductional mechanisms (Phosphorilation, glycosilation...)

GENOMEGENOME DYNAMIC PROTEOMEDYNAMIC PROTEOME

E N V I R O N M E N T E N V I R O N M E N T

30.000 GENESORF

(Open Reading Frames)

THE SEQUENCE OF

HUMAN GENOME

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

0.1% interindividual differences estimated in Homo

sapiens (Sachidanandam et al., Nature 2001)

INDIVIDUAL AGENOME

INDIVIDUAL AGENOME

INDIVIDUAL BGENOME

INDIVIDUAL BGENOME

Single NucleotidePolymorphisms

(SNPs)6.000.000 SNPs

93% genes at least one SNP40% genes ten or more

CC

GGTT AA

CCGG

GGCCAA

TT

AATT

CC

GGGGCC

3% expressed3% expressed

35,000 genes35,000 genes

Nuclear Human Genome: Nuclear Human Genome: 3.2OO 106 nucleotides3.2OO 106 nucleotides

GENETIC VARIABILITY

12% interindividual differences!!

(CNV’s) (Redon et al., Nature 2006)

50% of the total genes are expressed in

brain

< 15.000 tissue specific genes are may be

expressed

MAOAMAOA

NOTCH4NOTCH4

SYN3SYN3

L1CAML1CAM

RELNRELN

G72/G30G72/G30

DAAODAAO

PRODHPRODH GRM3GRM3

DysbindinDysbindin

RGS4RGS4

NTRK1NTRK1BDNFBDNF

NRG1NRG1IL-1BIL-1B

DRD2DRD2COMTCOMT

SLC6A4SLC6A4

DISC1DISC1DRD3DRD3

DRD4DRD4

SLC6A3SLC6A3

HTR1AHTR1A

ADRA1ADRA1

Candidate genes for mental disorders

Early environmental factors and morphological consequences

Early environmental factors and morphological consequences

Stress related, neuroprotectionStress related, neuroprotectionFunctional synaptic plasticityFunctional synaptic plasticityNeurotransmission Neurotransmission

Herbert

DuckworthHerbert

Duckworth

GeorgeGeorge StellaStella GeraldGerald

HarrietHarriet

LauraLaura

JuliaJulia

VanessaVanessa ThobyThoby VirginiaVirginia AdrianAdrian

Partial Family HistoryPartial Family History

Recurrent depressive illnessRecurrent depressive illness

CyclothymiaCyclothymia

Bipolar illnessBipolar illness

SuicideSuicide

Unspeciefied psychosisUnspeciefied psychosis

James StephenJames

Stephen JaneJane

HerbertHerbert LeslieLeslie JamesJames CarolineCaroline

Virginia WoolfVirginia Woolf

Life

time

risk

of

deve

lopi

ng S

Z a

nd B

PMultiple and shared genes for functional psychosesMultiple and shared genes for functional psychoses

~3 %~3 %

~ 10 %~ 10 %

~ 46 %~ 46 %

~1 %~1 %

General population

~3 %~3 %~ 8 %~ 8 %

SZ BP

~0.8 %~0.8 %

2nd degree

25% genes

1st degree

50% genes

MZ twins

100% genes

% of shared genes Relatives of schizophrenic patients

Adapted from Harrison and Weinberger, 2004

GRM3GRM3 G72G72 DAAODAAO COMTCOMT RGS4RGS4 PRODHPRODH PPP3CCPPP3CC IL-1BIL-1B NRG1NRG1 DysbindinDysbindin DISC1DISC1

Bipolar disorderBipolar disorder SchizoaffectiveSchizoaffective SchizophreniaSchizophrenia

GENE CONSEQUENCESGENE CONSEQUENCES

FUNCTIONALFUNCTIONAL ESTRUCTURALESTRUCTURAL

NeurotransmissionNeurotransmission PlasticityPlasticity SynaptogenesisSynaptogenesis

Gene regulation by hypoxia and the neurodevelopmental origin of schizophreniaSchmidt-Kastner R., van Os J., Steinbusch H. and Schmitz C., 2006.

Schizophrenia Research 84:253-271

ENVIRONMENT

Endophenotypes

CannabisLife events…

CannabisLife events…