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…