Transcript Eliot Slater’s contribution

Psychiatric Disorder:
Is It All In The Genes?
Peter McGuffin
MRC SGDP Centre
Institute of Psychiatry,
King’s College London
Sir Francis Galton (1822-1911)
‘…Nature prevails enormously over
nurture’(1883)
The history of twins as a criterion of the relative powers of
nature and nurture (1876)
‘..a devil,on who’s nature, nurture cannot
stick.’
(Michael Horton as
Caliban)
Psychiatrists’ opening gambits 1
Have you suffered vexation, grief
or reverse of fortune?
Phillipe Pinel
(quoted by Sir Michael Rutter)
Psychiatrists’ opening gambits 2
Are you a twin?
Eliot Slater
(quoted by Sir Denis Hill)
Excerpt from a
Bethlem Royal
Hospital front sheet
1823
Cardiff Study of Depression in
Siblings (Farmer et al 2000)
% reported
current
past
% CATEGO
cases
D-siblings
7.4
17.6
18.5
C-siblings
0
4.8
1.9
Behaviours that run in families
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Huntington’s disease
Alzheimer’s disease
Depression
Schizophrenia
Personality
Intelligence
Religious involvement
Attending medical school
Why might a disorder run in
families?
 Shared genes
 Shared environment
 A combination of the two
behaviour
Natural experiments teasing apart
genes and environment
Twin studies : is there more similarity
monozygotic ( one egg) than dizygotic ( two
egg) pairs?
Adoption studies: do individuals resemble
their biological relatives more than adopting
relatives?
The Cholmondeley Ladies c.1600-10
MZ TWINS
 MZ (monozygotic)
twins have 100% of
their genes in common
(they’re ‘natural
clones’)
 Shared environment
also makes them
similar
DZ TWINS
 DZ (dizygotic) twins
have 50% shared
genes
 They also share
environment to
roughly the same
extent as MZ twins
MZ and DZ Twin Similarity Expressed as
Correlations
childhood fatigue
ADHD
DZ
MZ
bulimic symptoms
depression (unipolar)
manic depression (bipolar)
autism
schizophrenia
0
0.2
0.4
0.6
0.8
1
Structural Equation Modelling: a
Simple Univariate Model
b
G1
G2
h
c
h
CE
P1
c
P2
r12 = bh2 + c2
Univariate models of genes, environment
and depression
Data from McGuffin et al 1996
genes 68%
shared E 2%
residual E 30%
Types of Gene Environment
Interplay
 Coaction
 Additive
 Interaction
 Multiplicative
 Covariation
 G & E correlated
Coaction
 Phenotype= Genes (G) + Environment (E)
Shared
Non-shared
GE Correlation Vs Interaction
 Correlation: genetic influence on exposure
to different environments
 Interaction: genetic control of sensitivity to
different environments
G-E interaction: antisocial behaviour and
adversity (Cadoret et al 1995)
antisocial behaviour %
30
25
20
parent ASP
no ASP parent
15
10
5
0
low
high
Life events in Camberwell
(McGuffin et al 1988)
40
35
30
25
20
proband related
15
not proband related
10
5
0
relatives
controls
The Causes of Depression
 Onsets of depression have a more than
chance association with adversity (‘life
events’)
 Depression is familial
 Life events are also familial
Life events in Camberwell
(McGuffin et al 1988)
40
35
30
25
20
proband related
15
not proband related
10
5
0
relatives
controls
Life events are familial
 Family studies:
 McGuffin et al 1988,Farmer et al 2000
 Twin studies:
 Plomin et al 1993, Kendler et al 1994,
Thapar et al 1998,Silberg et al 1999
Why are life events familial?
 Some events affect multiple members
 Hazard prone behaviour (risk taking or bad
planning)
 Threat perception (neuroticism or
‘dysfunctional attitudes’)
Life Events,Genes and
Depression: both GxE and rGE?
 Self reported events heritable, parent reported not
( Thapar and McGuffin 1996)
 Genetic overlap between self reports of life events
and depressive symptoms ( Thapar et al 1998)
 Genetic influence on sensitivity to events in twins
(Kendler et al 1995)
 Personality affects response to events in sib pairs (
Farmer et al 2003)
Karyotype@ensembl
Chromosome 12
Finding genes
 One of the major benefits of the Human Genome
Project is a dense map of markers (“signposts”for
genome searching)
 Linkage studies use genetic markers track genes in
families
 Association studies can pinpoint genes in
populations
Positional cloning
 Linkage(or LD)
 location
prediction
 gene identification
diagnosis
 structure and sequence
 gene product
treatment
Allelic association
 Cases
 Controls
Sib pairs
 Both affected by a disease
 Extremely alike or unalike on a continuum
eg neuroticism
Chromosome 12 UP & BP Depression
Findings
100
D12S1300/
D12S393
Chromosome 12
PAH
110
Abkevich23 (UP) lod = 4.6
Zubenko22 (UP) : lod = 1.9
Ekholm20 (BP): lod = 2
D12S78
Maziade21
D12S84
ATP2A2
McGuffin et al 2005
(BP) : lod >1.5
D12S1613
LOD = 1.57
Morisette11 (BP) lod = 2.5
Pedigrees 324 & 550: 1od = 4.7
120
130
D12S76 PLA2
Dawson16 (BP) : lod = 1.65
D12S342
Curtis18 (BP): lod = 2.9
D12S1639
Ewald17 (BP): lod = 3.4
140
150
D12S1609
LOD = 1.18
Serotonin genes
Mitochondria
MAOA
5-HTT/
SERT
MAOA = Monoamine oxidase A
5-HTT/SERT = Serotonin transporter
The serotonin transporter gene
14 repeats = “Short”
16 repeats = “Long”
From Lesch and MÖssner Biol. Psychiatry, 1998
Self reports of depression
symptoms, age 26
The association between SLEs and self-reports of
depression symptoms at age 26, as a function of
5-HTTLPR genotype
12.50
10.00
7.50
5.00
5-HTT gene
SS, n = 146
SL, n = 435
LL, n = 264
2.50
0.00
0
1
2
3
4+
Five groups of individuals having different
numbers of life events, ages 21-26
Caspi et al , Science 2003
G-E interaction and SERT
promoter polymorphism
• Maternal separation stress effects ( ACTH) in
macaque monkeys ( Barr et al 2004)
• Amygdala activation and fearful stimuli ( Hariri et
al 2002)
• Short allele and adversity => depressive symptoms
(Caspi et al 2003, Eley et al 2004)
• Response to antidepressants (SSRIs) (eg Uher et al
2009)
Specific genes that interact with
environments
 serotonin transporter, social adversity (and
medication) => depression
 Monoamine oxidase A,childhood
maltreatment => antisocial behaviour
 COMT, cannabis => schizophrenia
Wellcome Trust Case Control
Consortium.
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Bipolar disorder
Coronary artery disease
Crohn’s
Rheumatoid
T1D and T2D
Hypertension
Wellcome Trust Case Control
Consortium Design
 2,000 well defined ( OPCRIT) cases
( Cardiff, IoP, Aberdeen, Newcastle)
 3,000 ethnically matched controls ( blood
donors and 1958 birth cohort)
 Affymetrix 500k chip
Bipolar Disorder Genetic
Consortium (Sklar, Craddock et al)
 4,387 cases and 6,209 controls
 US, UK, Ireland (white Europeans)
 Identified 2 novel genes: Ankyrin-G (ANK)
and CACNA1C
Why do pharmacogenetics and genomics?
General response to therapeutic drugs
 Efficacious
 Little or no efficacy
 Toxic and not efficacious
 Efficacious but toxic
The impact of genetics: Post
genomic psychiatry
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targeted & tailored treatments
refined diagnosis
understanding of neurobiology
risk prediction and gene-environment
effects
 public perception and stigma
Psychiatrists’ opening gambits 3
I understand that life has
not been kind to you. Tell
me….
Anonymous wise old psychiatrist
(quoted by Prof Kenneth Rawnsely)
Psychiatrists’ opening gambits 3
… is
there any other
insanity in the family?
Anonymous wise old psychiatrist
(quoted by Prof Kenneth Rawnsely)