The Genetics of Mood Disorders
Transcript of The Genetics of Mood Disorders
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The Genetics of Mood The Genetics of Mood DisordersDisorders
Peter McGuffin, MRC SGDP Centre,Peter McGuffin, MRC SGDP Centre,Institute of Psychiatry, Kings College Institute of Psychiatry, Kings College LondonLondon
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Genetics and Genomics of Mood Disorders
• How much do genes contribute?
• How specific are the effects?
• Can we locate and identify genes?
• If so what do we do next?
• What will be the impact on clinical practice
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Genetics and Genomics of Mood Disorders
• How much do genes contribute?
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Affective disorder in first degree relatives ofbipolar and unipolar probands (McGuffin and Katz 1986)
Proband No. ofstudies
BZ Morbid risk
Bipolar Unipolar
Bipolar
Unipolar
12
7
3710
3648
2319
7.8
0.6
11.4
9.1
BZ=bezugsziffer (corrected denominator)
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Cardiff Study of Depression in Siblings (Farmer et al 2000)
% reported % CATEGO
current past cases
D-siblings 7.4 17.6 18.5
C-siblings 0 4.8 1.9
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Results: depression in siblings
Relative risk of being affected for D-siblings compared to C-siblings:
reported s = 5.42* (95% CI: 2.18, 13.57)
CATEGO s = 9.70* (95% CI: 2.34, 40.01)
* p<0.0001
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psychiatric disorder
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Teasing apart genesand environment
Twin studies
Adoption studies
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Affective illness in the parentsof adoptees
Biologicalparents (%)
Adoptiveparents (%)
Bipolar adoptees(n = 29)
Bipolar non-adoptees(n = 31)
Normal adoptees
28
26
5
12
-
9
Mendlewicz and Rainer, 1977
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Twin Concordance for DSM IV Major Depression (McGuffin et al 1996)
0
5
10
15
20
25
30
35
40
45
mzdz
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Twin concordance (%) for unipolar and bipolar affective disorder
05
1015
2025
3035
4045
50
UP MZ UP DZ BP MZ BP DZ
UPBP
Data from McGuffin et al 2003
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Genetic Causes of Affective Disorders
Several, perhaps many, genes confer a liability to develop
the disorder
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affected
liability
population
relatives
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Structural Equation Modelling: a Simple Univariate Model
G1 G2
CE
P1 P2
h hc c
r12 = h2 + c2
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Variances explained
0
10
20
30
40
50
60
70
80
BP disorder UPdepresssion
ACE
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Phenotype= Genes (G) + Environment (E)
Shared Non-shared
‘real’ error
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Caseness Stability and Heritability (Kendler et al 1993)
Index based on N of Sx, Rx, N of episodes and impairment
Stability associated with higher index
Heritability around 70% when 2 occasions of measurement used
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Genetics and Genomics of Mood Disorders
• Q.How much do genes contribute?• A. About 80% of the variance in liability to
BP Disorder
• A. Over 70% of the variance in liability to UP Disorder in clinically ascertained adult sample (30-40% in population based samples)
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Genetics and Genomics of Mood Disorders
• How specific are the genetic effects?
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Relatives affected +
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Relatives affected +
Relatives affected ++
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Correlations in liability UP and BP disorder
Cotwin
Proband
UP BP
UP 0.314 0.133
BP 0.304 0.426
McGuffin,et al (2003) Archives of General Psychiatry 60: 497-502.
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Bipolar Disorder :Bivariate Studies
genetic overlap with unipolar disorder?
genetic overlap with schizophrenia?
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UP BP
A C E
ed
A C E
hb cb eb
rgrc
re
hd cd
Components of phenotypic correlation
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Depression Mania
A E
ed
A E
ha eahd
Components of phenotypic correlation
rg=0.65re=0.59
E
A
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The relationship between schizophrenic and bipolar symptoms
SA ScBP
AEEA E
A
.82 .9
.7
.4 .57.4 .38 .4
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Nature, Nurture and Mood Disorder
High heritabilities
Environment 20-30%, but all non shared
Partial overlap with between UP and BP disorder
Partial overlap between BP disorder and schizophrenia
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Genetics and Genomics of Mood Disorders
• Can we locate and identify genes?
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Karyotype@ensembl
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Chromosome 12
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Positional cloning
Linkage(or LD)
location
gene identification
structure and sequence
gene product
prediction
diagnosis
treatment
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Linkage v Association
families
detectable over large distances >10 cM
large effects OR >3, variance>10%
case-control or families
detectable over small distances <1 cM
small effects OR<2, variance<1%
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Regions of recent interest in BP affective disorder
12q : linkage studies and Darier’s disease13q and 22q supported by meta-analysis18 centromeric or 2 regions on 18q?4p : one large and another moderately large
family21q one large and many small/moderate
size families
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Regions of recent interest in UP affective disorder
12q 2/3 studies15q 2/3 studies13q ?1p?
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Genome-wide linkage scan of recurrent depressive disorder
McGuffin et al., Hum Mol Genetics, 2005
1p36
MTHFR
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Approaches to association
Functional Candidates
Searching regions of interest (LD) for positional candidates
Whole genome association
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Examples of functional candidates
Serotonin pathways
NA pathways
DA pathways?
Others, eg BDNF
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Wang et al. (2004) ChRM2 and UPD
haplotype
.
3-SNP haplotype significant [rs1824024-rs2061174-rs324650] (χ2 = 29.69, p = 0.0001 [SUM]; χ2 = 24.52, p = 0.0009 [AVE])
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Genome-wide linkage scan of recurrent depressive disorder
McGuffin et al., Hum Mol Genetics, 2005
1p36
MTHFR
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Studies of the MTHFR C677T in depression (T/T vs. C/C)
Lewis et al., Mol Psychiatry, 2006
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MTHFR genotype frequency in depression patients and controls
12.7 45.3 42
13.4 41.9 44.7
0% 20% 40% 60% 80% 100%
Unaffected
Affected
T/T T/C C/C
12.1 46.9 41
12.1 42.8 45.1
0% 20% 40% 60% 80% 100%
Unaffected
Affected
13.1 44.2 42.7
14 41.6 44.4
0% 20% 40% 60% 80% 100%
Unaffected
Affected
Men: chi2 = 1.47, p = 0.48
Total: chi2 = 2.35, p = 0.31
Women: chi2 = 0.83, p = 0.67
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Chromosome 12q Depression & BD findings & DeNt
110
120
130
140
150
PAH Ekholm20 (BP): lod = 2
D12S78
D12S84
D12S76 PLA2
D12S342 Curtis18 (BP): lod = 2.9
ATP2A2
Dawson16 (BP) : lod = 1.65
Chromosome 12
Morisette11 (BP) lod = 2.5Pedigrees 324 & 550: 1od = 4.7
D12S1639 Ewald17 (BP): lod = 3.4
100
D12S1300/ Abkevich23 (UP) lod = 4.6D12S393 Zubenko22 (UP) : lod = 1.9
Maziade21 (BP) : lod >1.5
D12S1613D12S1613LOD = 1.57LOD = 1.57
McGuffin et alMcGuffin et al2005`2005`
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G72 (DAOA) and D amino acid oxidase (DAO)
G72 implicated by LD search across 13q22-34 linkage region
Primate specific geneInteraction with DAO found by yeast 2
hybrid studyEvidence of G72-DAO epistasisMultiple replications of G72 association in
both schizophrenia and bipolar disorder
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Genetics and Genomics of Mood Disorders
Can we locate and identify genes?
• What do we do next?
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Genetics and Genomics of Mood Disorders
What do we do next? Functional genomics
Proteomics
Behavioural Genomics
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Toward behavioral genomics
‘Top down’Whole organismAnimal models of component traitsGene environment interplay
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The serotonin transporter gene
From Lesch and MÖssner Biol. Psychiatry, 1998
14 repeats = “Short”
16 repeats = “Long”
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0.00
2.50
5.00
7.50
10.00
12.50
0 1 2 3 4 +
SS, n = 146
SL, n = 435
LL, n = 264
Five groups of individuals having different numbers of life events, ages 21-26
Se
lf r
ep
ort
s o
f d
epre
ssi
on
s
ymp
tom
s, a
ge
26
5-HTT gene
The association between SLEs and self-reports of depression symptoms at age 26, as a function of
5-HTTLPR genotype
Caspi et al 2003
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G-E interaction and SERT promoter polymorphism
• Tryptophan depletion effect ( Neumeister et al 2002)
• Amygdala activation and fearful stimuli ( Hariri et al 2002)
• Maternal separation stress effects ( ACTH) in macaque monkeys ( Barr et al 2004)
• Short allele and adversity => depressive symptoms (Caspi et al 2003, Eley et al 2004 –and review by Zammit and Owen 2006)
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The impact on psychiatry
• refined diagnosis
• understanding of neurobiology
• risk prediction and gene-environment effects
• influence on treatments
• public perception and stigma
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The impact on psychiatry
refined diagnosis +understanding of neurobiology+risk prediction and gene-environment effects+targeted & tailored treatments+improved public perception and no stigma
= the end of psychiatry!