The Genetics of Mood Disorders

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

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


• How much do genes contribute?

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)

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

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

psychiatric disorder

Teasing apart genesand environment

Twin studies

Adoption studies

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

Twin Concordance for DSM IV Major Depression (McGuffin et al 1996)

0

5

10

15

20

25

30

35

40

45

mzdz

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

Genetic Causes of Affective Disorders

Several, perhaps many, genes confer a liability to develop

the disorder

affected

liability

population

relatives

Structural Equation Modelling: a Simple Univariate Model

G1 G2

CE

P1 P2

h hc c

r12 = h2 + c2

Variances explained

0

10

20

30

40

50

60

70

80

BP disorder UPdepresssion

ACE

Phenotype= Genes (G) + Environment (E)

Shared Non-shared

‘real’ error

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


• 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)


• How specific are the genetic effects?

Relatives affected +

Relatives affected +

Relatives affected ++

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.

Bipolar Disorder :Bivariate Studies

genetic overlap with unipolar disorder?

genetic overlap with schizophrenia?

UP BP

A C E

ed

A C E

hb cb eb

rgrc

re

hd cd

Components of phenotypic correlation

Depression Mania

A E

ed

A E

ha eahd

Components of phenotypic correlation

rg=0.65re=0.59

E

A

The relationship between schizophrenic and bipolar symptoms

SA ScBP

AEEA E

A

.82 .9

.7

.4 .57.4 .38 .4

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


• Can we locate and identify genes?

Karyotype@ensembl

Chromosome 12

Positional cloning

Linkage(or LD)

location

gene identification

structure and sequence

gene product

prediction

diagnosis

treatment

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%

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

Regions of recent interest in UP affective disorder

12q 2/3 studies15q 2/3 studies13q ?1p?

Genome-wide linkage scan of recurrent depressive disorder

McGuffin et al., Hum Mol Genetics, 2005

1p36

MTHFR

Approaches to association

Functional Candidates

Searching regions of interest (LD) for positional candidates

Whole genome association

Examples of functional candidates

Serotonin pathways

NA pathways

DA pathways?

Others, eg BDNF

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])

Genome-wide linkage scan of recurrent depressive disorder

McGuffin et al., Hum Mol Genetics, 2005

1p36

MTHFR

Studies of the MTHFR C677T in depression (T/T vs. C/C)

Lewis et al., Mol Psychiatry, 2006

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

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`

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


Can we locate and identify genes?

• What do we do next?


What do we do next? Functional genomics

Proteomics

Behavioural Genomics

Toward behavioral genomics

‘Top down’Whole organismAnimal models of component traitsGene environment interplay

The serotonin transporter gene

From Lesch and MÖssner Biol. Psychiatry, 1998

14 repeats = “Short”

16 repeats = “Long”

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

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)

The impact on psychiatry

• refined diagnosis

• understanding of neurobiology

• risk prediction and gene-environment effects

• influence on treatments

• public perception and stigma

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!

Documents

The Genetics of Mood Disorders