Psychiatric Disorder: Psychiatric Disorder: Is It All In The Genes?Is It All In The Genes?

Peter McGuffinPeter McGuffin

MRC SGDP CentreMRC SGDP Centre

Institute of Psychiatry, Institute of Psychiatry,

King’s College LondonKing’s College London

Sir Francis Galton (1822-1911)

The history of twins as a criterion of the relative powers of nature and nurture (1876)

‘…Nature prevails enormously over nurture’(1883)

‘..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 % CATEGO

current past cases

D-siblings 7.4 17.6 18.5

C-siblings 0 4.8 1.9

Behaviours that run in families

Huntington’s diseaseAlzheimer’s diseaseDepressionSchizophreniaPersonalityIntelligenceReligious involvementAttending 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

0 0.2 0.4 0.6 0.8 1

schizophrenia

autism

manic depression (bipolar)

depression (unipolar)

bulimic symptoms

ADHD

childhood fatigue

DZ

MZ

Structural Equation Modelling: a Simple Univariate Model

G1 G2

CE

P1 P2

h hc c

r12 = h2 + 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

Interaction

Covariation

Additive

Multiplicative

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)

0

5

10

15

20

25

30

anti

soci

al b

ehav

iour

%

low high

parent ASPno ASP parent

Life events in Camberwell (McGuffin et al 1988)

0

5

10

15

20

25

30

35

40

relatives controls

proband relatednot proband related

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)

0

5

10

15

20

25

30

35

40

relatives controls

proband relatednot proband related

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

gene identification

structure and sequence

gene product

prediction

diagnosis

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

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 al McGuffin et al 20052005

D12S1609D12S1609LOD = 1.18LOD = 1.18

Serotonin genesSerotonin genes

MAOAMAOA

Mitochondria

MAOAMAOA = Monoamine oxidase A = Monoamine oxidase A

5-HTT/SERT5-HTT/SERT = Serotonin transporter = Serotonin transporter

5-HTT/5-HTT/SERTSERT

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 , 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.

Bipolar disorderCoronary artery diseaseCrohn’sRheumatoidT1D and T2DHypertension

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

targeted & tailored treatmentsrefined diagnosisunderstanding of neurobiologyrisk prediction and gene-environment

effectspublic 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)