Psychiatric Disorder: Is It All In The Genes

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Psychiatric Disorder Is It All In The Genes?

• Peter McGuffin
• MRC SGDP Centre
• Institute of Psychiatry,
• Kings College London

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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)
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..a devil,on whos nature, nurture cannot stick.
(Michael Horton as Caliban)
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Psychiatrists opening gambits 1

• Have you suffered vexation, grief or reverse of
  fortune?
• Phillipe Pinel
• (quoted by Sir Michael Rutter)

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Psychiatrists opening gambits 2

• Are you a twin?
• Eliot Slater
• (quoted by Sir Denis Hill)

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Excerpt from a Bethlem Royal Hospital front
sheet 1823
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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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Behaviours that run in families

• Huntingtons disease
• Alzheimers disease
• Depression
• Schizophrenia
• Personality
• Intelligence
• Religious involvement
• Attending medical school

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Why might a disorder run in families?

• Shared genes
• Shared environment
• A combination of the two

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behaviour
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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?

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The Cholmondeley Ladies c.1600-10
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MZ TWINS

• MZ (monozygotic) twins have 100 of their genes
  in common (theyre natural clones)
• Shared environment also makes them similar

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DZ TWINS

• DZ (dizygotic) twins have 50 shared genes
• They also share environment to roughly the same
  extent as MZ twins

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MZ and DZ Twin Similarity Expressed as
Correlations
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Structural Equation Modelling a Simple
Univariate Model
b
G1
G2
h
h
CE
c
c
P1
P2
r12 bh2 c2
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Univariate models of genes, environment and
depression

• Data from McGuffin et al 1996

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Types of Gene Environment Interplay

• Coaction
• Interaction
• Covariation

• Additive
• Multiplicative
• G E correlated

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Coaction

• Phenotype Genes (G) Environment (E)
• Shared
  Non-shared

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GE Correlation Vs Interaction

• Correlation genetic influence on exposure to
  different environments
• Interaction genetic control of sensitivity to
  different environments

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G-E interaction antisocial behaviour and
adversity (Cadoret et al 1995)
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Life events in Camberwell (McGuffin et al 1988)
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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

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Life events in Camberwell (McGuffin et al 1988)
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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

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Why are life events familial?

• Some events affect multiple members
• Hazard prone behaviour (risk taking or bad
  planning)
• Threat perception (neuroticism or dysfunctional
  attitudes)

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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)

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Karyotype_at_ensembl
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Chromosome 12
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Finding genes

• One of the major benefits of the Human Genome
  Project is a dense map of markers (signpostsfor
  genome searching)
• Linkage studies use genetic markers track genes
  in families
• Association studies can pinpoint genes in
  populations

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Positional cloning

• Linkage(or LD)
• location
• gene identification
• structure and sequence
• gene product

prediction
diagnosis
treatment
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Allelic association

• Cases
• Controls

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Sib pairs

• Both affected by a disease
• Extremely alike or unalike on a continuum eg
  neuroticism

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Chromosome 12 UP BP Depression Findings
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D12S1300/ Abkevich23 (UP) lod
4.6 D12S393 Zubenko22 (UP)
lod 1.9
McGuffin et al 2005
Chromosome 12
PAH Ekholm20 (BP) lod
2
D12S1613 LOD 1.57
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D12S78
Maziade21 (BP) lod gt1.5
Morisette11 (BP) lod 2.5 Pedigrees 324 550
1od 4.7
D12S84
ATP2A2
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Dawson16 (BP) lod 1.65
D12S76 PLA2
140
D12S1609 LOD 1.18
D12S342 Curtis18 (BP) lod
2.9
D12S1639 Ewald17 (BP) lod 3.4
150
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Serotonin genes
Mitochondria
MAOA
5-HTT/ SERT
MAOA Monoamine oxidase A 5-HTT/SERT
Serotonin transporter
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The serotonin transporter gene
14 repeats Short 16 repeats Long
From Lesch and MÖssner Biol. Psychiatry, 1998
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The association between SLEs and self-reports of
depression symptoms at age 26, as a function of
5-HTTLPR genotype
Self reports of depression symptoms, age 26
5-HTT gene
Five groups of individuals having different
numbers of life events, ages 21-26
Caspi et al , Science 2003
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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 gt depressive symptoms
  (Caspi et al 2003, Eley et al 2004)
• Response to antidepressants (SSRIs) (eg Uher et
  al 2009)

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Specific genes that interact with environments

• serotonin transporter, social adversity (and
  medication) gt depression
• Monoamine oxidase A,childhood maltreatment gt
  antisocial behaviour
• COMT, cannabis gt schizophrenia

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Wellcome Trust Case Control Consortium.

• Bipolar disorder
• Coronary artery disease
• Crohns
• Rheumatoid
• T1D and T2D
• Hypertension

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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

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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

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Why do pharmacogenetics and genomics? General
response to therapeutic drugs

• Efficacious
• Little or no efficacy
• Toxic and not efficacious
• Efficacious but toxic

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The impact of genetics Post genomic psychiatry

• targeted tailored treatments
• refined diagnosis
• understanding of neurobiology
• risk prediction and gene-environment effects
• public perception and stigma

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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)

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Psychiatrists opening gambits 3

• is there any other insanity in the
  family?
• Anonymous wise old psychiatrist
• (quoted by Prof Kenneth Rawnsely)