Aetiology – focusing on psychiatric genetics by ert554898

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									Leeds Institute of
Health Sciences



 Genetic Influences on Psychoses
                     Alastair Cardno
              Academic Unit of Psychiatry
               and Behavioural Sciences
                  Overview
• Phenotypes
• Quantitative genetics
  – Family, twin, adoption studies
• Molecular genetics
  – Linkage, association studies
  – Others eg chromosomal abnormalities
• Phenotypes revisited
• Clinical applications
           Example studies
• Maudsley Twin Psychosis Series
  – 224 twin pairs
  – One or both twins have psychosis


• Cardiff Affected Sibling Pair Study
  – 196 sibling pairs
  – Both siblings have schizophrenia or
    schizoaffective disorder
              Phenotypes
• Lifetime perspective
• In psychiatric genetics usually diagnosis of
  psychiatric disorder (categorical)
• Can also be quantitative, eg symptom
  score, age at onset
• Increasing interest in endophenotypes
  – lie between genotype and clinical phenotype
  – eg cognitive, neuroimaging,
    electrophysiological
psychiatric
 disorder
                    Approximate risks
                     Schizophrenia   Schizoaffective   Bipolar disorder


Risk in general      0.8-1%          0.3%              0.3-1%
population

Risk to siblings/    10%             2-3%              5-10%
first degree rels

Monozygotic (MZ)     45%             40%               40%
twin concordance

Dizygotic (DZ)       5-10%           5%                5%
twin concordance

Risk in adoption     8%              -                 14%
studies                                                (but small sample)
        Heritability: examples

• Schizophrenia             80%+
• Schizoaffective           80%+
• Bipolar/mania             80-90%

• Unipolar depression       40-70%
• Alcohol dependence        50-60%
• Anxiety disorders         20-30%
         Mode of inheritance
• (Single gene)

• Multifactorial
  – Genetics and environment both important
  – Many small risk factors have cumulative effect
  – Maybe also some rare larger risk factors
    Shared genetic risk factors
Disorders             Some shared genetic
                      risk factors?
Schizophrenia and     Probably
schizoaffective
Schizoaffective and   Probably
bipolar
Schizophrenia and     ?
bipolar
    Shared genetic risk factors
Disorders             Some shared genetic
                      risk factors?
Schizophrenia and     Probably
schizoaffective
Schizoaffective and   Probably
bipolar
Schizophrenia and     Probably
bipolar
 Familial co-aggregation of Sz, Sa
              and BP
• Eg Mortensen et al, Arch Gen Psych 2003
• Danish population cohort (2.1 million)
• Relative risk of BP if sibling has:
  – BP   14.2
  – Sa   4.7
  – Sz   4.8


• Also, Swedish study coming soon
   Localising susceptibility genes


• Linkage studies

• Association studies
Example of multiply-affected family
Affected sibling pair approach
Linkage
Example:
Williams et al
AJHG, 2003;
73:1355-67
         Association studies
• Population based
  – Case-control design most common


• Look for association of genetic marker with
  the disorder

• Good for detecting small effects, but
  marker needs to be very close to a
  susceptibility locus
Approaches to association studies
• Functional approach
  – Investigate candidate genes
    • but often questionable candidates for psychiatric
      disorders


• Positional approaches
  – In chromosomal regions showing linkage
  – In genome-wide association studies (GWAS)
      Functional candidate gene
     association studies: examples

•   DRD3 - Sz
•   5HT2a – Sz
•   5HTT – BP
•   MTHFR – Sz, BP
  Positional approach I: linkage then
 association (example: schizophrenia)
• Linkage regions of interest
  – On chromosomes 6p, 1q21-22, 13q
  – Also on chromosomes 8p, 6q, 22q, 5q, 10p,
    1q42
• Positional candidate genes from
  association studies
  – Dysbindin on chromosome 6p
  – Neuregulin on chromosome 8p
     • also association with bipolar with psychosis
 Positional approach II: genome-
 wide association studies (GWAS)
• Wellcome Trust Case Control Consortium,
  Nature 2007;447:661-678
• Using:
  – 2000 cases for each of 7 diseases
  – 3000 shared controls
  – 500,000 genetic markers


• Includes bipolar disorder
WTCCC, Nature 2007;447:661-678. Figure 4 (part)
   Subsequent collaborative GWAS
Study        Disorder   Locus       No.     No.        P-value     Odds
                                    cases   controls               ratio

O’Donovan    Sz         ZNF804A     7,308   12,834     1.61x10-7   1.12
2008                    (Chr 2q)
(Nat Genet
             Sz+BP      ZNF804A     9,173   12,834     9.96x10-9   1.12
40:1053-5)
                        (Chr 2q)


Ferreira     BP         ANK3        4,387   6,209      9.1x10-9    1.45
2008                    (Chr 10q)
(Nat Genet
40:1056-8)   BP         CACNA1C 4,387       6,209      7.0x10-8    1.18
                        (Chr 12p)
  Chromosomal abnormalities and
       psychosis: examples
• Deletion
  – Microdeletion on chromosome 22q11
  – Velocardiofacial syndrome (VCFS)


• Translocation
  – Between chromosomes 1 and 11
  – Chromosome 1 breakpoint disrupts a gene:
  – DISC1 (Disrupted in Schizophrenia 1)
 Copy number variants (CNVs)
• Deletions and duplications in DNA
  – (eg VCFS deletion)
• Associations with schizophrenia:
  – 1. Number of CNVs in the genome
     • ‘mutational burden’
  – 2. Presence of rare recurrent de novo CNVs
    at specific locations:
     • eg Chr1q21        Odds ratio 14.8
     (Stefansson et al, Nature 2008;455:232-7)
 Psychotic disorders: summary
• Major genetic influence on Sz, Sa,
  mania/BP
• Some shared genetic influences
• Many genetic loci of small effect
• Some rarer CNVs of larger effect (for Sz)
  Phenotypes revisited: psychotic
      symptom dimensions
• Positive
  – Delusions, hallucinations


• Negative
  – Restricted affect, poverty of speech
    (social withdrawal)


• Disorganised
  – Formal thought disorder, inappropriate affect
    (bizarre behaviour)
   Correlations in affected pairs of
              relatives
Phenotype      Affected sibling Affected MZ
               pairs            twin pairs
Positive       0.4              0.3

Negative       0.04            0.3

Disorganised   0.3             0.8

Age at onset   0.4             0.9
    Symptom dimensions, age at
        onset: next steps

• Heritability estimates in twin pairs
  – Age at onset of Sz: 70% (Neale et al, 1989)
  – Disorganised dimension: 84% (Rijsdijk et al,
    in prep)
• Linkage studies in sibling pairs

• Association studies in individuals
              Endophenotypes
• Should be (Gottesman and Gould, 2003):
  –   Associated with the disorder
  –   Heritable
  –   Present whether or not illness active
  –   Co-segregate with disorder in families
  –   Found in non-affected family members > general
      population
• Some issues
  – Feasible sample sizes
  – Genetic complexity of endophenotypes
         Clinical applications
• Quantitative genetics
  – Aetiology (genetics, environment, interaction)
  – Classification (eg schizophrenia spectrum)
  – Genetic counselling (empirical risks)


• Molecular genetics
  – Aetiology, pathophysiology, treatment
  – Classification
  – (Risk prediction)
          Acknowledgements
• Maudsley twin psychosis studies
  – P McGuffin, RM Murray, FV Rijsdijk, EJ Marshall, B
    Coid, AM Macdonald, TR Ribchester, NJ Davies, P
    Venturi, LA Jones, SW Lewis, PC Sham, II
    Gottesman, AE Farmer.
• Cardiff sibling pair studies
  – MJ Owen, MC O’Donovan, N Craddock, NM Williams,
    N Norton, H Williams, ML Hamshere, S Zammit, LA
    Jones, KC Murphy, RD Sanders, G McCarthy, MY
    Gray, G Jones, P Holmans.

								
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