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Genomic studies of schizophrenia: mapping madness

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Title: Genomic studies of schizophrenia: mapping madness


1
Genomic studies of schizophrenia mapping madness?
  • Mike Owen, Department of Psychological Medicine,
    Wales College of Medicine, Cardiff University, UK.

2
Genetic epidemiology of schizophrenia
  • Familial, ?s 10
  • Individual differences in liability are largely
    genetic
  • Heritability 0.6-0.9
  • Non-genetic factors also important
  • Multi-locus model consistently supported by
    analysis of family data
  • Genes with population ?s gt 3 unlikely
  • Number of susceptibility loci, degree of risk
    conferred by each and degree of interaction all
    unknown

3
Finding genes for schizophrenia
  • Linkage
  • Chromosomal abnormalities
  • Association
  • Convergent genomics

4
Genome wide significant
Multiple positives
Published linkage data 2006
5
Cardiff schizophrenia sib-pair genome screen
VCFS
CNP
351 microsatellite markers (10.3 cM) in 354
affected sib-pairs 179 (UK), 134 (Sweden), 41
(USA)
Williams et al. Am J Hum Genet 2003
6
Linkage studies of schizophrenia 2006
  • Data consistent with observed recurrence risks in
    relatives
  • Meta-analysis suggests some consensus
  • Many underpowered studies on uncertain value
  • Larger studies needed for more genes, stronger
    evidence, interactions and better location
  • 800-1000 ASPs optimal
  • A number of groups are now seeking genes in
    currently positive regions

7
Positional genetics and schizophrenia
  • Positional Candidates
  • NRG1, 8p 1
  • DTNBP1, 6p 2
  • G72 (DAOA), 13q 3
  • Multiple positive studies as well as negative
  • No clear pattern of associated alleles or
    haplotypes
  • Risk variants not identified

1. Stefansson et al. 2002 2. Straub et al. 2002
3. Chumakov et al. 2002
8
Positional candidate genes for schizophrenia
9
NRG1 association with schizophrenia
Tosato, Dazzan and Collier, Schiz. Bull. 2005.
10
DTNBP1 complex pattern of association findings
in schizophrenia
Williams, ODonovan and Owen, Schiz Bull, 2005,
11
DTNBP1 and schizophrenia
  • Multiple studies suggest that variation in DTNBP
    is associated with schizophrenia (11/14
    positive).
  • Protection may be mediated by IQ.
  • No individual SNPs or haplotypes have
    consistently been implicated in susceptibility.
  • No systematic study aimed at detecting all common
    genetic variation.
  • More studies needed to identify risk variants.
  • Reduced expression of message and protein in
    schizophrenia cause or compensation?
  • Cis-acting elements regulate DTNBP expression.
  • Can we relate specific haplotypes to gene
    expression?

12
DTNBP1 risk haplotype is associated with reduced
expression
  • Allele ratios at SNP rs1047631, stratified by
    heterozygosity for the defined schizophrenia risk
    haplotype.
  • Schizophrenia risk haplotype tags one or more
    cis-acting variants that result in a relative
    reduction in DTNBP1 mRNA expression in human
    cerebral cortex.
  • Further analyses suggest that risk haplotypes
    identified in other Caucasian samples also index
    lower DTNBP1 expression.
  • Ties risk haplotypes to altered function
  • Suggests explanation for some of the
    discrepancies between studies

Bray et al, Human Molecular Genetics, 2005.
13
Chromosomal abnormalities and schizophrenia
14
VCFS and Schizophrenia
  • 25 of adults with VCFS develop schizophrenia
    (Murphy et al 2000)
  • Does a gene on 22q11 predispose to schizophrenia
    in the general population?
  • Some claims (COMT, PRODH, ZDHHC8, ARVCF) but none
    convincing


15
DISC1 and schizophrenia (Porteous, Millar,
Blackwood, St Clair et al)
  • Possibility of position effect
  • Evidence for haplotype association with SZ
  • Associations with visual and working memory
    deficits
  • t (1,16) disrupts PDE4B (binding partner of
    DISC1) in family with psychosis (Millar et al
    2005)
  • DISC1 complex protein associated with numerous
    cytoskeletal proteins involved in centrosomal and
    microtubule function, and with cell migration,
    neurite outgrowth, and membrane trafficking of
    receptors and possibly mitochondrial function.

16
Candidate genes for schizophrenia
  • NRG1 and DTNBP1 multiple positive studies.
  • DAOA(G72) some positives for both schizophrenia
    and bipolar disorder
  • DISC1 highly promising.
  • Effect sizes small-moderate (OR 1.3-2)
  • RGS4 some positives but support weakening.
  • COMT, PRODH, ZDHHC8, PPP3CC, CAPON, CHRNA7, TRAR4
    and others not yet convincing.
  • Cannot be explained by variants with manifest
    functional consequences.
  • Presumably effects on expression, splicing etc.
  • Remain cautious until risk variants identified.
  • Inconsistencies between studies.
  • Lack of power
  • Genotyping error
  • Stratification
  • Incomplete genetic information from indirect
    studies
  • NB dysbindin
  • Susceptibility variants on different
    backgrounds??
  • Allelic heterogeneity/complexity
  • Heterogeneity differences in case definition and
    ascertainment

17
Emil Kraepelin, 1896, splits psychosis.
  • crystallized dementia praecox and
    manic-depressive illness from an amorphous mass
    of madness (Brockington Leff, 1979).
  • Organic
  • Functional
  • Dementia Praecox
  • Manic-depressive insanity

18
Deconstructing Psychosis Challenges to the
Kraepelinian Dichotomy.
  • No point of rarity
  • Risk factors in common (Murray et al 2004)
  • Familial co-occurrence of SZP, SA and BP
  • Cardno et al twin study
  • Overlapping linkage regions
  • 13q, 22q, 6q
  • New genetic studies confirm this and suggest
    association with clinical syndromes.

19
Studying candidate genes across the Kraepelinian
divide Dysbindin.
  • No association between BP and the Cardiff
    haplotype in DTNBP1.
  • Suggestive evidence for association with BP with
    predominant psychosis.

Upward trend p 0.014
Raybould et al, Biological Psychiatry, 57
696-701, 2005.
20
Studying candidate genes across the Kraepelinian
divide Neuregulin.
  • NRG1 HAPICE confers risk to illness with both
    schizophrenia and mood features.
  • Effect size of NRG1 HAPICE increases with
    preponderance of mood-incongruent psychotic
    symptoms (sign test p0.002).

Green et al, Archives of General Psychiatry, 2005.
21
Studying candidate genes across the Kraepelinian
divide G72 (DAOA).
  • Some positive replications of G72 but no clear
    associated alleles or haplotypes.
  • Independent support for association with Bipolar
    disorder in several studies.
  • G72 probably strongest candidate gene for BP.
  • Is this a gene for both disorders?

22
DAOA (G72) in schizophrenia and bipolar disorder
  • Significant whole gene association in BP (n706,
    p0.045) but not SZ (n709) vs controls (n1416).
  • Significant whole gene association in Mood (n
    1153, p0.0086) and in schizophrenia-mood (n112,
    p0.02) but not psychosis (n818).
  • DAOA is probably a susceptibility locus for mood
    disorder rather than schizophrenia per se.
  • Extent to which association seen in schizophrenia
    depends upon clinical characteristics of sample.

(Williams et al Archives of General Psychiatry,
2006).
23
DISC1 is associated with broad psychosis and mood
phenotype.
  • t(111) segregates with Sz, BP and UP.
  • Linkage to SA
  • Hamshere et al 2005.
  • Evidence for haplotype association
  • Hennah et al 2003
  • Hodgkinson et al 2004
  • Schizophrenia, SA and BP
  • Thomson et al 2005
  • SZ and BP.

24
Using genetics to dissect psychosis
Craddock, ODonovan and Owen, Schizophrenia
Bulletin, 2006.
25
Do genetic findings in psychosis point to a
common mechanism?
  • The genes most clearly implicated (NRG1, DTNBP1,
    G72) all code for proteins that potentially
    impact, directly or indirectly, on the function
    of glutamate synapses.
  • Harrison and Owen, Lancet, 2003.
  • But caution required!
  • proteins implicated poorly understood
  • multiple processes implicated for NRG1 and DTNBP1

26
White matter abnormalities in schizophrenia (Mt.
Sinai Conte Center)
  • Imaging studies
  • Defects of connectivity
  • DTI
  • Multiple gene expression studies in postmortem
    schizophrenia brains have found significant
    reduction of expression of myelin and
    oligodendrocyte related genes (e.g. Hakak et al.,
    2001)
  • Quantitative anatomical analyses have
    demonstrated decreased oligodendrocyte numbers in
    prefrontal cortex (Hof et al 2002, 2003).
  • Cause or effect?

27
  • CNP is marker for oligodendrocytes
  • Message and protein show reduced brain expression
    in schizophrenia
  • Located at 17q21.2
  • rs2070106 is associated with CNP expression
    (P0.001).
  • the lower-expressing allele was significantly
    associated with schizophrenia (P.04) in a
    case-control sample.
  • All affected individuals in a linked pedigree
    were homozygous for the lower-expression allele
    (P.03).

Archives of General Psychiatry (2006) 63 18-24.
28
Oligodendrocyte Lineage Transcription Factor 2
(OLIG2) a master regulator of all stages of
oligodendrocyte lineage.
  • Basic helixloophelix transcription factor
    central to oligodendrocyte development
  • Down-regulated in schizophrenia (Tchakev et al,
    2003 Katsel et al, 2005 Iwamoto et al, 2005)
  • Centrality in OL allows for a primary change
    responsible for several others (parsimony)

29
OLIG2 associated with schizophrenia non
redundant (r2lt0.9) positives (submitted).
Meff 9 (all 16 pooled SNPs) gene
corrected p 0.0009 Experiment-wide corrections

p 0.013 (primary 14 genes) p 0.038 (all
44 genes)
CONSERVATIVE
30
Conclusions
  • Some highly promising findings (NRG1, DTNBP1,
    G72/DAOA, DISC1)
  • Need to establish risk nucleotides/mechanisms
  • And this might not be easy without functional
    readout (endophenotypic, animal, cellular)
  • Needs more detailed studies, collaboration,
    re-sequencing
  • Expect allelic heterogeneity, effects of
    ascertainment
  • Refining the associated phenotype by iteration
    (Symptoms, Course and outcome, Cognitive
    function, Imaging). NB samples.
  • Curation of association data (its epidemiology)
  • Quality standards
  • Meta-analysis
  • Need to support genetic associations with biology
  • DTNBP1 and NRG1 expression studies

31
Future
  • There are more significant linkages to account
    for.
  • Few if any exhaustive fine mapping studies
  • WGAs
  • Depend on CDCV hypothesis
  • Need very large samples
  • Sample characteristics will be crucial
  • Data handling and statistical challenges are huge
  • WTCCC
  • CNV analysis
  • Candidate pathway analysis (GxG)
  • Inclusion of E in genetic studies (GxE)
  • WGS (CDRV)
  • Understanding gene regulation (identifying
    regulatory sequences, miRNA, chromatin effects
    etc)

32
Acknowledgements
  • N Williams
  • N Norton
  • H Williams
  • N Bray
  • A Preece
  • J Wilkinson
  • S Dwyer
  • Elaine Green
  • Rachel Raybould
  • Detelina Grozeva
  • T Peirce
  • B Glaser
  • L Carroll
  • M ODonovan
  • N Craddock
  • G Kirov
  • I Jones
  • M Hamshere, P Holmans. S Macgregor, V Moskvina,
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