Schizophrenia

Discovering Disease Genes- The Example of Schizophrenia Pippa Thomson, Medical Genetics Section, Dept of Medical Sciences, MMC, University of Edinburgh.

Importance of the illness
Severe psychiatric
Affects ~1% of the population
One of the top 10 causes of disability worldwide
Economic cost (23% Drug, 14% Hospital)
Pharmacological rationale for treatment weak or absent
1/3rd patients unresponsive or experience unacceptable side effects
Strong genetic component
concordance rate between identical twins of 60%

Schizophrenia Positive symptoms: visual & auditory hallucinations, delusions, incoherent speech

Schizophrenia Negative symptoms: withdrawal & isolation, impaired attention & blunted emotions

Altered brain structure & function

High Heels Cause Schizophrenia and 6 Other Outlandish Medical Theories 2. High-heeled shoes cause schizophrenia. You have to wonder where some medical theories originate. Why did Swedish scientist Jarl Flensmark decide to study a connection between heeled shoes and the incidence of schizophrenia ? The world may never know. But his initial research seems sound, and he has connected certain brain activity with stimulation of certain points on the feet. The spread of schizophrenia around the globe has closely followed the spread of availability of heeled shoes. Is it an eerie coincidence or a real cause for concern? Look out, men - this theory applies not only to stilettos, but to any shoe with a heel. remedicated.com

Relative risk of developing Schizophrenia Environment !

Benefits of gene identification
Understand aetiology
Improved drug development & testing
Development of definitive diagnostic tests
Understanding of interaction with non-genetic risk factors
Insight into normal brain development & function
Kraepelin, 1896 “ As we do not know what causes the illness there cannot be a rational treatment”

Allelic architecture and mapping strategy Magnitude of effect Frequency in population Family-based linkage studies Association studies in populations Unlikely to exist Fnct. Studies

Locus Identification-problems
Uncertainty in diagnostic boundaries
Non-Mendelian inheritance
Variable age of onset
Genetic heterogeneity
Many different genes can cause the illness
1% risk world wide
phenotypic variation
Oligogenic/polygenic causation
More than one mutant gene required to produce phenotype

Locus identification- reducing the problems
Single large families
Avoid bilineal descent
rigorous interviews
family history
Reduce genetic heterogeneity
Significant LOD score = gene of major effect
Reduce uncertainty of diagnosis
classify minor diagnoses as unaffected
>1 category of affected phenotype

Marker analysis in multiply affected family or families
Look for co-segregation of a particular allele with phenotype
Results expressed as a LOD score (Significant at > 3)
= log (likelihood of data, if locus & disease are linked)
----------------------------------------------------------------
(likelihood of data, if locus & disease are not linked)
Generally a large region is identified
Linkage Analysis

A balanced t(1;11)(q42;q14) translocation der1 der11 11 1 1 1q42 11q14 11

? recurrent major depression minor diagnosis unaffected schizophrenia bipolar affective disorder (1;11)(q42;q14) translocation translocation increases risk by 50-fold t(1;11) co-segregates with major mental illness

Genetic association studies seek to relate variation in human DNA sequence with a disease or trait
Association method provides greater power to detect common genetic variants conferring susceptibility to complex phenotypes
Estimates population attributable risk (effect size)
Controls should match cases and be a representative sample of the population.
Controls Schizophrenics 100’s Individuals = 1% Schizophrenia 100’s Individuals = 100% Schizophrenia

Case-control association studies
Comparison of frequencies of polymorphisms between populations of cases and controls (usually a simple chi-square test or logistic regression)
Polymorphism studied can be directly responsible for the defect  frequency of cases >>> controls
Polymorphism studied can be in linkage disequilibrium with the mutation responsible for the disease  %T cases >> controls
Association studies can be conducted for candidate genes, or through a whole region or across the whole genome (WTCCC)
p Mb T A G C

SNPs are genotyped in parent-offspring trios, initially in CEPH trios. This can be used to identify SNPs that co-segregate (i.e. are in linkage disequilibrium) versus those that segregate independently. A subset of SNPs can therefore be chosen that best represent the genetic diversity in a region/gene, reducing the costs of genotyping. Summary of genotyped SNPs: Populations CEU CHB+JPT YRI Total Non-Redundant 3,204,709 3,244,897 3,150,433 International HapMap project http://www.hapmap.org/

Region of interest HapMap genotyped SNPs Known SNPs* Known genes in the regions Linkage Disequilibrium (LD) *http://www.ncbi.nlm.nih.gov/SNP/

Tagging SNP selection Proportion of haplotype diversity explained : SNPs 1-23 - 97% SNPs 24-46 - 98%

DISC2 TRANSLOCATION LOD=7.1, SCOTLAND Genetic evidence implicating DISC1 in psychiatric illness 1 SCZ & BPAD & MDD SCOTLAND SCZ , BPAD HAPLOTYPE p =0.0044, p =0.0016 2 3 4 5 6 7 8 9 10 11 12 13 DISC1 LOD=2, BRITAIN & ICELAND (Curtis et al 2003) D1S251 LOD=1, TAIWAN (Hwu et al 2003) SCZ BPAD HAPLOTYPE p =0.00024, FINLAND (Hennah et al 2003) SCZ & SCZAFF LOD=3.21, FINLAND (Ekelund et al 2001) SCZ D1S2709 p =0.000027, North-America (Hodgkinson et al 2004) rs6675281 SCZAFF

Table 1. Summary of current evidence supporting several of the more promising genes implicated in schizophrenia, bipolar disorder, and mixed bipolar-psychosis phenotypes Craddock et al., SCZ Bulletin, 2006 Genes for Schizophrenia ? >130 genes implicated

DISC1 interactome protein-protein interactions Chris Carter, http://www.polygenicpathways.co.uk/disc11_vml.htm

ENU generated mouse mutants
Two independent lines with missense mutations in DISC1 exon 2
Q31L (Glutamine-Leucine)
Q- hydrophillic; L – hydrophobic
L100P (Leucine-Proline)
Predicted to cause transition in polypeptide chain direction
Normal levels of DISC1 protein in brain
L100P line models schizophrenia; Q31L, depression
Effects of altered DISC1 on gene expression Clapcote et al., Neuron. 2007 May 3; 54 ( 3 ): 387-402 .

Schizophrenia Depression Effects of Altered DISC1 on Behaviour ( How do you know if a mouse is schizophrenic? )

Effects of altered DISC1 on gene expression
Samples collected and microarray study ongoing
Mutated lines vs background strain (C57/BL6)
47,000 transcripts
Hippocampus
Adult and embryonic stage- Microarray
Confirmation/Investigation of changes
Series of embryonic; postnatal and adult stages
Drug treated adult mice
Detect disrupted pathways

Resequencing, SNP detection, genome comparisons, gene expression, transcription factor studies, small RNA analysis
Individual genomes – All SNPs in each individual
Currently :
Using the Illumina 1G to sequence genes in the DISC1 pathway.
Total sequence read 3.5megabases in 1200 individuals
Identify coding and non-coding polymorphisms
Mutation detection
Detection of variants in conserved regions
Detection of variants affecting binding of transcription factors
Whole genome sequencing

Psychiatric Genetics- Unanswered Questions
How many susceptibility genes are there? What is their function? Is function conserved across species? Can we relate gene (dys)function to mental (dis)order? Do gene variants predict risk, course, outcome and response to treatment? Will gene discovery lead to drug discovery? How do genes and environment interact? How and when will the patient benefit?

DISC1 Kirsty Millar Shaun Mackie Fumiaki Ogawa Jennifer Chubb Becky Carlyle Nick Bradshaw Sheila Christie Steve Clapcote Kathy Evans Sarah Brown William Hennah Medical Genetics Prof David Porteous Prof Douglas Blackwood Walter Muir Ben Pickard Other collaborators DISC1 Consortium Wellcome Trust CRF Illumina, San Diego Cold Spring Harbor laboratories Acknowledgements

Schizophrenia

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