COMSATS University, Islamabad

OVERDISPERSED GENE EXPRESSION IN

SCHIZOPHRENIA

SCIENTIST NAME:
Guangzao Huang
OVERDISPERSED GENE EXPRESSION IN
SCHIZOPHRENIA

GROUP MEMBERS:
Bushra Talat
Firra Qamar
Isra Jabbar Rana
Maryam Batool
Sana Kanwal
 INTRODUCTION
• SCHIZOPHRENIA (SCZ)
• Serious mental illness.

• Affects the way a person thinks,

acts, expresses emotions, perceives
reality, and relates to others.

• Effects 1% of general population.

 Symptoms of SCZ

SCZ affects patients differently.

Symptoms of SCZ
 Causes of SCZ
Genetics
• Different genes increase the risk of SCZ

Environmental Factors
• Malnutrition before birth, stressful surroundings

Chemical imbalance in the Brain

• Dopamine

Certain Drugs
• Cannabis
• Patients diagnosed with SCZ can be classified into:
• With neurodevelopmental impairment
• Impact of risk alleles, CNVs or early environmental insults
• Without neurodevelopmental impairment
• Affective dysregulation

• SCZ is a highly heterogeneous group of disorders.

• SCZ has a polygenic architecture:

• Numerous SNPs and CNVs
 OBJECTIVE
• The objective of this study is to analyze the overdispersion of
disease-relevant genes’ expression in schizophrenia patients.
 MATERIALS/METHDODS

Data Sets
 BrainSeq project
 Microarray Data Set
 CMC Knowledge Portal
 CMC Study (common mind consortium study)
BrainSeq Project
 Use of antipsychotic medications.
 Influence of medication.
 Effect on gene expression.

Microarray Data Set

 139 SCZ (schizophrenia patients).
 266 CTL (unaffected controls).
CMC Knowledge Portal
• European Ancestry.
• 212 SCZ
 77 females
 137 males
• 214 CTL
 91 females
 121males

CMC Study (common mind consortium study)

• Samples collected on large scale
• Well curated data
• Hidden variables
 Test for Homogeneity of Expression Variance of
Single Gene

 Brown Forsythe Test.

 Levene’s Test.
(statistical analysis to know the p-value)
 P-value
 P-value is used to measure differentially expressed gene
according to their pre-specified significance level

 If p value is less than 0.05 variances are considerable.

 If p value is more than 0.05 variances are non-

considerable.
 MD-based Multivariate Test
 To identify genes which have multivariate expression.
 Distance base test.
 Gene Features.
 Calculation of Mahalanobis distance (MD).
 RESULTS
• Obtained data from the CommonMind Consortium (CMC).
• Data generated using RNA sequencing (RNA-seq).
• For each gene, used Brown–Forsythe (B–F) test.
• 5% false discovery rate (FDR).
• Identified 87 genes (including VEGFA and BDNF), that showed
a significantly higher expression variance among SCZ samples
than CTL samples.
• In contrast, only one gene (TAMM41) showed the opposite
pattern.
• For example: Using one of DV genes, ZBTB24.
 Differential Variability (DV) Analysis On Single
Genes:

• Furthermore, using a data set from the BrainSeq project

(information on the use of medicine.)

• Contributions of antipsychotics and antidepressants to gene

expression variability in SCZ samples.
 Differential Variability (DV) Analysis On Single
Genes:

• Using the gene ontology (GO) enrichment test.

• No significantly enriched function was found to associated with the

88 DV genes, suggesting marked functional diversity of these genes.

• One of the most salient examples is VEGFA, a gene encoding

vascular endothelial growth factor.

• This signal protein also stimulates many neuronal function.
• Data from an independent microarray-based study confirms the
higher VEGFA expression variability in SCZ samples.
 Gene set with higher expression variability among
SCZ samples

• Multivariate homogeneity of group dispersions

• Analog of Levene’s test
• Mahalanobis distance (MD)
• Colinearity in expression level
• Enhance power analysis
• 110 genes with higher multivariate expression variance in SCZ
P value < 0.05
Gene Sets Involved In Brain Development
• Phosphatidylinositol 3 kinase complex signaling pathway
is involved in SCZ (15 out of 20 genes)
• 30 gene sets → brain development
• Cerebellar cortex formation
• Neuromuscular junction development

SCZ brains are

characterized by
abnormal high gene
expression
Gene Sets Other Than Brain Development

• Genes involved in brain functioning

Necrotic cell death
Folic acid containing compound metabolic
response

• Garthwaite-Koch partition applied

• Top five genes showed dispersed expression in

SCZ as compared to control
 Principal Component Analysis
• Expression data of 23 genes
• enhanced expression in SCZ than CTL

9 set of genes
showed smaller
expression
• Neurexin family
protein binding
• Neuron cell cell
adhesion
 Statistical Power Analysis
• Computer simulations
• Series of sample size and variance of SCZ and
CTL groups
• Sample size per group =800 → power increases
• Sample size per group = 1000 → highly sensitive
→statsitical power 80%
• MD test requires 700 samples to reach 80%
power.
Genetic Variants Contribute To Dispersed Gene
Expression In SCZ

• QTL mapping analysis

• Effect of SNPs In SCZ and CTL
• 2503 SCZ specific evQTLS involving 1453 autosomal
protein coding genes
• 2076 CTL specific evQTLS involving 1277 autosomal
protein coding genes
• Statistical significance is much stronger in SCZ.
 CONCLUSION

• DV analysis on single genes.

• Multivariate DV analysis.
• Contribution of common genetic variants.

Overall gene expression variability among SCZ samples

is significantly higher than that among CTL samples.
 FUTURE PERSPECTIVE

Underdispersion of gene expression in SCZ patients.

• More prominent implications.

• Severe dysregulated gene expression.
• Reliable clinical typology.
 CRITICS
Novel Features:
• Coherence
• Collection of brain samples
• Analysis of overdispersion of gene expression among
SCZ patients.
Limitations:
• Limited number of samples.
• Samples are generalized.
 TAKE HOME MESSAGE

“Happy families are all alike, each unhappy

family is unhappy in its own way”
(Leo Tolstoy)
 TAKE HOME MESSAGE

If you/anyone around you is facing any of the

symptoms of SCZ:
• Self-assessment or psychiatrist
• Do not ignore medications
THANK YOU !!