In this ppt we discuss the genetic basis of cognitive dysfunction associated with schizophrenia. We discuss the 5 main genes associated with both scz. and cognitive dysfunction. Another important aspect we cover is the dopaminergic pathway of signal transduction and its impairement in scz. patients.

1. GENETICS OF COGINITIVE DYSFUNCTION IN
SCHIZOPHRENIA
Submitted by: Rohit Bansal
Reg. No.: 17mslshg15
(Department of Human Genetics and Molecular Medicine)

2. INTRODUCTION TO SCHIZOPHRENIA
 Chronic and severe mental disorder
 1% people affected all over world (Kotlar et al., 2015)
 Usually between ages 16 and 30
CLINICAL SYMPTOMS
• Lose touch with reality
• Hallucinations and delusions
• Disorganized thinking and speech

3. CAUSES
GENETIC
CNVs SNPs
Rare
variants
ENVIRON
MENTAL
Parental
age
Maternal
parity
Low birth
weight
Cannabis
use

4. GENETICS OF SCHIZOPHRENIA
 Multiple gene disorder
 Different strategies like NGS and GWAS used to find rare
and common variants respectively
 Various SNP, rare alleles and CNV are responsible
 More than 128 common single nucleotide polymorphisms
(SNPs), and at least fifteen rare copy number variants
(CNVs) (Kotlar et al., 2015)

5. •By the study of CNVs
•No family history found
•Genes associated with post-synaptal pathway
•Greater connectivity in protein-protein interaction.
•Overlap with other disorder
DE-NOVO MUTATIONS

6. COPY NUMBER VARIANTS
 Gain or lose of genomic material
 15 genomic regions
 3q29 micro deletion is now known to be the single largest
schizophrenia risk factor
SOURCE: Genetics of Schizophrenia (Escudero and Johnstone., 2014)

7. RARE VARIANTS
 Allele frequency less than 1% (Keller, 2018)
 By next gen sequencing analysis of genes of NMDAR complex
 Low frequency but a large effect.
 It affects some pathways like calcium channel signalling

8. GWAS STUDY
 Genome wide association studies
 Associates SNPs with the trait
 Case- control study
 80% of true association for single nucleotide polymorphisms
(SNPs)(Kotlar et al., 2015)
 Required large no of samples

9. Source: New discoveries in schizophrenia genetics reveal neurobiological pathways:
A review of recent findings(Kotlar et al, 2015)
Location of Scz-associated alleles
More than 128 common single nucleotide polymorphisms (SNPs),
and at least fifteen rare copy number variants (CNVs)

10. COGNITIVE DYSFUNCTION AND SCZ
 Cognitive dysfunction is core feature of SCZ.
 Shared common gene loci
 many trait-associated SNPs
 “missing heritability”.

11. DOPAMINE HYPOTHESIS
.

12. SOURCE: The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia
(Howes O.D. et al., 2017)

13. Genetic Loci Jointly Influencing
Schizophrenia Risk and the Cognitive Traits
 Conjunctional false discovery rate (cFDR) statistical approach
 21 loci shared (Smeland and Andreassen, 2018)
 Expressed in developmental and adult human brain
 Gene locus 22q13.2, strongest overlapping signal
 It mainly include
 TCF20
 CYP2D6
 NAGA
 CACNA1C
 AKAP6

14. Conjunctional FDR Manhattan plot
SOURCE: Identification of genetic loci jointly influencing scz risk and cognitive traits(Smeland et al, 2017)

15. GENES
TCF20 GENE
 Chromosome no.
22
 Transcription
factor 20
 Transcriptional
coactivator
CYP2D6 GENE
 On chromosome 22
 Code for a enzyme
“cytochrome P450
2D6”
 Biosynthesis of
dopamine
NAGA GENE
 On chromosome 22
 Alpha-N-
acetylgalactosaminidase
enzyme
 Function in lysosomes
AKAP6 GENE
 On chromosome no. 14
 Code for A-kinase
anchoring protein
 Affects the reward
system
CACNA1C GENE
 On chromosome no. 12
 Code for protein, part
of voltage dependent
calcium channel
 Signalling pathways
affected

16. •Antipsychotic Pharmacotherapy
•Psychosocial Interventions
Cognitive remediation
Vocational rehabilitation
Assertive community treatment
Family intervention
•Diet and Activity
MANAGEMENT

17. FUTURE PROSEPECTIVE
Only a fraction of heritability of SCZ has been studied to date. GWAS and
sequencing studies will identify additional risk alleles. An increased
sample size will aid in identifying and characterizing more variants and
alleles. This will help in the production of personalized treatment
techniques for individuals suffering from schizophrenia.

18. REFERENCES:
• Irene. E., & Mandy. J . (2014). Genetics of Schizophrenia. Current Psychiatry Reports, 1- 6.
• Keller, M. C. (2018). Evolutionary Perspectives on Genetic and Environmental Risk Factors for
Psychiatric Disorders. Annual Review of Clinical Psychology, 10.1 – 10.23.
• Kotlar et al. (2015). New discoveries in schizophrenia genetics reveal neurobiological
pathways: A review of recent findings. European Journal of Medical Genetics, 704-714.
• Smeland et al.(2017). Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and
the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive
Function. JAMA Psychiatry, E1-E11.
• Smeland, O. B. and Andreassen, O. A. (2018). How can genetics help understand the
relationship between cognitive dysfunction and schizophrenic? Scandinavian Journal of
Psychology, 26–31.

19. THANK YOU