Schizophrenia is a multifactorial disorder caused by the combined effects of multiple genes and environmental factors, rather than a single gene. It does not follow Mendelian patterns of inheritance. While relatives of those with schizophrenia have a slightly higher risk, the incidence is only around 2-4%, indicating multiple genetic and environmental contributions rather than single gene mutations. Studies examine genetic associations through single nucleotide polymorphisms (SNPs) to identify candidate genes that may increase risk or impact treatment response for schizophrenia as a complex, multifactorial condition.

1. SCHIZOPHRENIA AS A
MULTIFACTORIAL DISORDER

2. Multifactorial Inheritance
• Diseases that show familial clustering but do
not conform to any recognized pattern of
single gene inheritance are termed
multifactorial disorders.
• They are determined by the additive effects of
many genes at different loci together with the
effect of environmental factors.

3. A Phenotype Depends on the
Genotype and the Environment

4. Mendelian Genetics Does not Apply to
Complex Diseases
• What is Mendelian genetics?
Mendelian way of inheritance(dominant, recessive or
sex-linked) is the way most of us studied genetics in
college.
Mendelian genetics applies to rare diseases only, such
as cystic fibrosis, Huntington’s disease, muscular
dystrophies, etc.
Mendelian genetics does not apply to schizophrenia or other complex
disorders such as diabetes, stroke, hypertension, coronary artery disease or most
cancers.

5. Complex Diseases
• Common diseases such as diabetes mellitus type 2, asthma, coronary artery disease or
schizophrenia are called complex diseases and their inheritance is multifactorial.
• Multifactorial Diseases can be detected by genetic association studies.
• Monogenic diseases are usually detected by genetic linkage studies.

6. Association Studies Determine
Probabilities
• A high probability (p) of a genetic locus being associated with a condition
(red bars)- in this example EGR3 gene signals the highest ( p) value.

7. Multifactorial Disorders
• These conditions show a definite familial
tendency but the incidence in close relatives
of affected individuals is usually around 2-4%
instead of the much higher figures that would
be seen if these conditions were caused by
mutations in single genes(25-50%).

8. Monogenic vs. Complex Disorders

9. Examples of Disorders of Multifactorial
Inheritance
Congenital Malformations:
-Congenital heart defects
-Neural tube defects
-Cleft lip/palate
-Pyloric stenosis
-Congenital hip displasia
Common non-communicable diseases:
-Asthma
-Schizophrenia
-Diabetes Mellitus
-Hypertension

10. Schizophrenia - From the Genes to
Phenotypes
• Multiple genes and the environment lead to vulnerability for the schizophrenia
phenotype.

11. Endophenotypes Are Between the Genes and the
Behavior
• Enlarged lateral ventricles is a frequent endophenotype in schizophrenia.

12. Heritability
• Heritability of a trait or disease is the proportion
of the total variance that is genetic.
• The overall variance of the phenotype is the sum
of the environmental and genetic variance.
• Heritability provides information of the
importance of genetic factors in the causation of
a disease.

13. Example of Heritability Estimates
• Schizophrenia 85
• Asthma 80
• Pyloric stenosis 75
• Ischemic heart disease 65
• Essential hypertension 60
• Spina bifida 60
• Diabetes mellitus 40

14. SNPs Are Markers On The DNA Road
• A SNP occurs every 500-1000 nucleotides
(base pairs).
• They can be thought of as mile-markers.

15. Single Nucleotide Polymorphism(SNP)
• The human genome sequence is 99.6% identical in all people.
• However there are certain positions on the DNA where some people have one nucleotide
pair, while others have another. These positions are known as SNPs.
• SNPs make up 0.4% of the genome (12 million base pairs). Differences at these places make
us unique.
• A SNP can be thought of as an address of a house on a street. The “occupants” are the four
nucleotides A,T,C,G.

16. SNPs May or May not Affect the
Structure of the Proteins
• Synonymous: SNP in the coding region (exons)
that do not influence the structure of the protein.
• Conservative: Alter the structure of the protein,
but not its function
• Functional: Alter the function of the protein.
• SNPs can occur in any part of the DNA, such as in
exons(coding regions of DNA)
introns (non-coding regions of DNA)
regulatory regions of DNA

17. Identifying Candidate SNPs
• DNA of a group of patients is scanned for specific SNPs and compared to a control group.
• If a SNP is more frequent in the patients compared to the control group it may be a marker or
candidate SNP.

18. SNP Chips
• Very efficient methods have been developed for comparing SNP alleles.
• This chip can test over a million SNPs for a person in one step. The chip is simply soaked in
saliva or blood, then placed in a machine that collects the data and sends it to a computer.
Example of RESULT:

19. Variant genes in schizophrenia relevant
to clinical practice
• DRD2 = carriers of the Del allele may demonstrate less satisfactory
antipsychotic drug response compared to Ins/Ins allele.
• COMPT= Patients with the homozygous Val/Val allele may be less
likely to respond to SSRI treatments .
• COMPT 158 Val/Val genotype=dopamine is degraded at a higher
rate increasing chances for cognitive defects.
• CACNA1C=The A allele has been associated with elevated rates of
mood disorders.
• SLC6A4=Carriers of (S) or L(G) alleles may be less likely to respond
to SSRIs and more likely to experience side effects.