SCHIZOPHRENIA AS A MULTIFACTORIAL DISORDER

• 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.

Multifactorial Inheritance

A Phenotype Depends on the Genotype and the Environment

• 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.

Mendelian Genetics Does not Apply to 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.

Complex Diseases

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.

• 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%).

Multifactorial Disorders

Monogenic vs. Complex Disorders

Congenital Malformations:-Congenital heart defects-Neural tube defects-Cleft lip/palate-Pyloric stenosis-Congenital hip displasiaCommon non-communicable diseases:-Asthma-Schizophrenia-Diabetes Mellitus-Hypertension

Examples of Disorders of Multifactorial Inheritance

Schizophrenia - From the Genes to Phenotypes

• Multiple genes and the environment lead to vulnerability for the schizophrenia phenotype.

• Enlarged lateral ventricles is a frequent endophenotype in schizophrenia.

Endophenotypes Are Between the Genes and the Behavior

• 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.

Heritability

• Schizophrenia 85• Asthma 80• Pyloric stenosis 75• Ischemic heart disease 65• Essential hypertension 60• Spina bifida 60• Diabetes mellitus 40

Example of Heritability Estimates

• A SNP occurs every 500-1000 nucleotides (base pairs).

• They can be thought of as mile-markers.

SNPs Are Markers On The DNA Road

• 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.

Single Nucleotide Polymorphism(SNP)

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

• 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.

Identifying Candidate SNPs

• 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:

SNP Chips

• 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.

Variant genes in schizophrenia relevant to clinical practice