Mental illness and_genetics_presentation

ISMAIL SADEKLecturer of psychiatry

Faculty of medicine

• Determine the sequence of the 3 billion nucleotides that make up human DNA

• Characterize variability in the genome• Identify all the genes in human DNA

• The Era of Genomic Medicine: – Improve prediction of drug efficacy or toxicity – Improve the diagnosis of disease– Earlier detection of genetic predisposition to disease

Human Genome Project

DNA is Information• DNA

• A, T, G, C

• Codon

• Gene

• Chromosome

• Genome

• ENGLISH

• Abcdefg….xyz

• Word

• Sentence

• Chapter

• Book

Mutation: difference in the DNA code that occurs in less than 1% of populationOften associated with rare diseases

Cystic fibrosis, sickle cell anemia, Huntington’s disease

Polymorphism: difference in the DNA code that occurs in more than 1% of the populationA single polymorphism is less likely to be the main cause

of a diseasePolymorphisms often have no visible clinical impact

Pronounced “snip”Single base pair difference in the DNA sequence

Over 2 million SNPs in the human genomeOther polymorphisms:

Insertion/deletion polymorphismsGene duplicationsGene deletions

Alleles = different DNA sequences at a locusCodon 389 1-AR

Arg (0.75)Gly (0.25)

Genotype = pair of alleles a person has at a region of the chromosomeCodon 389 1-AR

Arg389Arg Arg389Gly Gly389Gly

Population genetics:Family studiesTwin studiesAdoption studies

Epidemiologic studies:Genetic cohorts

Molecular methodsLinkage studiesAssociation studiesExpression studies(epigenetic

analyses)

Animal models

Population studies

Molecular methods

Candidate genes (polymorphisms)

biological hypotheses

Epidemiologic analyses Genetic Risk

Mental Mental IllnessIllness& &

GeneticsGenetics

SchizophrSchizophreniaenia Bipolar Bipolar DisorderDisorder

Alzheimer’s Alzheimer’s DiseaseDisease

DepressionDepression

Alzheimer’s Disease Age-relatedForgets entire experiences Forgets part of an experience

Is gradually unable to care for self

Is usually able to care for self

Rarely remembers later Often remembers later

Is gradually unable to follow written/spoken directions

Is usually able to follow written/spoken directions

Alzheimer dementia

● Main symptoms: Progressive deterioration of cognitive abilities, agitation, hallucinations.

● Neurodegenerative disease, EC: neuritic plaque, IC: neurofibrillar filaments, beta-amiloyd

● Familial AD (5%): mendelian transmission, dominant, early manifestation: APP (amyloid precursor protein), presenilin1, presenilin 2

● Sporadic AD (95%): polygenic, late-onset: apolipoprotein E e4 allele risk factor, GWAS replicated

● APP gene on chromosome 21- association with Down-trisomy

• Risk genes increase the likelihood of developing a disease, but do not guarantee it will happen.

• Scientists have so far identified one Alzheimer risk gene called apoliprotein E-e4 (APOE-e4).

• Deterministic genes directly cause a disease, guaranteeing that anyone who inherits them will develop the disorder.

• Rare genes that directly cause Alzheimer’s have been found in only a few hundred extended families worldwide.

• A gene on chromosome 19 involved in making ApoE, a substance that helps carry cholesterol in the bloodstream.

• The APOE e4 gene is considered a “risk factor” gene for AD and appears to influence the age of onset of the diesease.

• Genetic tests are available for both APOE-e4 and the rare genes that directly cause Alzheimer’s.

• Health professionals do not currently recommend routine genetic testing for Alzheimer’s disease.

*The serotonin transporter gene is linked to depression.*It controls two parts of the brain: amygdala and cingulate*Two types of this gene: the long and short version*Those with two copies of the long version show better connectivity between the amygdala and cingulate

http://www.nimh.nih.gov/science-news/2005/depression-gene-may-weaken-mood-regulating-circuit.shtml

*Identical twins have identical genetic material. -If twins are raised together and one twin develops

clinical depression, the other twin develops clinical depression 76% of the time.

-If twins are raised apart and one twin develops clinical depression, the other twin develops clinical depression 67% of the time*Shown to go through families*If a parent or sibling has had a major depression, the person may be 1.5 to 3 times more likely to develop depression

• Research• Twin Studies• Genes

– GRK-3 gene, chromosome 22

– FAT-1 gene, chromosome 4– AY070435 gene (Slynar),

chromosome 12• Thought to be on 18 & 21• Then 1, 6, 7, & 10, 22• 11 & X-Chromosome• Polymorphisms

Genetics of mood disorders

● Highly prevalent disorders (MDD~15%, BD~6%)● Familial transmission straightforward in BD (h2: 0.8,

MZ: 65%, DZ: 14%), moderate in MDD (h2: 0.39, MZ:50%, DZ:18%)

● GWAS studies yielded a few significant markers in BD with only 1 gene in concert with linkage results (CACNA1C, OR=1.14), again explaining only 2% of heritability variance

● No markers reached significance in MDD, and the main candidate gene (SLC6A4) association was dismissed by recent meta-analyses

Schizophrenia

● Main symptoms: delusions, hallucinations, disorganized thoughts and behavior

● Familial transmission is straightforward (heritability: 0.8, MZ twins: 48-59%, DZ twins: 16% concordance)

● Referred to as the totally unsuccessful example of linkage and association studies

● GWAS studies did not replicate previously implicated candidate genes, and significant markers only explain 3% of the heritability -> “missing heritability”

Heredity

• Researchers have found possible gene defects linked to schizophrenia on the following chromosomes:

1, 6, 8, 10, 13, 18, 22, and the X chromosome

• Polygenic: caused by a combination of gene defects

• Genes and Environment?