Multifactorial Inheritance Flashcards
Genetics cause…
Down syndrome
Cystic fibrosis
Huntington disease
Haemophilia
Environmental (malnutrition,trauma)
Poor diet
Infection
Drugs
Accidents
In between genetic and environmental (Multifactorial)
Spina bifida
Cleft lip/palate
Diabetes
Schizophrenia
Hypertension
Definition of Multifactorial
Diseases that are due to a combination of genetic and environmental factors
Most common diseases are Multifactorial
If the condition is more common in one particular sex, the relatives of an affected individual of the less frequently affected sex will be a higher risk than relatives of an affected individual or the more frequently affected sex i.e if a boy has the condition then female relatives are more at risk and vice versa.
How do you identify that a condition has a
genetic component?
By clinical observation
Family studies
Twin studies
Adoption studies
Family studies- is when the incidence of a disease is compared amongst the relatives of the affected individual with the general population
In Multifactorial condition:
The risk of the condition in relatives of an affected individual is dramatically higher than in the general population
the risk varies directly with the degree of genetic relationship
the risk varies with the severity of the proband’s illness
Proband: person serving as the starting point for the genetic study of a family
the risk varies with the number of relatives affected
Monozygotic twins
Genetically identical
Dizygotic twins
Genetically non identical twins
Concordance
The inheritance by two related individuals of the same genetic characteristics
concordance rate
the % of twin pairs studied that both have the condition.
The concordance rates give a rough figure for the hereditability of a multifactorial disorder
If a condition has a genetic component you would expect the concordance rate to be higher in monozygotic twins than in dizygotic twins
The high risk for MZ twins is found even when they are reared apart
Adoption studies
adopted children of a parent with a multifactorial condition have a high risk of developing the disease
Can look at adopted individuals with a condition and look at the rates of that condition in the biological and adoptive families
high in the biological families only
Hereditability
The proportion of the aetiology (causes) that can be ascribed to genetic factors as opposed to environmental factors
Heritability is expressed as…
as a proportion of 1 or as a percentage e.g.in schizophrenia hereditability is about 0.85 or 85%
Can calculate heritability from…
the concordance rate in monozygotic twins
Characteristics of Multifactorial
Inheritance
• The incidence of the condition is greatest amongst relatives of the most severely affected patients
• The risk is greatest for the first degree relatives and decreases rapidly in more distant relatives
• If there is more than one affected close relative then the risks for other relatives are increased
Characteristics of Multifactorial Inheritance
If the condition is more common in one particular sex, then relatives of an affected individual of the less frequently affected sex will be at higher risk than relatives of an affected individual of the more frequently affected sex.
The Liability / Threshold Model
Look on GoodNotes ppt (slide 12)
The Liability / Threshold Model
The factors that influence the development of a multifactorial disorder, genetic and environmental can be considered as a single entity known as liability
Curve:
the liabilities of all individuals form a continuous variable which has a normal distribution
the curve for relatives is shifted to the right compared to the general population
the closer the relationship the greater the shift to the right
a threshold exists above which the abnormal phenotype is expressed
in the general population the proportion beyond the threshold is the population incidence and among relatives is the familial incidence
GWAS – Genome wide association studies
Utilises the fact that a gene can have several variants –alleles
Pathogenic
Some variations in a gene cause that gene to be inactivated or behave abnormally
Polymorphisms
frequent hereditary variations at a locus
Doesn’t cause problems (thats mutations)
Polymorphisms can be you more/less efficient or make you more/ less susceptible to disease.
When Most genetic variation still results in a functioning gene
Different types of polymorphisms
SNPs (single nucleotide polymorphisms)
Differing lengths of a CA repeat.
GWAS (example of prostate cancer in ppt slide 18)
compare the frequency of markers in a sample of patients and a sample of healthy controls.
Can use candidate genes or nowadays try to aim for complete coverage of the genome
Look for markers e.g. a SNP that is seen more frequently in the disease population
Sequence that area to try to identify the gene and the particular allele that is associated with the increased likelihood of developing the condition
Neural Tube Defects (image on slide)
Defective closure of the developing neural tube during the first month of embryonic life
Environmental factors
poor socioeconomic status
multiparity
valproate.
Recurrence risks are about 4-5 % without treatment, highest in people of Celtic origin.
In Ireland about 10% of cases can be attributed to mutations in the methylenetetrahydrofolate (MTHFR) gene which leads to decreased plasma folate levels.
Periconceptual folate supplementation reduces recurrence risk to about 1%
Environmental Agents acting on embryogenesis (images on slide)
Drugs and Chemicals e.g. thalidomide,
anticonvulsants, alcohol
Maternal Infections e.g. rubella, CMV
Physical Agents e.g. radiation
Maternal Illness e.g. diabetes, phenylketonuria
Post-natal Environmental Factors
Type 2 diabetes- Obesity
Breast cancer- Hormonal factors: The pill, HRT, parity, breast feeding, obesity
Lung cancer-Smoking
Schizophrenia– Recreational drugs
Using DNA:
What your DNA says about you
Carrier status- Find out if your children are at risk for inherited conditions, so you
can plan for the health of your family.
Health risks
Drug response- how your body will respond to drugs
Autosomal
Chromosomes 1-22, all chromosomes except the sex chromosomes (XY)
Locus
The position of a gene/DNA on the genetic map.
Genotype
genetic constitution of an individual
Phenotype
Appearance of an individual which results from the interaction of the environment and the genotype
Variable expression
Variation in clinical features (type and severity) of a genetic disorder between individuals with the same gene alteration
Sex limitation
Expression of a particular characteristic limited to one of the sexes
Late-onset
Condition not manifested at birth (where it does this is called congenital).
Classically adult-onset e.g Huntington’s
Barrbody
inactive X chromosome since packaged in heterochromatin (cannot be transcripted)
Khudson’s 2-hit hypothesis
Gene mutations may either be inherited or acquired during a persons life
• Sporadic cancers = 2 acquired mutations
• Hereditary cancers = 1 inherited mutation + 1 acquired mutation
Ideogram
diagrammatic form of chromosome bands, bands are numbered according to distance to centromere
