L4- multifactorial disease Flashcards
What is meant by the term Mendelian?
Means that a certain disease obeys Mendel’s laws of segregation for example it being: dominant, recessive, X-linked
What is meant by the term Complex?
Describes something with an inherited but non-Mendelian component
What is meant by the term Polygenic?
The result of the action of multiple genes
What is meant by Multifactorial?
the result of multiple factors, usually including both genetic and environmental factors
Useless question?: What does the sign Lambda s mean?
Relative risk to 2nd sibling
Does a multifactorial disease have a genetic
component? Example of twin studies…
Twin studies: genetic characters should have a higher concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins
What are the issues with twin studies?
- large differences in birth weight for MZ twins (ie differences in prenatal environment of each twin)
- variation in the time of splitting of the early embryo
- diamniotic monozygotics (with separate amniotic cavities) survive much better than monochorionic
Issues with adoptive studies?
-child is put into a totally different environment to its birth environment because of adoption
- share genes but not environments with the biological parents
- share environments but not genes with their adoptive parents
- BUT still share uterine environment
What are the human characteristics with multifactorial Inheritance?
- Phenotypes determined by action of many genes at different loci
- Genes are not dominant or recessive but additive
- Includes many human traits/common diseases; blood pressure, head circumference, height, intelligence
- traits tend to be normally-distributed in the general population ie forms a Gaussian “bell-shaped curve”
Examples of disorders which show multifactorial inheritance
-Congenital malformations: cleft lip/palate, congenital hip dislocation, congenital heart defects, neural tube defects, pyloric stenosis, talipes
-Acquired diseases of childhood & adult life:
asthma, autism, cancer, diabetes mellitus, epilepsy, glaucoma, hypertension, inflammatory bowel disease (Crohn disease), ischaemic heart disease & stroke, bipolar disorder, multiple sclerosis, Parkinson disease, psoriasis, rheumatoid arthritis, schizophrenia
-Effect of the environment
E.g like NTD (neural tube defects) maternal folic acid insufficiency
What is the purpose of Genetic association studies ?
To relate variation in human DNA sequence with a disease or trait
Association method provides greater power to detect common genetic variants conferring susceptibility to complex phenotypes
Estimates population attributable risk
Frequency in population vs magnitude of effect of multifactorial traits/diseases
see slide 15
Linkage disequilibrium can occur in population association studies …why?
Because most disease bearing chromosomes in population are descended from one (or a few) ancestral chromosomes, therefore present day individuals can be affected by these chromosomes
Alzheimer’s Disease
most common form of dementia >40 yr
symptoms: inability to cope, loss of memory, brain damage
neurology: shrinkage of brain, tangles of b-amyloid protein in nerve fibres of hippocampus
Important genes: presenilin 1 (PSEN1) and presenilin 2 (PSEN2) for transmembrane aspartyl-proteases
g-secretase activity responsible for proteolytic cleavage of amyloid beta A4 precursor protein (APP) and NOTCH receptor proteins
missense mutations in APP lead to a build up
APOE haplotypes
APOE has three haplotypes: APOEE2, APOEE3, and APOE*E4
*E4 haplotype confers increase in susceptibility
*E2 haplotype confers a protective effect
E4/E4 homozygotes are affected much earlier than heterozygotes
E2/E3 vs. E4/E4:
risk for late-onset AD increases 20 → 90%
mean age of onset decreases 84 → 68 years
risk is increased still further if there is high blood pressure
