Lecture 15: Multifactorial diseases Flashcards
What is Medilian?
obeys Mendel’s laws of segregation – dominant, recessive, X-linked
What is meant by the word complex?
tends to be used vaguely to describe something with an inherited but non-Mendelian component
What is polygenic?
the result of the action of alleles of multiple genes
What is multifactorial?
– the result of multiple factors, usually including both genetic and environmental factors
Does a multifactorial disease have a genetic
component?
1) Twin Studies
2) Familial clustering
Are multifactorial common or rare?
Rare
What is unique about twin studies?
Twin studies: genetic characters should have a higher concordance in monozygotic (identical) than dizygotic (non-identical) twins…
What is familial clustering?
the clustering of certain traits, behaviours, or disorders within a given family. Family aggregation may arise because of genetic or environmental similarities
Risk of Cancer between twins?
Normal rate of cancer = 32%
Non - identical twins risk of cancer = 37%
Identical twins risk of Cancer = 46%
Risk of Cancer between twins?
Normal rate of cancer = 32%
Non - identical twins risk of cancer = 37%
Identical twins risk of Cancer = 46%
Risk of hypertension between twins?
Normal risk of hypertension = 36%
non identical risk of hypertension = 48%
identical risk of hypertension = 62%
multifactorial inheritance: Congenital malformations?
cleft lip/palate, congenital hip dislocation, congenital heart defects, neural tube defects, pyloric stenosis, talipes
Multifactorial inheritance: Acquired diseases of childhood and 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
Alzheimer disease key concepts?
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
Which haplotype increases susceptibility of Alzheimer’s disease?
*E4 haplotype confers increase in susceptibility
early onset at 68 rather than 84
What alleles effect people with Alzheimer’s disease earlier on in their life?
E4/E4 homozygotes are affected much earlier than heterozygotes
early onset at 68 rather than 84
risk is increased still further if there is high blood pressure
What are the Mapping strategies for Mendelian Vs Multifactorial traits/diseases?
Function study
Linkage analysis
Association Study
What is the aim of Genetic association studies?
Genetic association studies seek to relate variation in human DNA sequence with a disease or trait
What is the aim of an association method?
Association method provides greater power to detect common genetic variants conferring susceptibility to complex phenotypes
Estimates population attributable risk (effect size)
What should control studies match?
Controls should match cases and be a representative sample of the population.
Example of Control study?
100 individuals = 1% affected
Example of a patient study?
100 individuals = 100% affected
What is a single nucleotide polymorphism?
A difference at a single nucleotide
What are SNPs predominantly?
diallelic
What can a SNP lead to?
Can cause disease (missense, nonsense, regulation)
Can be non-causal markers that tag haplotypes
What percentage is SNPs responsible for genetic variation?
90%
How abundant are SNPs?
- SNPs with MAF ≥ 1% occur on average every 300 bases
What have linkage disequilibrium and population association studies lead found?
most disease bearing chromosomes in population are descended from one (or a few) ancestral chromosomes
can detect association to <2-3 cM
What are the draw back to Linkage disequilibrium and population association studies
drawbacks are that careful selection of the control group is essential, large numbers of cases are needed and association may depend on the population history
What is Linkage disequilibrium?
the occurrence in members of a population of combinations of linked genes in non-random proportions
