Lecture 15 - complex diseases Flashcards
What is a complex disease?
- complex diseases are common (66% lifetime risk)
- multifactorial
- i. polygenic
- ii. environmental
Identified risk alleles susceptibility - are NOT deterministic
Are familial
What are examples of complex diseases?
- Obesity
- Rheumatoid arthritis
- Insulin dependent diabetes (Type 1)
- Insulin independent diabetes (Type 2)
- multiple sclerosis
- premature cardio-vascular disease
- epilepsy
- peptic ulcer
- hyperthyroidism
- certain cancers
What are complex psychiatric conditions?
- Alzheimer’s
- Bipolar affected disorder
- Depression
- Tourette’s syndrome
What are complex congenial disorders?
- cleft lip & palate
- neural tube defects
- pyloric stenosis
Why identify genetic components of complex diseases?
- early diagnosis and treatment
- will allow lifestyle changes to lower risk
- help understand the molecular basis to develop therapeutics
Describe how we identify susceptibility or risk alleles
- 11-15 million common variants - single nucleotide polymorphisms (SNPs)
- SNPs found in both coding and non-coding regions of genome
- Minor allele frequency (MAF) is the second most common allele in a population
- Common SNP’s MAF >5%
- Rare SNPs MAF <5%
- the risk conferred by each SNP can be small
- correlation between genotype and disease phenotype can be weak
- identifying alleles which increase risk requires large number of individuals
What are 2 methods to find risk alleles in complex disease?
- Family based Linkage analysis
- Genome-wide association studies (GWAS)
What is family based linkage analysis as a method to find risk alleles in complex disease?
looks for linkage between mapping markers and occurrence of disease in families
What is a negative about family based linkage analysis?
usually has a small sample size
What is genome-wide association studies (GWAS)?
- search for alleles in a population that occur more frequently in disease cases then in matched controls
- more powerful at identify rare risk alleles and those that contribute a small increase in risk
What is phenotypic variation?
the sum of genetic and environmental variation
phenotypic variance = genetic variance + environmental variance
What is heritability?
the degree of variation within a population that is due to genetic variance
Heritability = Genetic variance/Phenotypic variance
Is heritability of a disease a fixed number?
no, as it can change depending on population assessed and the environment they are in
What does a higher heritability score mean?
a higher heritability score - the greater the genetic contribution. However, environmental factors can still influence likelihood of disease
How can heritability be experimentally determined?
Twin studies allow the effect of genetics (heritability) and environment on phenotypic variance
What are the 2 types of twin studies?
- monozygotic twins (MZ)
- dizygotic twins (DZ)
Describe monozygotic twins
- identical twins
- share - 100% of genes
- shared environment
Describe dizygotic twins
- non-identical twins
- share - 50% of alleles
- shared environment
Assume equal environment influence for identical & non-identical twins
Describe twin studies
ACE model of phenotypic variance - what proportion of variance is genetic & environmental
- Genetic variance of heritability (A)
- Common environment variance (C)
- Specific environmental variance (E)
What is concordance in twin studies?
the % of identical or non-identical twins that share phenotype/disease
What is the correlation of Monozygotic twins?
Genetic (100%) + C (common environment)
What is the correlation of Dizygotic twins?
Genetic (50%) + C (common environment)
What is concordance a measure of?
Difference in concordance between indelicate and non-identical is a measure of the effect of 50% of genes on variation in the population
- the greater the difference in concordance between mono and dizygotic twins, the greater the heritability of the trait
Describe phenotypic variation in complex disease
- most phenotypes show a continuous variation (e.g. height)
- threshold for developing disease
