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
How do most phenotypes show a continuous variation (e.g. height)?
- some complex disease also show a spectrum of variation
- disease is controlled by multiple polygenes
- each allele segregates according to Mendelian laws
- Many polygenes + environment –> continuous phenotypic variation
How is there a threshold for developing disease?
- most diseases are discontinuous
- an individual either has or doesn’t have the condition
How can polygenic diseases show a continuous phenotype?
- continuous phenotype variation can arise
- in complex diseases many loci may contribute to this variation, leading to broad range of phenotypic variation
- environmental factors will also affect phenotype; the same genotype will display different phenotypes
- not all alleles will contribute the same risk
- an increase in the number of loci, the greater the distribution of variation
Do all alleles contribute the same amount of risk?
No - environmental factors can affect phenotype
How can complex diseases show a continuous phenotype?
- identified 44 significant risk loci for major depression
- all humans carry greater or lesser numbers of genetic risk factors
- associated with clinical features and included drug targets
What is the hypothesis for disease susceptibility?
- most diseases phenotypes are discontinuous
- polygenes and environment produce a distribution of liability
- the disease occurs when liability produce a distribution of liability
- the disease occurs when liability exceeds threshold
- relatives of affected individuals have an increased risk
What is evidence of threshold hypothesis?
Pyloric stenosis
- projectile vomiting after feeding in infants
- 5 times more common in male infants
- females have a higher liability threshold than males
- affected females carry more risk alleles
- relatives of affected females have greater risk than relatives of affected males
What are different possible architecture of complex diseases?
- small number of dominant alleles confer a larger risk - Parkinson’s
- common disease, common variant model (CDCV) - many alleles confer a small increase in risk - Type 2 diabetes
- intermediate - one major allele exerts a large effect, numerous lower risk alleles - breast cancer
