Genetics of common disease Flashcards
Familial clustering
Phenotypes and disorders, that occur more likely in families than unrelated individuals
Genes and the environment
They don’t occur with single gene/mendelian disorders - they occur with a mixture of genes and environment
Main point
A person will have a complex disorder/trait if they have the right combination of genetic differences and environmental exposures.
Twin studies
Monozygotic twins - Share 100% of germline genetic variation
Dizygotic twins - Share 50% of germline genetic variation
Estimating heritability
Heritability (h2) is the proportion of variation in a trait explained by inherited genetic variants
Correlation
1 indicates a strong positive relationship
-1 indicates a strong negative relationship
0 indicates no relationship at all
Electrocardiogram
- Cardiac conductivity : ElectroCardioGram
* ECG Intervals measured in ms
Heritability of cardiac electrical function
h2 scored between 0 and 1
High heritability = strong resemblance
What do you do after heritability?
GWAS
Once you have determined that a phenotype/disease is influenced by genetic variation i.e. the trait heritability is >0.4 the next step is to identify what that genetic variation is.
Heritability - genetic susceptibility
13,000 adult same-sex twins from the UK, recruited since the 1990s.
>3000 traits have been measured in these twins.
Many published heritability studies.
Genetic association study
What are the genetic variants that are associated with variation in human disease risk, or a human trait/phenotype?
Categorical: disease yes/no
Continuous: BMI, heart rate, height
Common variation
Our genomes vary from person to person.
Often, a difference will be in just one base pair.
These variations are called:
SINGLE-NUCLEOTIDE POLYMOPRHISMS (SNPs)*
They are the most common variation in human genome.
Genotyping loads of SNPs
Commercial probe-based SNP array platforms (e.g. Illumina) can now genotype, with >99% accuracy, about one million SNPs in an individual in one assay.
Linkage disequilibrium and SNP array design
Rather than directly measuring genotypes at all genetic polymorphisms, we rely on association between the polymorphisms we do assay and those which we do not assay.
SNP-SNP association, or linkage disequilibrium (LD), is fundamental to our ability to sample the whole genome with relatively few SNPs.
Linkage disequilibrium
Linkage Disequilibrium is defined as the difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association.
LD and SNPs
In general, LD between two SNPs decreases with physical distance as more likely to have a recombination event between them.
Extent of LD varies greatly depending on region of genome i.e. recombination hot spots.
If LD strong, need fewer SNPs to capture variation in a region – cheaper and easier/quicker to analyse.
The first SNP chips had at least 317,000 SNPs distributed across the genome.
Newest: >1 million.
GWAS
Variants associated with the disease/trait (or within the same haplotype as a variant associated with a disease), will be found at a higher frequency in cases than in controls.
Statistical analysis is carried out to indicate how likely a variant is to be associated with a trait.
Goal of GWAS
• Identify genetic regions that explain differences in phenotype among individuals in a study population
i.e. to better understand the biology of the disease/phenotype
• To identify genetic variants that can be measured to determine whether an individual is at higher risk of disease
• To identify potential drug targets to treat the disease
