12. Human genetics(4) Flashcards
What are the 3 possible genetic architecture of complex disease?
- Small number of dominant alleles confer a large increase in risk
- Common disease, common variant model- Many alleles confer a small increase in risk
- Intermediate- One major allele exerts a large effect, numerous other lower risk alleles
In which ways can SNPs occur in the coding region? (2)
- Synonymous (no change in encoded amino acid)
- Non-synonymous (e.g., missense or nonsense mutations)
(missense - change in encoded amino acid, nonsense - premature stop codon added)
What is an Exome Aggregation Consortium (ExAC)?
• Exomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies
- 7.4 million variants mapped
- records frequency of alleles in a population • documents rare mutations
- Highly pathogenic variants seen with a lower frequency in the general population
- gnomAD aggregates over 125,000 exome and 15,000 genome data sets
What are Genome Wide Association Studies?
- Examine a panel of SNPs in the genome for association with the disease phenotype.
- Search for alleles that occur more frequently in disease cases then in matched controls
- Requires many participants
- GWAS studies have been performed for most common diseases
- Many risk loci have yet to be identified
- Missing loci contribute to the “missing heritability problem
What is the purpose of Genome Wide Association Studies (GWAS)?
- GWAS compare the allelic frequency across the entire genome in case and control populations
- Significant differences in allelic frequency constitutes an association with disease
How SNPs are associated with disease? (2)
- The SNP itself can increase risk
* The SNP correlates with the risk allele due to linkage disequilibrium
What do association studies tell us?
Association studies can tell us if an allele is associated with a disease
What is Linkage disequilibrium (LD)?
The non-random association of alleles at different genomic sites
What does Linkage Disequilibrium depend on? (2)
o Distance between alleles
o Recombination rate
How can patterns of LD in the human genome be summarised?
summarised as haplotype blocks
How are alleles associated to the disease measured?
The likelihood of a SNP being associated with a disease is measured in an odds ratio (OR)
- OR = 1 Events are Independent
- OR > 1 Events are correlated
- OR < 1 Events are negatively correlated
What dos the Common disease common variant (CDCV) model of complex diseases mean?
multiple alleles with OR <1.2 showing weak association to the disease phenotype
What is required for an accurate genome wide association study? (2)
-Statistical significance is needed to differentiate true positives from false positives.
• Genome wide significance is where p value < 5x10-8
• 1 in 20 events are non-significant (nominal significance= 0.05)
-Very large numbers of participants are required
Is diabetes multifactorial (genetic and environmental)?
Yes
What can missing risk arise from (Not detected in GWAS) (5)
o False negatives in GWAS studies o Rare variant alleles with a MAF 1-5% o Structural alteration of the genome o Epigenetics o 3D genome organisation
