Genetics of Complex Disease Flashcards
What are inter-individual genetic variations?
The variations in phenotypes between individuals.
What kinds of inter-individual genetic variations are there?
SNPs
Structural variants
What does SNP stand for?
Single nucleotide polymorphism
What are SNPs?
A genomic variant at a single base, differences in phenotypes.
Why are SNPs important?
Can act as biomarkers for disease.
Near a regulatory region can have a direct role in disease by affecting the gene’s function.
What genetics make us unique?
Physical traits
Disease susceptibility
Response to drugs/medicine
Why is genetic variation important?
Evolution
Explain the lactate example for genetic variation in disease in relation to evolution.
During starvation, adults with their lactate gene switched on after breastfeeding survived by drinking milk, whereas adults with the gene switched off got intolerance symptoms and died which left only the lactose tolerant left to breed.
What is the difference between an SNP and a mutation?
The frequency in a population, SNP is more than 1% MAF whereas mutation is less than 1%.
What are the characteristics of SNPs?
*Change in 1 single base in DNA sequence
*Heredity
- Most not functional
What does MAF stand for?
Minor allele frequency.
What does a SNP on a promotor region affect?
TF binding site
What is the effect of a SNP on the TF binding site?
Increase/Decrease in gene expression.
What does a SNP on a 5’ & 3’ UTR affect?
mRNA regulation
What is the effect of a SNP on the mRNA regulation?
mRNA stability.
Transcription regulation.
What does a SNP on a coding region affect?
synonymous
non-synonymous-missense
non-synonymous-nonsense
What effect does a SNP have on synonymous missense?
No AA change-silent
Genetic code degeneracy
What effect does a SNP have on non-synonymous missense?
AA change which leads to protein activity, stability, and regulation.
What effect does a SNP have on non-synonymous nonsense?
Create a premature STOP codon.
What would a SNP on an intron affect?
Splicing site
What is the effect of a SNP on a splicing site?
mRNA processing
What would an SNP on an intergenic affect?
Enhancer, or silencer.
What is the effect of a SNP on an enhancer/silencer?
Increase or decrease in gene expression.
What is crossing over?
In prophase I of meiosis, non-sister chromatids of homologous chromosomes can exchange genetic materials.
Why are SNPs important for inheritance of disease?
If an A allele in the ancestral chromosome increases the risk of a disease, the two individuals in the current generation who inherit that part of the ancestral chromosome will be at increased disease risk.
What are the 2 types of SNPs transmission?
Independent
Linked
What does it mean if transmission of SNP is independent?
Alleles do not travel together, due to
recombination in late prophase I generation and being too far apart forming new allele combinations.
What does it mean if transmission of SNP is linked?
SNPs are too close to be separated so no recombination occurs between SNPs. Allele combination occurs the same.
What is linkage disequilibrium?
The non-random association of alleles at different loci in a given population.
What is the linkage disequilibrium for a linked SNP transmission?
100%
What is haplotype?
Set of alleles at multiple loci located on the same chromosome that tend to be inherited together from a single parent because of genetic linkage.
What is the problem with allele transmission of a haplotype?
Alleles within an haplotype are in high LD and transmitted to offspring as a haplotype block.
What is the advantage of haplotype allele transmission?
Knowing the genotype of SNP1 suggest the genotype of the rest.
Define GENOTYPE.
DNA sequence at given locus
Define HAPLOTYPE.
Combination of genotypes from a group of genes (located on the same chromosome) and that are inherited together.
Define PHENOTYPE.
Physiological expression of trait, results from genotype + environmental influences.
What are the gene to environment interactions in multifactorial disease?
Same environmental stressors can have different effects on individuals with different alleles for a SNP.
SNP (allele) effect on disease risk can be modified by
environmental factor
What are the gene to gene interactions in multifactorial disease?
*SNP effect on disease risk can be changed by another SNP
*Susceptibility to diseases determined by combination of genotypes.
What epigenetic factors contribute to inter-individual variations?
Histone modification
DNA methylation
MicroRNA
How do histone modifications affect inter-individual variations?
Affect the extent to which DNA is wrapped around histones and gene regulation.
What is hypomethylation?
Increase in gene expression due to less methylation.
What is hypermethylation?
Decrease in gene expression due to more methylation.
What is the role of microRNA?
Promote mRNA degradation or suppression of protein translation.
What is the role of epigenetic mechanism?
Regulate gene expression levels independently of DNA sequence.
When do epigenetics turn genes off and on?
–Particular cell type
–Response to stimulus
–Distinct disease states
When are methylation patterns determined?
During embryogenesis and passed over to differentiating cells and tissues
What is embryogenesis?
Human embryonic development.
How are epigenetics affected during complex disorders?
*Affected by environmental stressors
*Altered in common complex disorders and modulate health outcomes
Why are epigenetics so important in complex disorders?
Heritable
Reversible changes in gene expression
Potential therapeutic target.
Why is it hard to isolate the effect of a single factor contributing to a complex disease?
– Difficult to discover and characterise
– Obscured or confounded by other contributing factors
What is important about studying the genetic factors of complex disease?
– Understand the mechanisms supporting disease development
– “Predict” disease risk in individuals
– Initiate prevention strategy
What are the approaches to studying the genome?
Genomics
Transcriptomics
Proteomics
Metabolomics
What can we achieve from the identification of susceptibility genes of a disease?
Novel biology insights
Personalised medicine
What are the advantages of novel bioglocial insights of complex diseases?
*Mechanisms involved in disease aetiology or normal tissue function
*Identification of biomarkers
*Novel therapeutic targets
What is the aim of Case-Control study & Genetic Association studies when investigating complex diseases?
Identify a genetic association between having a given genotype for a SNP and disease
What approach is used when searching for clinically relevant SNP when the genes involvement is known and the SNP function is known?
Candidate SNP approach.
What approach is used when searching for clinically relevant SNP when the genes involvement is known and the SNP function is unknown?
Pathway approach
What approach is used when searching for clinically relevant SNP when the genes involvement is unknown for both known and unknown SNP functionality?
Genome Wide Association Approach
What is know functionality?
Impact of SNP on function.
What is unknow functionality?
May or may not affect function
What is the candidate SNP approach?
- Aimed at finding a link between functional SNPs and a disease trait
- Select SNPs with a known function in genes that is involved in disease pathway
- Compare allele frequency between cases and controls
What is the study group in Candidate SNP approach?
Small to medium (100-1000s) and generally well defined.
What are the advantages of candidate SNP approaches?
Can be used to determine the interactions of the gene with other genes AND nutrients
Can use matching cases/controls for age, smoking, dietary factors, this excludes environmental projects.
Relatively cheap
What are the limitations of candidate SNP approach?
Selected SNPs may not be involved.
Requires prior knowledge about the function of SNP
and role of gene is disease mechanisms
Limited number of SNPs (1-20)
Study population’s characteristics limit extrapolation to whole population.
May be difficult to replicate in another pop.
What is the main thing that need to be considered when using the pathway approach?
Large number of SNPs studied
Why is the large number of SNPs studied such a big aspect of the pathway approach?
Multiple statistical tests are carried out which increases the risk of false positives.
Therefore the statistical power must be increased which uses a very large study population.
This means we must reduce the number of SNP to genotype.
Needs to use of TagSNPs.
What is the statistical power?
Power to determine whether or not there is a statistically significant association.
What is the purpose of TagSNPs?
Used to represent the genotype of all SNPs in the haplotype rather than targeting just one,
This limit genotyping cost and number of tests carried out.
What is the pathway approach?
Aimed at finding alleles in genes within a molecular pathway associated with a disease trait
Test association disease with all SNPs (tagSNP + functional SNPs) in all genes in a molecular pathway linked to a disease
Case/control study
What are the advantages of the pathway approach?
Tests interactions of gene with other genes as well as nutrients.
Includes functional SNPs
Can use matching cases/controls for age, smoking, dietary factors which eliminates environmental factors.
Still relatively cheap
What are the limitations of the pathway approach?
Pathway may not be involved, needs prior
knowledge
SNPs of known + unknown functionality
Study population’s characteristics limit extrapolation to whole population.
May be difficult to replicate in another pop.
What is the aim of Genome Wide Association studies (hypothesis-free)?
Identify (all) SNPs associated with a disease or a trait.
What is does it mean if an approach is hypothesis free?
Unbiased, requires no prior knowledge.
What does genome wide mean?
In theory, simultaneously genotype “all SNPs” in genome but in reality, only tagSNP ~ 1000s to 1-5M SNPs genotyped.
What are association studies
Cases/control association study
Statistical test for each locus to determine whether locus associated with disease trait
Requires very large populations.
What are the advantages of Genome Wide Association Approaches?
No prior knowledge required
Identification of novel associations with gene / SNPs
Info on potential molecular pathways
What are the limitations of Genome Wide Association Approaches?
Very expensive
Requires very large population
Limited by population’s characteristics- no matching cases/controls
Cannot test for gene interactions
What are some overall limitations of the SNP genotyping approaches?
Can’t be transferred between populations.
Gives nothing on functionality.
Doesn’t incorporate the effect of other factors
Why can’t results from genotyping SNPs be transferred between different populations?
Different allele frequency between populations
Different LD patterns between populations
Different risk factors for a given disease between populations
