Multifactorial Disease Flashcards
What is the law of segregation?
Genes come in different versions, or alleles. A dominant allele hides a recessive allele and determines the organism’s appearance.
When an organism makes gametes, each gamete receives just one gene copy, which is selected randomly –> this is the law of segregation
What is a Mendelian disorder?
A type of genetic disorder primarily resulting due to alterations in one gene or as a result of abnormalities in the genome.
Dominant, recessive, X-linked
What is a polygenic disease?
A genetic disorder that is caused by the combined action of more than one gene
What is a multifactorial disease?
The result of multiple factors, usually including both genetic and environment factors
What are monozygotic twins? Dizygotic twins?
Monozygotic twins –> identical twins.
Dizygotic: –> non-identical twins.
Difference in fertilisation between mono and dizygotic twins?
Mono: They result from the fertilisation of a single egg that splits in two. Identical twins share all of their genes and are always of the same sex.
Di: They result from the fertilisation of two separate eggs during the same pregnancy.
How does being a MZ or a DZ twin affect disease rates?
Higher concordance rate for DZ and even higher for MZ twins for diseases such as cancer, hypertension, bipolar, cytomegalovirus
I.e. if you have a MZ twin with cancer, this increases your risk of getting cancer
What does λs stand for?
The relative risk to the second sibling
What is familial clustering?
Familial clustering of a disease is defined as the occurrence of the disease within some families in excess of what would be expected from the occurrence in the population.
Example: schizophrenia
If the risk to the general population is 1% and the risk to siblings is 9%, what is λs?
λs = 9
As there is a 9 fold increase in risk
How do neural tube defects show multifactorial inheritance?
What is the effect of the environment here?
Partly due to genetics and partly due to the environment
50-70% of NTDs can be prevented by maternal folic acid supplementation 1m before conception to 3m after conception
What is the λs in Alzheimer’s?
3 to 10
What is early onset of Alzheimer’s now known to be?
Genetically heterogenous
Three causative genes have been associated with INHERITED autosomal dominant familial AD and 1 genetic risk factors.
What are these?
Causative genes; APP, PSEN1 and PSEN2
Risk factor; APO-e4
Is Alzheimer’s genetic?
The genes you inherit from your parents can contribute to your risk of developing Alzheimer’s disease, although the actual increase in risk is small. But in a few families, Alzheimer’s disease is caused by the inheritance of a single gene and the risks of the condition being passed on are much higher.
What gene implicated in heart disease plays a role in protecting against Alzheimer’s?
Apo-lipoprotein E (APOE) –> having a highly functioning APOE seems to be protective against Alzheimer’s
APOE is polymorphic. What does this mean?
Exists in different forms
What are the 3 types of APOE?
APOEE2
APOEE3
APOE*E4
What form of APOE seems to be less effective, and therefore a risk factor for Alzheimer’s?
APOE*E4
How does having 2 copies of E4/E4 vs E2/E3 affect chance of Alzheimer’s?
- Risk for late-onset AD increases
- Mean age of onset decreases
- Risk is increased further still if there is high blood pressure
What is the most common genotype in the population regarding APOE?
E2/E3
What is an association study?
An approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease.
What is the purpose of a genetic association study?
Seeks to relate variation in human DNA sequence with a disease or trait.
Controls vs patients
Benefit of association method?
Provides greater power to detect common genetic variants conferring susceptibility to complex phenotypes
What does an association study estimate?
Estimates population attributable risk (effect size)
What should the controls be representative of in an association study?
Controls should match cases (as alike to patients as possible) and be a representative sample of the population.
What would whole genome association study (WGA) show for Alzheimer’s?
Huge presence of APOE-E4 allele in AD patients vs control
How can SNPs be used in GWA?
Studies identify SNPs and other variants in DNA associated with a disease, but they cannot on their own specify which genes are causal.
Look at SNPs spread across all of the 22 autosomes and look for differences between cases and controls.
Can see if there is a SNP causing a disease, or NEAR to something causing a disease
What are SNPs?
Single nucleotide polymorphisms
Is a variation at a single nucleotide (A, C, T, G) in a DNA sequence among individuals.
If this variation is present at >1% of a population, then this variation can be classified as a SNP.
SNPs are predominantly diallelic. What does this mean?
If a SNP occurs within a gene, then the gene is described as having more than one allele (i.e. 2 different alleles)
Are SNPs only associated with genes?
No, they can also occur in noncoding regions of DNA.
How can SNPs cause disease?
Can lead to missense, nonsense, regulation mutations
What is a regulatory mutation?
Loss of an enhancer element - is called a regulatory mutation. It affects the spatial or temporal regulation of the gene.
All the SNPs from the results of a GWA study are plotted on one graph.
What is the x-axis?
What is the y-axis?
What is this plot called?
X-axis: shows the position in the genome (i.e. chromosome number 1-22)
Y-axis: shows the significance (-log10 of the p-value)
Called the Manhattan plot
What is the Bonferroni correction?
Method used to counteract the problem of multiple comparisons.
This correction assumes all tests are independent of one another and this is frequently not the case in genetics (e.g. testing multiple SNPs across one gene with strong linkage)
What is an allele?
A variant form of a gene
What is association (genetic)?
When one or more genotypes within a population co-occur with a phenotypic trait, more often than it would be expected by chance
What is CNV?
Copy number variation (CNV): A genomic segment of at least 50 bp that differs in copy number based on the comparison of two or more genomes
What is a haplotype?
A set of DNA variations, or polymorphisms, that tend to be inherited together (from same chromosome)
What is age-related macular degeneration (AMD)?
It’s the leading cause of severe, permanent vision loss in people over age 60. It happens when the small central portion of your retina, called the macula, wears down.
Characterised by the early deposition of drusen, a hallmark risk factor for AMD
AMD is multifactorial. What are the genetic components?
Major effects: CFH (1q), ARMS2 (10q)
Risk alleles in these genes
What are the environmental factors of AMD?
Smoking (major effect)
Light exposure (medium effect)
What is linkage disequilibrium?
Refers to the non-random association of alleles at two or more loci in a general population. When alleles are in linkage disequilibrium, haplotypes do not occur at the expected frequencies.
How is linkage disequilibrium implemented in GWA studies?
GWA studies detect an excess of SNP variants in linkage disequilibrium with variants that increase the risk of the disease in patients.
I.e. its not the SNPs that are being tested, its the SNPs nearby –> an association signal (nearer they are, bigger the effect)
On a Manhattan plot, what is the significance threshold?
p = 5x10^-8
Why is this the threshold for a Manhattan plot?
It is necessary to correct for multiple testing
