multifactorial disease Flashcards
how would you spot a multifactorial genetic disease?
twin studies and sibling relative tests
how would you spot genetic variants that contribute to multifactorial disease?
SNPs, halotyping, linkage disequilibrium, genome wide association studies
what are examples of multifactorial disease?
type 1 diabetes
schizophrenia
ageing muscular dystrophy
alzheimers
what does mendelian mean?
obeys mendels laws of segregation - dominant, recessive and X linked
what does complex mean?
tends to be used vaguely to describe something with an inherited but non mendelian component - multiple genes together with the environment
what is polygenic?
the result of the action of alleles of multiple genes - a disease that results from interaction of alleles of more than one gene
what does multifactorial mean?
the result of multiple factors including genetic and environmental factors
how can twin studies help to determine the genetic composition of multifactorial disease?
genetic characteristics should have a higher concordance in monozygotic twins than dizygotic
what is an atypical cluster headache?
a severe headache on one side of the head with a genetic component
how would familial clustering show the genetic composition of multifactorial disease?
look for the relative risk in those that are affected - take every individual known condition and look at siblings to see relative risk of sibling - see if there is an increased risk in those that share half a genome than those who do not
what would lambda s for siblings = 9 mean?
it would mean that if you are a sibling of someone with a disease who are 9 times more likely to get the disease than the general population
how can twin studies show there is an environmental risk?
for monozygotic if you share a genome there is only a 50% risk as there is also environmental factors
what is ascertainment bias?
when geneticists want to prove something is inherited so go out and look for a large family that this is the case for - may be a singular case and not standardised to population
why are genes known as additive instead of dominant or recessive?
they can combine with polygenic or complex or multifactorial inheritance and the different genes present add up - influenced by the environment, diseases can run in families but not simply in mendelian fashion
how are phenotypes determined?
determined by action of many different genes at different loci
what disorders how multifactorial inheritance?
congenital malformations, acquired disease of childhood and adult life, effects of the environment
what are some congenital malformations?
cleft lip/palate, congenital hip dislocation, congenital heart defects, NTDs, pyloric stenosis and talipes
what are acquired diseases of childhood and adult life?
asthma, autism, cancer, diabetes, epilepsy, glaucoma, hypertension, IBD, IHD and stroke, biploar, MS, PD, psoriasis, RA, schizophrenia
what is the effect of the environment on NTDs?
50-70% of NTDs can be prevented by maternal folic acid supplementation 1-3 months after conception
what do you inherit in alzheimers?
susceptibility
what is alzheimers?
it is the most common form of dementia over 40 years old resulting in the inability to cope, loss of memory and brain damage. It is due to the shrinkage of the brain, tangles of b-amyloid protein in nerve fibres of teh hippocampus.
what is familial clustering in alzheimers?
the relative risk to second sibling is 3-10
the early onset form of alzheimers is genetically heterogenous, what does this mean?
different genes may be involved in different families but will result in the same end stage symptoms.
what genes can be involved in genetic heterogenous alzheimers?
presenilin 1 and 2 both encode novel transmembrane aspartyl-proteases with g-secretase activity responsible for proteolytic cleavage of amyloid beta A4 precursor protein and NOTCH receptor proteins - missense mutation in APP
what has a large effect on the age of onset of alzheimers disease?
the sequence variants at the polymorphic locus - mostly due to apo-lipoprotein E which is implicated in heart disease
what are the three halotypes of APO-E proteins?
APO-EE2, APO-EE3, APO-E*E4
what is E2 and E4 involved in?
E2 - protective effect
E4 - earlier onset of alzheimers - E4/E4 homozygotes are affected much earlier than heterozygotes
what is the difference in codons between E2, 3 and 4?
position 112 and 158
2: 112 - cys and 158: cys
3: 112: cys and 158: arg
4: 112: arg and 158: arg
what is the relationship between magnitude of effect and frequency in population?
as magnitude increases frequency generally decreases - unusual for high magnitude effect and high frequency to exist due to natural selection
what does a genome wide association study do?
determine what causes the susceptibility and associated cases within 50-100kB of the allele - relate variation in human DNA sequence with disease or trait
what does the association method provide?
greater power to detect common genetic variants conferring susceptibility to complex phenotypes - estimates the population attributable risk and effect size
what is an SNP?
it is a common change in one nucleotide that are predominantely diallelic - >1% occur on average every 300 bases and account for 90% of human variation. They can causes disease (missense, nonsense, regulation) and can be non causal markers that tag haplotypes
what are the characteristics of a linkage study?
they are for recombination events in the family pedigree using 300-400 markers for genome coverage. There is a limited resolution and uses very polymorphic alleles - transmission of loci for diseases. It is powerful for rare variants
what is association mapping?
it exploits events in past generation and unrelated population samples. It has around 1 million markers for genome coverage and uses bi-allelic markers with a higher resolution. It is powerful for common variants and detects linkage disequilibrium
what is linkage disequilibrium and what does it result in?
it is when there is the non random association of two alleles at loci in general population - can indicate the genetic processes structuring population, meaning that when two alleles are in linkage disequilibrium the haplotypes do not occur at expected frequencies
what are population association studies for?
they are to identify patterns of polymorphisms that vary systematically ebtween individuals with difference disease states and therefore predict the effects of protective or susceptibility alleles
what is the basis of linkage disequilibrium?
that most disease bearing chromosomes in population are descended from one or few ancestral chromosomes - there will be the same mutation in current day chromosomes but with new stretches that are introduced with recombination
how can linkage disequilibrium affect association studies?
it can be used to indicate the genetic processes around disease and give power to association studies
what are the drawbacks of population association studies?
careful selection of the control group is essential, large numbers of cases are needed and association may depend on population history, multiple testing images
what does linkage disequilibrium between two alleles depend on ?
genetic distance, population history and time of mutation events
what are association targets?
the are linkage regions that may be large and pedigree specific
what are benefits of genome wide association studies?
non-parametric, objective
what is a manhattan plot?
visualisation of GWAS results, all SNP results are plotted on one graph - X axis shows the position in the genome and Y axis shows the significance
what is the a level in testing?
it is the probability of rejecting the null hypothesis given that it is true and is most often set at 0.05 for a single test
what does the bonferroni correction do?
sets the significance cut off at a/n (number of tests)
what does the bonferroni test assume?
all tests are independent of one another - not always the case in genetics due to linkage between SNPs
what are some reasons for genotype disease association?
the locus is a causal or functional variant - direct association
indirect association - there is linkage disequilibrium between locus and functional or causal variant
spurious association Type I error
population stratification (confounding)
systematic error (genotypes found differently)
replication in independent cohorts
what does the thrifty phenotype hypothesis say?
that there is a link between genes and environment - foetus is in harsh environment when maternal malnutrition resulting in foetal malnutrition - reduced B cell mass or islet function, reduced fetal growth, infant malnurtrition, reduced adult B cell function - non insulin dependent diabetes. Even when a foetus grows up then they will start to lay down fat as they get older so have a predisposition to T2 diabetes
what is age related macular degeneration?
it is the leading cause for irreversible central visual dysfunction cause by degeneration of the macula. It is characterised by the early deposition of drusen - a hallmark risk factor for AMD and has relatively simple multifactorial genetic traits - loss of central and colour vision - simplest multifactorial condition
what did GWAS find for AMD?
complement factor H is strongly associated with disease
what is assumed in sample sizes?
that there is a equal number of cases and controls to give a p value of 0.001
why is AMD so simple for multifactorial?
smoking and light exposure (70 increase in risk), CMF and ARMS2 genes
how can you identify genes involved in a disease?
association studies - genotype haplotypes SNPs in large cohorts
what is an allele?
a variant form of a gene or a genetic marker
what is association (genetic)?
when one or more genotypes co-occur within a population with a phenotypic trait, more often that would be expected by chance
what is a CNV?
a copy number variant is a genomic segment of at least 50 bps that differs in copy number based on the comparison of two or more genes
what is dominant?
the relationship between alleles of one genes, in which the effect of the phenotype of one alleles masks the effect of the other allele
what is a genotype?
it is the combination of alleles located on a homologous chromosome that determines a specific characteristic or trait
what is a haplotype?
a set of DNA variations or polymorphisms that tend to be inherited together
what is the hardy weinberg equilibrium?
the situation where the allele and genotype frequency remain constant in a population from generation to generation where there is an absence of other evolutionary influences
what is heritability?
a statistic used in breeding and genetics to estimate how much variation in a phenotypic trait in a population is due to genetic variation among individuals in that population
what are hyper-normal controls?
they are unaffected individuals that are selected from the extreme of a quantitative trait
what is microsatellite DNA?
tract of repetitive DNA in which certain DNA motifs are repeated, typically 5-50 times
what is recessive?
related to heritable characteristics that are only expressed in offspring when inherited from both parents
what is a genetic trio?
a set of three individuals that comprises a mother, father and their child
