Genetic Epidemiology Flashcards
what does genetic epidemiology study
influence of genes and environment on measures of health and disease susceptibility in populations
uncover the role of genetic factors in determining health and disease
outline basic genetics DNA
DNA is series of nucleotides - adenine, guanine, cytosine, thymine
genome = 23 pairs of chromosomes - 1 pair sex chromosome
what is an allele
alternative form of genetic material at a locus
what is a genotype
combination of alleles at a locus (different chromosomes)
what is a haplotype
combination of alleles at different loci (same chromosome)
how identical are genetic sequences of unrelated humans
99.9% identical
the differences are mostly single nucleotide polymorphisms
what are single nucleotide polymorphisms
deletions
inversions (opposite sequence)
copy number variants or short tandem repeats
what is a polymorphism
a DNA variation that is relatively common in the population
what is a mutation
DNA variation that is relatively rare in the population
what is the mechanism of inheritance
each organism carries two factors that determine together the organisms phenotype
an adult organism can only transmit one of the two factors to each of its offspring
what is Mendels law of segregation
when a parent passes one of their two inherited alleles to offspring, these are transmitted with probability 0.5
what is Mendels law of independant assortment
alleles located sufficiently far apart (or on different chromosomes) will be inherited independantly of eachother
in families though this depends on physical proximity of loci on the DNA strands
what is Mendels law of dominance
interaction between the two alleles of a gene in a given individual such that the dominant allele masks the influence of the recessive allele on the individuals phenotype
outline dominant and recessive disorders
dominant - one disease allele required for an individual to get the disease
recessive - two disease alleles are required for an individual to get the disease
what is the first step to identifying disease in genetics
family aggregation studies
clustering of disease within families
family history
measured by relative recurrence risk (RRR) or familial risk ratios (FRR)
are family aggregation studies sufficient to infer the importance of genetic susceptibility?
no
environmental and cultural influences can aggregate in families and increase risk
what is monogenic
one gene with a large effect
what is oligogenic
few genes each with a moderate effect
what is polygenic
many genes each with small effect
what is non-classical inheritance?
mitochondrial diseases, genomic imprinting
what is the purpose of genetic linkage studies
associate functionality of genes to their location on chromosomes - find the location of disease genes
what is the purpose of genetic association studies
find candidate genes or genome regions that contribute to specific disease by testing for correlation between disease status and genetic variation
outline linkage analysis
large pedigrees each containing affected individuals
tests the hypothesis that a particular locus is linked to a locus that causes disease
outline co-segregation of linkage studies
co-transmission
of alleles at 2 or more genetic marker loci
alleles at markers close together tend to be transmitted together
there will be correlation between disease alelles and phenotype resulting in co-segregation of alleles at other locus
outline genome association analysis
determine whether particular genetic variant influences risk of developing disease
is association is present allele will be seen more often than expected
indicates direct or indirect causal relationship. and is a statistical finding
what are the main types of genetic association study
family based
case/control
total association
outline family based genetic association analysis
investigate transmission of particular high risk alleles through a number of pedigrees
avoids problem of population heterogeneity
outline case/control studies as genetic association analysis
compare distribution of alleles or genotype at locus in affected and unaffected people or population-based control sample
easy to collect
outline total association studies as genetic association analysis
e.g all individuals with quantitative trait
need to account for correlations in genotype and phenotype due to relatedness
what does the word linkage refer to
the relationship of loci
what are genome wide association studies
examination of many common genetic variants in a group of individuals to see if any variant is associated with a trait
what is linkage disequilibrium
correlation between alleles at 2 or more loci that lie close together at population level
occurs due to consideration of population history as in the past everyone had identical haplotypes at any given stretch of DNA
new alleles arise due to rare mutations
over generations LD decays as recombination breaks up haplotype as new mutations occur
how do we visualise linkage disequilibrium
haplotype blocks
haplotype = set of SNP on single chromatid of chromosome pair which are statistically associated
haplotype blocks = regions over which there is little evidence for historical recombination only few common haplotypes observed
outline tagging SNPs
if 2 SNP are in strong LD then genotype at SNP2 will be predicted by genotype at SNP1
they can be correlated with disease phenotype
can pick a reduced set of SNPs to genotype that provide us with as much info as the full set
what statistic does GWAS provide
p value
GWAS requires stringent significance levels to overcome the multiple testing problem when we test too many SNPs
what is needed for GWAS to be valid
large sample size (1000s of individuals) to have sufficient power and detect a true association
what do we expect to see in GWAS at any location showing significant association
several SNPs in same region showing association with phenotype due to correlation (LD) between neighbouring SNPs
what is used in GWAS to visualise the strength of association
Manhattan plots
why should we identify environmentally modifiable factors that influence disease risk (mendelian randomisation)
it is fundamental to public health improvement strategies
outline models of gene environment interaction
- genotype exacerbates effect of risk factor e.h UV radiation, genetic mutation, skin cancer
- risk factor exacerbates effect of genotype mutation, baribiturates, skin irritation
- both genotype and risk factor are required
- genotype and risk factor influence independantly e.g mutation of clotting factor V Leiden, oral contraceptive pill -> thrombosis
what is the gold standard for mendelian randomisation
randomised controlled trials
but its expensive and could require very long follow up
not every intervention is ethical
outline mendelian randomisation
its a method of assessing the causal nature of some environmental exposures in observational studies
based on Mendel’s law of segregation, instead of randomising, populations are separated according to their genetic profile
genetic variation is NOT influenced by life style, geographical or other confounding factors
what statistical method is mendelian randomisation
it is an instrumental variable (IV) analysis
instrument is a variable that is only related to the outcome through its association with exposure
MR uses genetic variants as IVs
what is the future of genetic epidemiology
identification of genetic factors affecting disease prognosis
understanding the contribution of different aspects of genetics - copy number variation, epigenetics, rare variants
refine risk estimates
use genes as tools to better understand the environmental processes
