Genetic Epidemiology

Question 1

what does genetic epidemiology study

Answer 1

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

Question 2

outline basic genetics DNA

Answer 2

DNA is series of nucleotides - adenine, guanine, cytosine, thymine
genome = 23 pairs of chromosomes - 1 pair sex chromosome

Question 3

what is an allele

Answer 3

alternative form of genetic material at a locus

Question 4

what is a genotype

Answer 4

combination of alleles at a locus (different chromosomes)

Question 5

what is a haplotype

Answer 5

combination of alleles at different loci (same chromosome)

Question 6

how identical are genetic sequences of unrelated humans

Answer 6

99.9% identical
the differences are mostly single nucleotide polymorphisms

Question 7

what are single nucleotide polymorphisms

Answer 7

deletions
inversions (opposite sequence)
copy number variants or short tandem repeats

Question 8

what is a polymorphism

Answer 8

a DNA variation that is relatively common in the population

Question 9

what is a mutation

Answer 9

DNA variation that is relatively rare in the population

Question 10

what is the mechanism of inheritance

Answer 10

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

Question 11

what is Mendels law of segregation

Answer 11

when a parent passes one of their two inherited alleles to offspring, these are transmitted with probability 0.5

Question 12

what is Mendels law of independant assortment

Answer 12

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

Question 13

what is Mendels law of dominance

Answer 13

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

Question 14

outline dominant and recessive disorders

Answer 14

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

Question 15

what is the first step to identifying disease in genetics

Answer 15

family aggregation studies
clustering of disease within families
family history
measured by relative recurrence risk (RRR) or familial risk ratios (FRR)

Question 16

are family aggregation studies sufficient to infer the importance of genetic susceptibility?

Answer 16

no
environmental and cultural influences can aggregate in families and increase risk

Question 17

what is monogenic

Answer 17

one gene with a large effect

Question 18

what is oligogenic

Answer 18

few genes each with a moderate effect

Question 19

what is polygenic

Answer 19

many genes each with small effect

Question 20

what is non-classical inheritance?

Answer 20

mitochondrial diseases, genomic imprinting

Question 21

what is the purpose of genetic linkage studies

Answer 21

associate functionality of genes to their location on chromosomes - find the location of disease genes

Question 22

what is the purpose of genetic association studies

Answer 22

find candidate genes or genome regions that contribute to specific disease by testing for correlation between disease status and genetic variation

Question 23

outline linkage analysis

Answer 23

large pedigrees each containing affected individuals
tests the hypothesis that a particular locus is linked to a locus that causes disease

Question 24

outline co-segregation of linkage studies

Answer 24

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

Question 25

outline genome association analysis

Answer 25

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

Question 26

what are the main types of genetic association study

Answer 26

family based case/control total association

Question 27

outline family based genetic association analysis

Answer 27

investigate transmission of particular high risk alleles through a number of pedigrees avoids problem of population heterogeneity

Question 28

outline case/control studies as genetic association analysis

Answer 28

compare distribution of alleles or genotype at locus in affected and unaffected people or population-based control sample easy to collect

Question 29

outline total association studies as genetic association analysis

Answer 29

e.g all individuals with quantitative trait need to account for correlations in genotype and phenotype due to relatedness

Question 30

what does the word linkage refer to

Answer 30

the relationship of loci

Question 31

what are genome wide association studies

Answer 31

examination of many common genetic variants in a group of individuals to see if any variant is associated with a trait

Question 32

what is linkage disequilibrium

Answer 32

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

Question 33

how do we visualise linkage disequilibrium

Answer 33

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

Question 34

outline tagging SNPs

Answer 34

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

Question 35

what statistic does GWAS provide

Answer 35

p value GWAS requires stringent significance levels to overcome the multiple testing problem when we test too many SNPs

Question 36

what is needed for GWAS to be valid

Answer 36

large sample size (1000s of individuals) to have sufficient power and detect a true association

Question 37

what do we expect to see in GWAS at any location showing significant association

Answer 37

several SNPs in same region showing association with phenotype due to correlation (LD) between neighbouring SNPs

Question 38

what is used in GWAS to visualise the strength of association

Answer 38

Manhattan plots

Question 39

why should we identify environmentally modifiable factors that influence disease risk (mendelian randomisation)

Answer 39

it is fundamental to public health improvement strategies

Question 40

outline models of gene environment interaction

Answer 40

1. genotype exacerbates effect of risk factor e.h UV radiation, genetic mutation, skin cancer 2. risk factor exacerbates effect of genotype mutation, baribiturates, skin irritation 3. both genotype and risk factor are required 4. genotype and risk factor influence independantly e.g mutation of clotting factor V Leiden, oral contraceptive pill -> thrombosis

Question 41

what is the gold standard for mendelian randomisation

Answer 41

randomised controlled trials but its expensive and could require very long follow up not every intervention is ethical

Question 42

outline mendelian randomisation

Answer 42

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

Question 43

what statistical method is mendelian randomisation

Answer 43

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

Question 44

what is the future of genetic epidemiology

Answer 44

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