Genetic Epidemiology

genetic epidemiology

study of the genetic factors determining health and disease in families and populations

family studies

compare rate of an illness or trait in the family members of an affected individual to the rate of illness in the general population

case-control approach

proportion of cases vs controls with a positive family history

cohort approach

proportion affected among relatives of cases vs relatives of controls

case-control approach outcome

case or control status

case-control approach exposure

positive family history

cohort approach outcome

disease status of relatives

cohort approach exposure

being the relative of a case proband or a control proband

odds ratio

compares odds of being a case with exposure to odds of being a case without exposure

odds ratio equation

(+ FH cases / + FH controls) / (-FH cases / -FH controls)

odds ratio = 1

no association between exposure and outcome

odds ratio > 1

exposure is associated with higher odds of disease

odds ratio <1

exposure is related with lower odds of disease

relative risk

compares risk in an exposed group to risk in an unexposed group

relative risk equation

(affected relatives of cases/ total number of relatives of cases) / (affected relatives of controls / total number of relatives of controls)

relative risk = 1

no association between exposure and outcome

relative risk >1

exposure has a increased risk of disease

relative risk <1

exposure has a decreased risk of disease

relative risk calculation

recurrence risk / population prevalence

concordance rates

how often co-twin is also affected when one twin is affected

MZ:DZ concordance ratio

2 (dominant) to 4 (recessive)

large MZ:DZ ratio

indicates multiple loci are involved

small MZ:DZ ratio

indicates very significant environmental factors

MZ:DZ ratio = 1

no evidence the disorder has a genetic component

heritability

the proportion of the total phenotypic variance that is caused by additive genetic factors

heritability calculation

variance due to additive genetic factors / total variance

heritability → 1

phenotypic variance is primarily genetic

heritability calculation twins

(%MZ concordance - %DZ concordance) / (100 - %DZ concordance)

high risk studies

prospectively follow individuals at risk for developing a genetic illness

segregation analysis

compare observed patterns of illness within a series of pedigrees with a certain illness

pedigree analysis

compare observed patterns of illness within a large pedigree

ascertainment bias

families with at least one affected individual are more likely to be selected in genetic studies

genome mapping method

compare inheritance patterns of the disorder and markers from different regions of all the chromosomes to establish linkage

genetic linkage

two genes that do not independently assort but tend to be inherited together

recombination

chromosomal breakage and exchange that occurs during cross-over events

recombination fraction

the probability that recombination will occur between two loci

recombination fraction range

0 (no recombination) to 0.5 (independent assortment)

parametric linkage analysis

uses formal models to describe the relationship between genotype & phenotype

LOD score

compares likelihood of alleles being linked to likelihood of alleles not being linked

LOD score calculation

log10 (odds ratio)

LOD 3.0

supports linkage with clear pattern of inheritance

LOD -2.0

alleles are not linked

LOD between -2.0 and 3.0

inconclusive evidence of linkage

parametric linkage analysis requires

frequency of of disease-causing allele

penetrance for different genotypes

recombination between marker and disease locus

linkage analysis of complex traits types

“affected-only” parametric analysis

nonparametric analysis

affected sib pairs analysis

affected pedigree member analysis

nonparametric linkage score

loci 10 cM apart

expect recombination once per 10 informative meiotic events

loci 1 cM apart

expect recombination once per 100 informative meiotic events