Study Design and Handling Data

Genotype Relative Risk

Approx equal to Odds Ratio

Defined as the factor by which the baseline penetrance has to be multiplied by to get the penetrance in the genotype category of interest

One category is chosen as the Genotype Baseline category e.g NN (for homozygous not-diseased). The genotype relative risk for this category becomes 1.0. To work out the relative risk for the other categories you work out the distance between each category's penetrance and the baseline penetrance and multiply that by the baseline relative risk. E.g. if DN = 0.5. Then DN penetrance/ NN penetrance = 0.5/0.1 =5. Then NN relative risk times 5 = 1x5 = 5.0 relative risk for DN

The genotype relative risk in whatever category chosen as the baseline will equal 1 as doing the above calculation results in dividing NN by itself. e.g NNpen / NNpen = 1

Family Studies

Traditional method to investigate genetic contribution to disease using large families/pedigrees. Used to address questions such as:

• Is there any evidence for genetic contribution to disease
• Can we localise the underlying genetic contributors? (to chromosomal location or genomic region

Only in certain situation do pedigrees provide information to answer: can we identify the genetic cause of disease (the gene involved and genetic mutation/variant). So require other techniques such as study of model organsims (mouse, zebrafish etc.) through breeding experiments or CRISPR/Cas9 gene knockouts or functional experiments in different human or animal cell types.

Segregation Analysis

Can be used to fit a mathematical model to the pattern of inheritance seen in a family:

• To estimate the parameters ( gene frequencies, shared environmental effects etc.) that best explain the inheritance pattern seen
• Allows fitting of more complicated oligogenic models (rather than just dominant or recessive) including one or more major genes, possibly operating against a polygenic background (lots of minor genetic effects), possibly subject to environmental effects

However in practice still not that useful for complex disease

Recurrence Risk

Another method to assess genetic contribution to a given disease

Denoted KR and defined as the probability of getting disease for specified "type R" relatives of an affected proband. 

R takes different values according to the relationship we are interested in e.g.

• KS is the risk of disease for a sibling of an affected individual
• KO is the risk for an offspring of an affected individual
• KMZ is the risk for a monozygotic twin of an affected individual

Recurrence Risk is often expressed relative to the background population risk K.

λR = KR / K

λR is known as the recurrence risk ratio (for relationship type R) e.g. the sibling relative risk, λS. If λS for a given disease is 3 then KS/ K=3. So a sibling of an affected person has 3 times the population risk. The assumption is that this increase is due to shared genetic factors but note siblings may not share environmental factors.

Parametric Linkage Analysis

Traditionally genetic determinants of disease have been…