Process of Genetic Epidemiology Migrant Studies Familial AggregationSegregation Association StudiesLinkage Analysis Fine Mapping Cloning Defining the Phenotype Characterization

Familial Aggregation Does the phenotype tend to run in families?

Recurrence (‘Familial’) Risk Ratios Compares the probability a subject is affected given they have an affected family member to the population risk: R = K R /K, where K R is the risk to relatives of type R K is the population risk S = recurrence risk to siblings of probands versus the general population risk. 

Recurrence Risk Ratios R = P(Y 2 = 1 |Y 1 = 1) / K P(Y 2 =1|Y 1 =1)P(Y 1 =1) = P(Y 2 =1, Y 1 =1) P(Y 2 =1|Y 1 =1) = P(Y 2 =1, Y 1 =1)/P(Y 1 =1) K = P(Y 1 =1) R = P(Y 2 =1, Y 1 =1)/P(Y 1 =1) 2

Estimating RRR With case-control data, calculate FRR as: Proportion of affected relatives of the cases (observed) / Proportion of affected relatives of controls (expected) (assumed to estimate K) The higher the value of, the stronger the genetic effect

Examples of s Alzheimer Disease3-4 Rheumatoid Arthritis12 Schizophrenia13 Type I Diabetes15 Multiple Sclerosis20-30 Neural Tube Defects25-50 Autism75-150

s versus GRR How well does s estimate the genetic risk ratio? s = P(Y 2 =1|Y 1 =1) / P(Y 2 =1|Y 1 =0) ? P(Y 2 =1|D) / P(Y 2 =1|dd) = GRR Sibs disease not necessarily hereditary At risk individual may not have inherited D Sib unaffected doesn’t mean other sib doesn’t carry D

GRRDominantRecessive q= P(G)= s versus GRR

Heritability Analysis Evaluates the genetic contribution to a trait Y in terms of variance explained. Y = Genetics + Environment Var(Y) = overall variation in phenotype Y = Var(G) + Var(E) + 2Cov(G,E) Broad sense heritability: H 2 = Var (G) / Var (Y) where Var(G) = genetic part of variance = V A +V D (Additive + Domince)

Narrow Sense Heritability Proportion of phenotypic variance that is explained only by additive genetic effects: h 2 = V A / Var (Y) A number of ways to estimate heritability. Commonly done with twin studies.

Twin Studies Compare the phenotype correlation or disease concordance rates of MZ (identical) and DZ (fraternal) twins. Twin 1

MZ Twins (Identical) Twin 1 Twin 2 Both alleles are shared identical by descent (IBD)

DZ Twins (Fraternal) Twin Twin 2: any of the four IBD can be 2, 1, or 0

DZ Twins (Fraternal) Twin 1 100% 50% 50%0% Average sharing is 50%

IBD Sharing # of alleles shared IBD 210 Pr(2)Pr(1)Pr(0) Prop IBD Relationship Self, MZ twins Parent, Offspring /2 Full siblings 1/4 1/2 1/41/2 Gr-child, Gr-prt01/43/41/4 First cousins 0 1/4 3/4 1/8 Proportion of alleles shared IBD = # alleles x Pr(# alleles) / 2

Twin Studies Assume MZ twins share all genes & envt., DZ share ½ genes & all envt. Correlation among twins: r mz = V A + V E r dz = ½ V A + V E where V E = common environment H 2 = 2(r mz - r dz ) Heritability ~ two times difference in correlation between MZ and DZ twins.

Example of Twin Study: PCa TwinConcordant pairs (A) Discordant pairs (B+C) Concordance 2A / (2A+B+C) MZ DZ Heritability: 0.42 ( ) Non-shared Environment: 0.58 ( ) Lichtenstein et al NEJM ;343: Twin registry (Sweden, Denmark, and Finland) 7,231 MZ and 13,769 DZ Twins (male) Limitations of heritability calculations?

Segregation Analysis Study families. Estimate ‘mode of inheritance’ & what type of genetic variant might be causal. Determine whether the disease appears to follow particular patterns across generations. Estimate whether variants are rare or common, etc.

Segregation: Harry Potter’s Pedigree Harry Potter Lily EvansJames Potter Petunia Dursley Vernon Dursley Dudley Dursley Muggle Wizard / Witch

Segregation Analysis What is the best model of inheritance for observed families? Dominant Recessive Additive –Disease allele frequency? –Magnitude of risk? Fit formal genetic models to data on disease phenotypes of family members. The parameters of the model are generally fitted finding the values that maximize the probability (likelihood) of the observed data. This information is useful in parametric linkage analysis, which assumes a defined model of inheritance.