Familial Aggregation of Diseases

Naeim Ehtesham

Supervisor: Dr yadegarfar

The goals

• Familial aggregation?

• Genetic epidemiologist?

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Outline

Introduction

Methods in familial aggregation studies

Heritability

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Introduction

• One way for genetic study of complex trait

• The first step of genetic analysis of complex diseases is:

• Establish a genetic component to the disease

• Establish the relative size of the genetic effect in comparison to other sources of variation, such

as common household effect and random environmental effect

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Cont…

• Because relatives share a greater proportion of their genes with one another than with unrelated

individuals a primary characteristic of diseases with complex inheritance is that affected

individuals tend to cluster in families (familial aggregation)

• The converse, however, is not necessarily true: familial aggregation of a disease does not mean

that a disease must have a genetic contribution

• Family members may develop the same disease or trait by chance alone, particularly if it is a

common one in the population

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Cont…

• Detection and estimation of familial aggregation is the first step in the genetic analysis of any

multifactorial trait

• In general, very few traits are influenced only by genes or only by the environment

• It is the task of the genetic epidemiologist to determine whether familial aggregation is

coincidental or the result of factors common to members of the family and to assess the extent to

which those common factors are genetic and environmental

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Methods in familial aggregation studies

• Relative risk(ʎr )

• Case-control studies

• Adoption studies

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Relative risk(ʎr )

• The familial aggregation of a disease can be measured by comparing the frequency of the disease

in the relatives of an affected proband with its frequency (prevalence) in the general population.

The relative risk ratio ʎr Is defined as:

ʎ𝑟 = 𝑝𝑟𝑒𝑣𝑎𝑙𝑒𝑛𝑐𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑑𝑖𝑠𝑒𝑎𝑠𝑒 𝑖𝑛 𝑎𝑟𝑒𝑙𝑎𝑡𝑖𝑣𝑒 "𝑟" 𝑜𝑓 𝑎𝑛 𝑎𝑓𝑓𝑒𝑐𝑡𝑒𝑑 𝑝𝑒𝑟𝑠𝑜𝑛𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑝𝑟𝑒𝑣𝑎𝑙𝑒𝑛𝑐𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑑𝑖𝑠𝑒𝑎𝑠𝑒

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Cont…

• The value of ʎr is a measure of familial aggregation that depends both on the risk of the disease

recurring in the family and on the population prevalence: the larger ʎr is, the greater the familial

aggregation

• The population prevalence enters into the calculation because the more common a disease, the

greater is the likelihood that aggregation may be just a coincidence rather than a result of sharing

the alleles that predispose to disease

• A value of ʎr =1 indicates that a relative is no more likely to develop the disease than is any

individual in the population.

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Case-control studies

• Patients with a disease (the cases) are compared with suitably chosen individuals without the

disease (the controls) with respect to family history of disease (as well as other factors, such as

environmental exposures, occupation, geographical location, and previous illnesses)

• To assess a possible genetic contribution to familial aggregation of a disease, the frequency with

which the disease is found in the extended families of the cases (positive family history) is

compared with the frequency of positive family history among suitable controls, matched for age

and ethnicity, but who don't have the disease.

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Cont…

• Spouses are often used as controls in this situation because they usually match the cases in age

and ethnicity and share the same household environment.

• Other frequently used controls are patients with related diseases matched for age, occupation,

and ethnicity.

• For example, in a study of Parkinson disease (PD), 6.3 percent of first- and second-degree living

relatives of patients with PD also had PD, a prevalence that was significantly higher than the 1.2

percent prevalence of PD among the relatives of matched controls with other neurological

diseases but not PD.

• Therefore, a family history of PD is found more frequently among patients with PD than in

controls, indicating that some familial aggregation is occurring in PD

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Cont…

• Case-control studies for familial aggregation are subject to many different kinds of errors

• One of the most troublesome is ascertainment bias, a difference in the likelihood that affected

relatives of the cases will be reported to the epidemiologist as compared with the affected

relatives of controls.

• A proband's relatives may be more likely than a control's relatives to know of other family

members with the same disease or may be more motivated to respond to a questionnaire because

of familiarity with the disease (recall bias)

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Cont…

• Another confounding factor is the choice of controls

• Controls should differ from cases only in their disease status and not in ethnic background,

occupation, gender, or socioeconomic status, any of which may distinguish them as being

different from the cases in important ways that have little or nothing to do with the fact that they

are not affected by the disease

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Cont…

• Finally, an association found in a case-control study does not prove causation

• For example, if two factors are not independent of each other, such as ethnic background and

dietary consumption of certain foods, a case-control study may find a significant association

between the disease and ethnic background when it is actually the dietary habits associated with

ethnic background that are responsible

• For example, the lower frequency of coronary artery disease (CAD) among Japanese compared

with that among north Americans becomes less pronounced in first-generation Japanese who

emigrated to north America and adopted the dietary customs of their new home

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Adoption studies

• Comparing disease rates among the adopted offspring of affected parents with the rates among

adopted offspring of unaffected parents

• Certain biases can influence these studies:

(1) parental environment could have long-lasting effects on an adopted child

(2) adoption agencies attempt to match the adoptive parents with natural parents in terms of

socioeconomic status

(3) children might be several years old when adopted, introducing the potential for many

environmental confounds

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Heritability

• The concept of heritability (symbolized as ) was developed to quantify the role of genetic

differences in determining variability of quantitative traits

• Heritability is defined as the fraction of the total phenotypic variance of a quantitative trait that

is caused by genes and is, therefore, a measure of the extent to which different allele's at various

loci are responsible for the variability in a given quantitative trait seen across a population

• The higher the heritability, the greater is the contribution of genetic differences among people in

causing variability of the trait

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Cont…

• The value of h2 varies from 0, if genes contribute nothing to the total phenotypic variance, to 1, if genes are

totally responsible for the phenotypic variance.

• There are, however, a number of practical difficulties in measuring and interpreting h2:

• One is that relatives share more than their genes; they also share environmental exposures, and so the

correlation between relatives may not reflect simply their familial genetic relationship

• Even when the heritability of a trait is high, it does not reveal the underlying mechanism of inheritance of

the trait, such as the number of loci involved or how the various alleles at those loci interact

• Heritability is a population specific estimate, and thus can vary from population to population

THANKS FOR YOUR ATTENTION