Unit 9:

Genetic Epidemiology

Unit 9 Learning Objectives:1. Understand characteristics, uses, strengths,

and limitations of genetic epidemiology study designs:--- Family studies--- Twin studies--- Adoption studies--- Migrant studies--- Genetic marker studies

2. Calculate, compare, and interpret concordance rates of disorders between monozygotic and dyzogotic twins.

3. Distinguish between association and linkage genetic marker studies.

Unit 9 Learning Objectives:4. Understand the concept of gene-environment

interaction.5. Understand characteristics and interpret

results from gene-environment studies:--- Traditional studies--- Case-only studies--- Case-parental control studies--- Twins studies

6. Distinguish between statistical and biological gene-environment interaction, including assessment of when interaction is present.

Background andDefinitions

Background• Definitions:

Gene: Particular segment of DNA molecule on a chromosome that determines the nature of an inherited trait.

Locus: Site or location on a chromosome occupied by a gene.

Allele: One or two or more alternate forms of a gene that occurs at the same locus.

• Definitions:

Genotype: Genetic constitution of an individual, often in reference to a particular trait.

Phenotype: Realized expression of the genotype. In epidemiology, genotype is modified by the environment to affect the phenotype.

Proband: The individual in a family that brings attention to the investigator (e.g. the case or control proband of a set of twins).

Background

• Case-control design (covered in-depth in Unit 10) is particularly well-suited to current genetic epidemiology studies because:

1) Genetic markers are stable – no reliance on individual recall.

2) Temporal relationship to environmental factors is known.

3) Good for studying rare disorders.

Background

• As stated in Unit 1, Introduction, ALL chronic diseases have “multi-factorial” etiololgies:

Minimally, the individual must be genetically susceptible to the disorder:

AND

There must be at least some interaction with the environment.

Background

• Classic Example of Gene-Environment Interaction:

--- Persons with HLA-B27 are approximately 90 times more likely to develop ankylosing spondylitis than persons without HLA-B27

BUT

--- Only 10% of all persons with HLA-B27 will develop ankylosing spondylitis.

Background

• Gene-Environment Disease Heterogeneity

--- Keep in mind that for many chronic diseases, there may be “hereditary” (familial) and “non-hereditary” (sporadic) forms of the diseaseExample: BRCA1 and inherited breast cancer.

--- In many instances, the inherited form, which still requires environmental interaction, often occurs at an earlier age of onset, and may have an overall poorer prognosis.

Background

Study Designs in Genetic Epidemiology

Study Designs in Genetic Epidemiology1) Family Studies2) Twin Studies3) Adoption Studies4) Migrant Studies5) Genetic Marker Studies

--- Gene/Environment interactionsOverall, basic strategy of these designs are to:a) Hold environment constant:

allow genetic factors to varyb) Hold genetics constant:

allow environmental factors to vary

Traditional

Recent

Study Designs in Genetic Epidemiology1) Family Studies2) Twin Studies3) Adoption Studies4) Migrant Studies5) Genetic Marker Studies

--- Gene/Environment interactions

Traditional

Recent

In general, the “traditional” studies have been used to assess the relative contribution of genetics to disease occurrence, whereas the “recent” studies also attempt to identify factors (e.g. genes) that play a causal role in disease development.

Family StudiesFamily Studies: vary genetics, keep

environment constant:1) Identify individual with particular disorder (case-proband) – determine rates of the disorder in relatives of the proband.2) Identify individual without the disorder of interest (control-proband) – determine

rates of the disorder in relatives of the proband.

3) Calculate prevalence ratio between relatives of case and relatives of control proband.

Family StudiesProband

Relatives

Case Control

Prevalence ratio (PR) = (3 / 5) / (1 / 5) = 3.0

NOTE: Unlike incidence, the upper limit of the PR is markedly restricted if the disorder of interest is common in the general population.

Family StudiesLimitations of Family Studies:

a) Important environmental factors (e.g. SES, social support, etc.) also tend to be “familial.”

b) There may be “assortative mating” – the tendency for those with particular disorders to mate preferentially with those who have similar disorders – may lead to overestimate of genetic effect.

Family StudiesOther Uses of Family Studies:

c) Identify probable mode of transmission of disorders (e.g. dominant or recessive, autosomal or X-linked, etc.).

d) Examine validity of diagnostic categories by assessing specificity of transmission of symptom patterns and disorders.

e) Investigate phenotypic and etiologic heterogeneity.

f) Assess co-morbidity of disorders within families.

Twin StudiesTwin Studies: vary genetics, keep

environment constant:1) Identify one twin with disorder of interest.2) Assess whether other twin has the disorder of interest.3) Calculate the concordance rate (CR)4) Compare concordance rates between

monozygotic (MZ) and dyzogotic (DZ) twins.5) To support genetic etiology, concordance rates for MZ twins should exceed rate for DZ twins.

Concordance rate: (pairwise method):# twin pairs concordant

CRPW = ------------------------------------------ total # twin pairs

Concordance rate: (probandwise method): 2C1 + C2

CRPB = --------------------------------------------------------- 2C1 + C2 + D

Where C1 = Concordant pairs: both twins independently ascertained C2 = Concordant pairs: only one twin independently ascert.

D = Number of discordant pairs

Twin Studies

Pairwise concordance is used when the probability of selecting both case probands as twins is very low (e.g. selecting one proband case from each city).

Probandwise concordance is used when the probability of selecting both case probands as twins is not rare (e.g. selecting every third person as a proband case from a local registry of disease cases).

The probandwise method usually results in somewhat higher concordance rates.

Twin Studies

Twin Studies

+ -

+ A B

- C D

Twin 1

Twin 2

MZ Twins DZ Twins

+ -

+ A B

- C D

Twin 1

Twin 2

CRMZ = A / (A + B + C) CRDZ = A / (A + B + C)Genetic contribution: CRMZ / CRDZ

Note: Discordance rate = (B + C) / (A + B + C)

The null value for the concordance ratio between MZ and DZ (e.g. no genetic contribution) is 1.0.

However, if the value exceeds 1.0, there still remains the possibility that MZ twins share more similar environments than DZ twins. This also includes a more similar intrauterine environment.

Also, may be publication bias against studies with low concordance rates in MZ twins.

Note: Can also compare concordance of continuous variables by correlation coefficient.

Twin Studies

Twin Studies

+ -

+ 30 48

- 62 1256

Twin 1Twin 2

MZ Twins DZ Twins

+ -

+ 32 130

- 126 2210

Twin 1

Twin 2

In the above example, is there evidence supporting a genetic contribution to development of the disorder?

Does the disorder appear to have a strongenvironmental component?

Twin Studies

+ -

+ 30 48

- 62 1256

Twin 1Twin 2

MZ Twins DZ Twins

+ -

+ 32 130

- 126 2210

Twin 1

Twin 2

CRMZ = A / (A + B + C) CRDZ = A / (A + B + C)Genetic contribution: CRMZ / CRDZ

CRMZ = (30 / 140) = 0.2143 CRDZ = (32 / 288) = 0.1111

CRMZ / CRDZ = 0.2143 / 0.1111 = 1.93

Twin Studies

+ -

+ 30 48

- 62 1256

Twin 1Twin 2

MZ Twins DZ Twins

+ -

+ 32 130

- 126 2210

Twin 1

Twin 2

CRMZ / CRDZ = 0.2143 / 0.1111 = 1.93

The MZ/DZ ratio of 1.93 suggests that genetics have a strong influence on development of the disorder. The relatively low concordance rates among both MZ & DZ twins also suggest a strong environmental component.

Some Other Uses of Twin Studies:

a) MZ twins reared apart give unique (but rare) opportunity to study influence of genetics in the absence of shared environmental factors.

b) Can look at children of discordant MZ twins. If the rate of the disorder in the children of the twins is similar, suggests genetic susceptibility that may be prevented (not expressed) in the presence of environmental factors.

Twin Studies

Twin Studies – Discordant MZ twins

MZ Twins

Children

Twin 1 Twin 2

Genetic susceptibility not expressed in some instances.

Children

Important Features of Twin Studies:

a) Twins constitute about 1.8% of adult population. Use of twin registries allows study in the community rather than the hospital (avoids treatment seeking bias and lack of generalizability).

b) When 2 or more disorders are studied in twins, can estimate comorbidity due to shared genetic and shared environmental factors.

c) Keep in mind that the “equal environment” assumption between MZ and DZ twins may be suspect.

Twin Studies

Adoption Studies: vary environment, keep genetics constant:1) Based on premise that if genes are important, familial transmission should occur in the biologic,but not adoptive family. If environment is important, familial transmission should occur in the adoptive rather than biologic family.

2) Three major adoption study designs:-- Parent-as-proband design-- Adoptee-as-proband design-- Cross-fostering design (most

powerful)

Adoption Studies

Adoption Studies:

a) Parent-as-proband design: Compares rate of illness in the adopted offspring of parents with and without the disorder of interest.

If genetic factors are important, rates of illness should be higher in adopted children of ill parents compared with adopted children of well parents.

Adoption Studies

Adoption Studies – Parent-as-Proband

BiologicalParents

AdoptedOffspring

Parent 1 Parent 2

Suggests genetic heritability

AdoptedOffspring

b) Adoptee-as-proband design: Start with ill and well adoptees, and examine rates of illness in both biologic and adoptive relatives.

If biologic relatives show higher rates of illness than adoptive relatives, suggests a genetic component. However, if adoptive relatives show higher rates of illness, environmental hypothesis gains support.

Adoption Studies

Adoption Studies – Adoptee-as-Proband

BiologicRelatives

Adoptee 1 Adoptee 2

AdoptiveRelatives

BiologicRelatives

AdoptiveRelatives

(Suggests genetic component)

Cross-fostering design: Compares rates of illness for 2 groups of adoptees:

Group 1: Adoptee has well biologic parents, raised by ill adoptive parents.

Group 2: Adoptee has ill biologic parents, raised by well adoptive parents.

Higher rates of illness in Group 1 suggests non-genetic mode of transmission.

Adoption Studies

Adoption Studies – Cross Fostering Design

Biologic

(Suggests environmental component)

Parent ofAdoptees

Adoptive

Adoptees

Biologic Adoptive

Adoptees

Limitations of Adoption Studies:

a) Limited generalizability since adoptees and their families not representative of the general population.

b) Adoptees are often at greater risk of illness than non-adopted children (e.g psychiatric disorders).

c) Parents of adopted children are known to have higher rates of some disorders (e.g. psychopathology).

d) May be difficult to find sample of adoptees separated from parents at birth (e.g. biologic relationship “contaminated” by environment of biologic parents).

Adoption Studies