EPB PHC 6000 EPIDEMIOLOGY FALL, 1997

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Unit 9 Genetic Epidemiology
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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.
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• 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.

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Background and Definitions
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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.
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Background
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).
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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.

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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.
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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.
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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
disease Example 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.
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Study Designs in Genetic Epidemiology
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Study Designs in Genetic Epidemiology

• 1) Family Studies
• 2) Twin Studies
• 3) Adoption Studies
• 4) Migrant Studies
• 5) Genetic Marker Studies
• --- Gene/Environment interactions
• Overall, basic strategy of these designs are to
• Hold environment constant
• ? allow genetic factors to vary
• Hold genetics constant
• ? allow environmental factors to vary

Traditional
Recent
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Study Designs in Genetic Epidemiology
1) Family Studies 2) Twin Studies 3) Adoption
Studies 4) Migrant Studies 5) 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.
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Family Studies
Family 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) Identi
fy 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.
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Family Studies
Case
Control
Proband
Relatives
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.
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Family Studies
Limitations 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.
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Family Studies

• Other Uses of Family Studies
• Identify probable mode of transmission of
  disorders (e.g. dominant or recessive, autosomal
  or X-linked, etc.).
• Examine validity of diagnostic categories by
  assessing specificity of transmission of symptom
  patterns and disorders.
• Investigate phenotypic and etiologic
  heterogeneity.
• Assess co-morbidity of disorders within families.

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Twin Studies
Twin 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.
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Twin Studies
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
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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.
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Twin Studies
MZ Twins
DZ Twins
Twin 1
Twin 1
Twin 2
Twin 2
CRMZ A / (A B C)
CRDZ A / (A B C)
Genetic contribution CRMZ / CRDZ
Note Discordance rate (B C) / (A B C)
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Twin Studies
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.
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Twin Studies
MZ Twins
DZ Twins
Twin 1
Twin 1
Twin 2
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 strong environmental component?
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Twin Studies
MZ Twins
DZ Twins
Twin 1
Twin 1
Twin 2
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
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Twin Studies
MZ Twins
DZ Twins
Twin 1
Twin 1
Twin 2
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.
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Twin Studies

• 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.

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Twin Studies Discordant MZ twins
Twin 1
Twin 2
MZ Twins
Children
Children
Genetic susceptibility not expressed in some
instances.
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Twin Studies

• Important Features of Twin Studies
• 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).
• When 2 or more disorders are studied in twins,
  can estimate comorbidity due to shared genetic
  and shared environmental factors.
• Keep in mind that the equal environment
  assumption between MZ and DZ twins may be suspect.

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Adoption 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-f
ostering design (most powerful)
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Adoption Studies

• Adoption Studies
• 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.

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Adoption Studies Parent-as-Proband
Parent 1
Parent 2
Biological Parents
Adopted Offspring
Adopted Offspring
Suggests genetic heritability
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Adoption Studies
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.
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Adoption Studies Adoptee-as-Proband
Adoptee 1
Adoptee 2
Biologic Relatives
Adoptive Relatives
Biologic Relatives
Adoptive Relatives
(Suggests genetic component)
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Adoption Studies

• 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.

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Adoption Studies Cross Fostering Design
Biologic
Adoptive
Biologic
Adoptive
Parent of Adoptees
Adoptees
Adoptees
(Suggests environmental component)
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Adoption Studies

• Limitations of Adoption Studies
• Limited generalizability since adoptees and their
  families not representative of the general
  population.
• Adoptees are often at greater risk of illness
  than non-adopted children (e.g psychiatric
  disorders).
• Parents of adopted children are known to have
  higher rates of some disorders (e.g.
  psychopathology).
• May be difficult to find sample of adoptees
  separated from parents at birth (e.g. biologic
  relationship contaminated by environment of
  biologic parents).