Transcript EPB PHC 6000 EPIDEMIOLOGY FALL, 1997

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 and
Definitions
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:
Background
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
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 “nonhereditary” (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.
Study Designs in
Genetic Epidemiology
Study Designs in Genetic Epidemiology
1) Family Studies
2) Twin Studies
Traditional
3) Adoption Studies
4) Migrant Studies
5) Genetic Marker Studies
Recent
--- Gene/Environment interactions
Overall, basic strategy of these designs are to:
a) Hold environment constant:
 allow genetic factors to vary
b) Hold genetics constant:
 allow environmental factors to vary
Study Designs in Genetic Epidemiology
1) Family Studies
2) Twin Studies
Traditional
3) Adoption Studies
4) Migrant Studies
5) Genetic Marker Studies Recent
--- Gene/Environment interactions
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 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) 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 Studies
Proband
Case
Control
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.
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.
Family Studies
Other Uses of Family Studies:
a) Identify probable mode of transmission of
disorders (e.g. dominant or recessive,
autosomal or X-linked, etc.).
b) Examine validity of diagnostic categories by
assessing specificity of transmission of
symptom patterns and disorders.
c) Investigate phenotypic and etiologic
heterogeneity.
d) Assess co-morbidity of disorders within
families.
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
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
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
MZ Twins
DZ Twins
Twin 1
Twin 1
+
-
+
A
B
-
C
D
Twin 2
CRMZ = A / (A + B + C)
+
-
+
A
B
-
C
D
Twin 2
CRDZ = A / (A + B + C)
Genetic contribution: CRMZ / CRDZ
Note: Discordance rate = (B + C) / (A + B + C)
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.
Twin Studies
MZ Twins
DZ Twins
Twin 1
Twin 1
+
-
+
30
48
-
62
1256
Twin 2
+
-
+
32
130
-
126
2210
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?
Twin Studies
MZ Twins
DZ Twins
Twin 1
Twin 1
+
-
+
30
48
-
62
1256
Twin 2
CRMZ = A / (A + B + C)
+
-
+
32
130
-
126
2210
Twin 2
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
MZ Twins
DZ Twins
Twin 1
Twin 1
+
-
+
30
48
-
62
1256
Twin 2
+
-
+
32
130
-
126
2210
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.
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.
Twin Studies – Discordant MZ twins
MZ Twins
Children
Twin 1
Twin 2
Children
Genetic susceptibility not expressed in some
instances.
Twin Studies
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.
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-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 – Parent-as-Proband
Biological Parent 1
Parents
Adopted
Offspring
Parent 2
Adopted
Offspring
Suggests genetic heritability
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.
Adoption Studies – Adoptee-as-Proband
Adoptee 1
Biologic
Relatives
Adoptive
Relatives
Adoptee 2
Biologic
Relatives
(Suggests genetic component)
Adoptive
Relatives
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.
Adoption Studies – Cross Fostering Design
Parent of
Adoptees
Biologic Adoptive
Adoptees
Biologic Adoptive
Adoptees
(Suggests environmental component)
Adoption Studies
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).