Uploaded by Prashan Perera

Polygenic Disorders

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Huntington's disease
Single
gene
Disorders
Hemophilia
血友病
亨廷顿氏舞蹈症
Duchenne muscular
dystrophy
杜氏肌营养不良
Albinism
白化病
Brachydactyly
短指症
Example:
A woman/man who is a prolific writer has a
daughter who becomes a successful novelist.
Yan,Geling
(严歌苓)
and her
father
Example:
An overweight man /woman have
obese children.
Example:
A man whose father suffers
from alcoholism has the same problem.
Question
 Are these characteristics—writing talent,
obesity, and alcoholism—inherited or
learned?
 Are they a combination of nature (genetics)
and nurture (the environment)?
What are Polygenic Disorders ?


Polygenic disorders are the diseases result
from complex interaction between multiple
gene and variety of environmental exposures
that trigger, accelerate, exacerbate the
disease process.
Also called multifactorial disorders, complex
disorders.
NOTE:
1. Multi-gene involvement, with each gene exerting
a small additive effect.
2. Often have environmental factors influences.
Gene
Gene
Gene
environment
al factors
Gene
Polygenic trait
polygenic disorder
The difference of polygenic disorders and
single-gene disorders
 Unclear transmittance patterns
These disorders show a definite familial tendency, but
the pattern of inheritance is different from single gene
disorders.
 The incidence in close relatives of affected
individuals is usually around 2~4%,lower than
single-gene disorders.
 Both genetic factors and environmental factors are
all involved in causing these disorders.
Polygenic Traits:Height、skin color and weight
Genes
Height
Improved diet
Yao Ming
Chinese basketball player
(爸爸)姚志源 2.08m
(妈妈)方凤娣 1.88m
(儿子)姚明 2.26m
Polygenic disorders
Hypertension
高血压
Schizophrenia
精神分裂症
Asthma
哮喘
Section 1. Principles of Multifactorial
Inheritance
Single-gene disorders: qualitative trait
Mendelian trait that is either present or absent.
One has the trait or not. such as “normal” versus
“affected.”

Exhibit discontinuous variation among the
phenotypes.

Example – albinism ;
green peas vs yellow peas
Qualitative trait
AA
Aa
AA
Compete dominance




Aa
aa
Incompete dominance
Mendelian trait
Single gene trait
Present or absent
With no overlap
RR
rr
AA/Aa
aa
Rr
Polygenic Disorders: quantitative trait

A polygenic trait, the combined action of many genes
often produces a “continuously varying” phenotype.


which are measurable characteristic .
Often fit normal distribution
Examples - height, blood pressure, skin color,
intelligence
Quantitative trait
 Polygenic Trait
 Continuous variation: phenotypes distribute
from one extreme to another in an
continuous fashion
 Physiological or biochemical quantities
Example:
The distribution of height in a
population
1920
The tallest people :
5′9′′ tall
1997
The tallest :
6′5′′ tall
Height is influenced by genes and environment during growth
Improved nutrition can impact height
Polygenic traits show continuous distribution in the general
population.
Mean
Number of men (thousands)
12
a symmetrical bellshaped curve
10
8
6
4
2
0
150
155
Height(cm)
160
165
170
175
180
185
190
Regression to the mean
Shortest
Tallest
P
Francis Galton
 Multifactorial inheritance was first
studied by Galton, a close relative of
Darwin. Galton established the
principle of what he termed
"regression to mediocrity."
F1
F2
Polygenic trait
 In general, Galton noticed that
extremely tall fathers tended to have
sons shorter than themselves, and
extremely short fathers tended to
have sons taller than themselves.
QUESTION:
How do genes generate such
a normal distribution?
Use height as a model trait
Assume that height is controlled by a single
locus with genotypes AA, Aa, and aa.
Allele A tends to make people tall, and allele
a tends to make them short.
intermediate
Assume: two separate loci (Aa, and Bb) are
involved in determining final adult height.
P1
gametes
AaBb x AaBb
AB
ab
Ab
AB
AABB
AaBb
AABb
AaBB
ab
AaBb
aabb
Aabb
aaBb
Ab
AABb
Aabb
AAbb
AaBb
aB
AaBB
aaBb
AaBb
aaBB
aB
According to mendelian law, it is can be produced
16 fertilization recombination, 5 phenotypic classes.
The distribution of height, assuming
that height is controlled by two loci
2
1
0
3
4
Number of
dominant allele
There are now five distinct phenotypes instead of three,
and the distribution begins to look more like the
normal distribution.
 Genome-wide association studies have
identified more than 200 loci associated with
human height.
 We now extend our example so that many
genes and environmental factors influence
height, each having a small effect.
 Then there are many possible phenotypes,
each differing slightly, and the height
distribution approaches the bell-shaped curve
.
Distribution of height, assuming that
multiple factors, each with a small effect,
contribute to the trait
(the multifactorial model).
Another example: Human Eye Color
Light blue, deep blue, light
brown, medium brown ,and
black
Example: Human skin Color
Another example: Blood pressure


There is a correlation between parents’ blood
pressures and those of their children.
But blood pressure is also influenced by
environmental factors, such as diet and stress.
Summary of Section 1 :
The Multifactorial Model
Many traits are thought to be influenced by multiple
genes as well as by environmental factors.
The genes underlying continuous traits are following
Mendelian principles of segregation and independent
assortment.
Genes can generate a continuous trait when they act
together.
As the number of loci involved in a trait increase, the
number of resulting phenotype classes increase, the
distribution looks increasingly like a Normal
distribution, also called the Bell Curve.
Question
If polygenic traits are quantitative traits with
continuous distribution, how can account for
discontinuous polygenic disorders (either present
or absent in individuals)?
These are best explained by the liability/threshold
model.
Spina bifida
Section 2 The Liability/Threshold Model
Liability
The genetic determination of an individual’s
predisposition to the disease is called susceptibility,
while the genetic and environmental determination of
the predisposition is defined their liability.
Threshold

To account for a discontinuous phenotype (i.e.
affected or not affected) with an underlying
continuous distribution, it is proposed that a
threshold exists above which the abnormal
phenotype is expressed.
Distribution of liability in the population
Threshold
•Below the threshold,
normal development is
observed.
•Beyond the threshold,
disease results;
unaffected
affected
population incidence
low
liability
average
liability
high
liability
The liabilities of all individuals in a population form a continuous variable,
which has a normal distribution both in the general population and in
relatives of affected individuals.
A liability distribution for a multifactorial
disease in a population.
Example: cleft lip/palate
Threshold 阈值
Liability Low
Few of the alleles or
environmental
factors
High
More of the disease
causing alleles and
environmental factors
Threshold model for polygenic disorders
1. The threshold model assumes that there is a liability
toward development of a disorder that is normally
distributed in the general population.
2. This liability is composed of contributions from both
genetic and environmental factors that can lead to
expression of the trait.
3. Individuals will have more or less liability toward the trait,
depending on how many of the predisposing genes
they have inherited and the degree to which they are
exposed to the relevant environmental factors.
4. The trait is expressed only in individuals whose liability
exceeds a threshold.
NOTE:
 This is a hypothesis rather than proven fact, is that
it provides a simple explanation for the observed
patterns of familial risks in conditions, such as cleft
lip/palate and spina bifida.
 Liability cannot be measured, but the mean liability
of a group can be determined from the incidence of
the disease in that group using statistics of the
normal distribution.
Section 3 Estimating Recurrence Risk of
polygenic Disorders
• Risk estimation is more complex for multifactorial
diseases
• Geneticists use empiric risks, which are based on
incidence in a specific population.
Empiric risks
 Empiric risk is not a calculation, but a population
statistic based on observation.
 Empirical recurrence risks for multifactorial
diseases are based on studies of large
collections of families.
 These risks are specific to a given population.
Section 3 Estimating Recurrence Risk of
polygenic Disorders
1. The recurrence risk is related to heritability.
Condition: the frequency in population is 0.1%~1%
and the heritability is 70%~80%。
The risk of recurrence for first-degree relatives, i.e.
siblings and offspring, approximates to the square
root of the general population incidence.
Edward Formula
qr = f
qr :The risk for offspring and
sibling of probands
f :Prevalence in population
For example, cleft lip/palate
The population incidence : 0.17%, Heritability: 76%
The first-degree relative risk : 4%
2. The recurrence risk for the disease usually
decreases rapidly in more remotely related
relatives.
Familial aggregation of quantitative traits.
The risk is greatest among close relatives of the
affected individual and decreases rapidly in more
distant relatives.
For example:
In spina bifida the risks to first, second and thirddegree relatives of the affected individual are
approximately 4%, 1% and less than 0.5%,
respectively.
Empiric risk of cleft palate
Relationship
Recurrence
Risk
General population
0.1%
First cousin
0.3%
Niece or nephew
0.8%
Child
3.5%
Sibling
4.1%
Identical twin
40.0%
As the degree of relatedness increases, the
number of gene in common increases.
3. The recurrence risk is increasing with
the number of affected members in a family.
For example: spina bifida
If one siblings are affected, the risk to a
subsequent sibling is approximately 4%.
If two siblings are affected, the risk to a subsequent
sibling is approximately 10%.
Note
 This increase does not mean that the family’s
risk has actually changed.
 Rather, it means that we now have more
information about the family’s true risk: because
they have had two affected children, they are
probably located higher on the liability distribution
than a family with only one affected child.
 In other words, they have more risk factors
(genetic and/or environmental) and are more
likely to produce an affected child.
Threshold 阈值
Liability
Low
One couple have one
affected child
High
Another couple have two
affected child
4. The recurrence risk is increasing with
the severity of affected members within a
family
For example, in cleft lip/palate
If the proband has a unilateral cleft lip ,the risk of
first-degree relatives is only 2%.
If the proband has bilateral cleft lip and palate , the
risk of first-degree relatives is 6%,
The more severely affected the individual, the more genes
he/she has to transmit, and the higher the recurrence risk.
Example: cleft lip/palate
Liability Low
Threshold 阈值
High
unilateral cleft lip
(one side)
bilateral cleft lip and palate
(both sides)
5. The recurrence risk is higher if the
proband is of the less commonly affected sex

A lower male threshold implies
that fewer disease-causing
factors are required to
generate the disorder in males.
 The recurrence risk is higher
when the proband is female
than when the proband is male.
For example: Pyloric stenosis
• An overgrowth of muscle at the
juncture between the stomach
and the small intestine.
• The condition must be
corrected surgically shortly after
birth, or the newborn will be
unable to digest foods.

It occurs in about 0.05% newborn males but only in
about 0.01% newborn females.

The risk of recurrence to the offspring of male probands
are 5.5% for sons and 2.4% for daughters, whereas
the risks to the offspring of female probands are 19.4%
for sons and 7.3% for daughters.

The recurrence risk is higher for families in which the
proband is female than where the proband is male.
Two threshold diseases
Example : Pyloric stenosis
mean
0.05%
0.01 %
low
high
The reason


A female, being more rarely affected, is
presumed to require a greater liability in order
to cross the threshold.
A couple having a daughter with pyloric stenosis,
is likely to transmit a greater number of genes
predisposing to the disorder and therefore has
a higher recurrence risk than those who have a
son with the disorder.
Question
How much of a given phenotype is genetic
(inherited) and how much is environment?
Heritability: H

The proportion of the phenotypic variation for a
particular trait that is due to genetic difference .
If H is high --- phenotypic variation is largely genetic
H= 1 (100%) - genes only
If H is low --- phenotypic variation is largely environmental
H= 0 (0%) - environment only
Heritability of various disorders
Disorder
Schizophrenia
Asthma
Hypertension (essential)
Type II diabetes (NIDDM)
Cleft lip ± cleft palate
Heritability
(%)
85
80
62
26
76
Note:
1. Heritability measures the genetic contribution to a
polygenic trait.
2. It is specific to a particular population at a particular
time. (e.g. the heritability of skin color )
3. Remember that heritability is a population phenomenon
and applied to groups, not to individuals.
4. The greater the value for the heritability the greater the
role of genetic factors!!!
Winter Summer
Two research strategies that are often used
to estimate the relative influence of genes
and environment
1.Twin studies
2. Adoption studies
1. Twins Studies

Monozygotic twins (MZ twins, or identical ): are
derived from a single zygote and therefore are
genetically identical.
Monozygotic twins, showing a
striking similarity in physical
appearance. Both twins developed
myopia as teenagers.

Dizygotic twins (DZ twins, or fraternal twins ):
develop from 2 fertilized sperm. They share half
their genes in common, as do any pair of siblings.
 If both members of a twin pair share a trait,
they are said to be concordant. If they do
not share the trait, they are discordant.
 For a trait determined completely by genes,
MZ twins should always be concordant, and
DZ twins should be concordant less often.
•Concordance measures the frequency of
expression of a trait in both members of MZ or
DZ twin pairs.
•For a trait largely determined by genes, concordance
is higher for MZ than DZ twins.
•A trait molded mostly by the environment exhibits
similar concordance values for both types of twins.
For example

If one MZ twin has sickle cell disease, the other twin will
also have sickle cell disease. (100%)
GAG
GTG
hemoglobin-beta gene
For example
In contrast, when one MZ twin has type 1 diabetes
mellitus, only about 40% of the other twins will also
have type 1 diabeties.
Greater concordance in MZ versus DZ twins is strong
evidence of a genetic component to the disease.
Formula for heritability (H) in twin studies
H = (Monozygotic Concordance % - Dizygotic Concordance %)
/(100 - Dizygotic Concordance %)
For example: Schizophrenia
25 Monozygotic twins , 20 have the disease. concordance is 20/25.
20 Dizygotic twins , 2 have the disease, concordance is 2/20.
Please calculated the heritability.
H =
CMZ – CDZ
80 – 10
=0.78=78%
=
100 – CDZ
100 – 10
2. Adoption Studies
Studies of adopted children are also used to estimate
the genetic contribution to a multifactorial trait.
They consist of comparing disease rates among
the adopted offspring of affected parents with the
rates among adopted offspring of unaffected
parents.
For example, schizophrenia is seen in 8% to 10%
of adopted children whose natural parent had
schizophrenia, whereas it is seen in only 1% of
adopted children of unaffected parents.
Some examples of polygenic disorders
1. Congenital malformations
•
Example: Cleft lip/palate, Neural tube defects
2. Acquired diseases of childhood and adult life
•
Example: Diabetes mellitus, Hypertension
1. Congenital Malformations
Club foot
Congenital heart defects
Cleft lip/palate
Clubfoot can range from mild to
severe, but typically has the
same general appearance. The
foot is turned inward and there
is often a deep crease on the
bottom of the foot.
Neural tube defect
llustration of a child with
spina bifida the most
common NTD
The normal structure of the heart (left) in
comparison to two common locations for
a ventricular septal defect (right), the
most common form of congenital heart
defect.[1]
2. Multifactorial Disorders in the Adult
Population
• Cardiovascular Disorders
• Hypertension
• Diabetes mellitus
• Obesity
• Alzheimer Disease
• Alcoholism
• Psychiatric Disorders
Summary
1.
The concept of polygenic inheritance has been
proposed to account for the common congenital
malformations and acquired disorders that show nonMendelian familial aggregation. These disorders are
thought to result from the interaction of genetic and
environmental factors.
2. Human characteristics such as height and
intelligence, which show a normally distributed
continuous distribution in the general population,
are probably caused by the additive effects of many
genes.
Summary
3. According to the liability/threshold model for polygenic
inheritance the population’s genetic and environmental
susceptibility, which is known as liability, is normally
distributed. Individuals are affected if their liability
exceeds a threshold.
4. Risks for multifactorial diseases usually increase if
more family members are affected, if the disease has
more severe expression, and if the affected proband
is a member of the less commonly affected sex.
Summary
5. Recurrence risks decrease rapidly with more remote
degrees of relationship.
6. In general, the sibling recurrence risk is
approximately equal to the square root of the
prevalence of the disease in the population.
7. Heritability is a measure of the proportion of the
total variance of a character or disease that is due to
the genetic variance.
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