Download sheet#10,by farah odeh

Multifactorial diseases
human diseases are caused by multiple causes genetic
environmental or both.
Some disease genetic predominate like Down syndrome
and some environmental like infections (viruses).
Most chronic diseases are caused by both
(schizophrenia and diabetes ancongenetal malformation
Genotype + environmental = phenotype
polygenic trait (two or more genes determine it)
multifactor traits are controlled by two or more genes
and also interact with environment.
-most human traits are polygenic.
Polygenic inheritance (when a single trait is controlled
by two or more sets of alleles)
**inheritance and expression of a phenotype being
determined by many genes at different loci each gene
exert a small additive effect **
additive effect >> the effects of genes are cumulate no
one gene is dominant or recessive to another
genes are rarely acted alone environmental factors and
other genes may modify expression.
Traits are:
mandolin: single gene
polygenic: multiple genes
multifactor (Complex): interaction between gene and
environment.
…..
Complex trait: cumulative effect of genes and the
influence of environment.
Polygenic traits: Controlled by one or more genes and
pattern of inheritance can be measured quantitavely.
Multifactor traits: result from interaction of two or
more genes and one or more environmental factor.
…..
Phenotypes are influences by many genes and also by
environment.
Two types of phenotype.
A.Discontinous: phenotype that can be fall into two or
more distinct no overlapping classes..
Discontinuous traits - For example, if we cross a tall and
short pea plant and look at F2 plants, we know the genotype
of short plants, and we can give a generalized genotype for
the tall plant phenotype. Furthermore, if we know the
genotype we could predict the phenotype of the plant.
These types of phenotypes are called discontinuous traits
and fall into discrete classes - eg.either tall or short.
B.continous: phenotype that is distributed from one extreme to
another in an overlapping fashion
Continuous traits - Other traits do not fall into discrete classes.
Rather, when a segregating population is analyzed, a
continuous distribution of phenotypes is found. An example
is ear length in corn. Black Mexican Sweet corn has short
ears, whereas Tom Thumb popcorn has long ears. When
these two inbred lines are crossed, the length of the F1 ears
are intermediate to the two parents. Furthermore, when the
F1 plants are intermated, the distribution of ear length in the
F2 ranges from the short ear Black Mexican Sweet size to
the Tom Thumb popcorn size. The distribution resembles
the bell-shaped curve for a normal distribution.
………
*when the number of genes which are controlling the trait
increase the number of phenotype classes increase.
………
polygenic traits are continuous not discrete and the effect of
gene is additive or synergistic and its quantities trait loci and the
genes which are involved may have major or minor impacts.
(Height, hair color, body weight, cholesterol levels, IQ)
skin color: is phenotype interaction between pigment gene and
environment, melanin production result in skin pigmentation and
also protects skin from UV radiation.
In genetic sense race based on skin color has little meaning and
93% of genetic traits are equally frequent among all people.
Eye Color: eye color genes are UN known and analysis revealed
many genes. ** Mice have more than 60 eye color genes.
………
Multifactorial inheritance:
The type of hereditary pattern seen when there is
more than one genetic factor involved and,
sometimes, when there are also environmental factors
participating in the causation of a condition.
Many common traits are multifactorial. Skin color, for
example, is multifactorially determined. So is height
and so also is intelligence.
The most common diseases tend also to
multifactorial. Type 2 diabetes, the most common
type of diabetes, is multifactorial. It is due to the
inheritance of susceptibility genes (genes that
make one susceptible to developing diabetes)
plus environmental factors such as obesity.
Obesity, in turn, clearly is multifactorial in
causation.
** They show familial clustering and determined
by the additive effects of many genes at different
loci (each gene controlling the trait contribute a
small amount to the phenotype) with the effect of
environment (interact with the genotype to
produce the phenotype)
the variation of expression are due to
environmental factors.
What are the factors that increase the probability of
recurrence in a particular family??
1. More than one member of the family is affected.
2. Severty or early onset disease.
3. High heritability of disorder
4.close relationship to proband. (A term used most
often in medical genetics and other medical fields to
denote a particular subject (person or animal) being
studied or reported on) * Male or female *.one sex
may be affected more than other sex**multifactorial
conditions have an unequal sex ratio.
5. proband of more rarely affected sex.
The chance of this trait to happen again depends upon
how close the family member with the trait is related to you
if your brother and sister higher chance than if your cousin
is affected.
(Examples of disorders of multifactorial inheritance)
*Congenital malformation:
heart defect
neural tube defects
cleft lip/palate.
Pyloric stenosis
congenital hip dysplasia
*common non-communicable diseases:
asthma
schizophrenia
DM
hypertension
Multifactorial inheritance as a mode of inheritance for
condition is more likely if:
• Condition is relatively common
• Incidence in relatives lower than for single gene
disorder but higher than in general population
• Risks to sibs similar to that of children
• Incidence falls rapidly in more distant relatives
• Incidence in relatives rises as the manifestations
become more severe in the index case
• Risk to relatives higher when index case is of the
least commonly affected sex
• Observed risk rises following the birth of two
affected children
(Refer to the slides)
liability –threshold model
All of the factors that influence the development of a
multifactorial disorder whether genetic or environmental
can be considered as a single entity known as liability
.
(**The threshold model was first applied to behavior
by Irving Gottesman and James Shields in their
classic twin study of schizophrenia. They postulated
that a number of different genes along with a number
of environmental variables acted as risk and
protective factors for the development of
schizophrenia. When enough risk factors accumulate
and greatly outweigh the protective factors, then
schizophrenia may develop. Because many factors
contribute to schizophrenia,
the liability or predisposition or vulnerability towards
schizophrenia is really a continuous, quantitative
dimension. Once, however, that liability (or
predisposition or vulnerability) passes a certain point
(the threshold), then a discrete phenotype emerges
(affected with schizophrenia versus unaffected with
schizophrenia).
 The liabilities of all people form a continuous
variable and have a normal distribution in both
general population and relatives of affected
individuals.
The incidence of the condition is greatest among
relatives of the most severely affected patients.
 The risk is greatest among close relatives and
decreases rapidly in more distant relatives.
 The incidence of the condition is greatest among
relatives of the most severely affected patients.
 If there is more than one affected close relative then
the risks for other relatives are increased
 Liability = quantitative trait that presents a genetic risk
for a threshold trait
 Individuals with a liability above threshold develop the
trait
 The risk of manifesting a threshold trait has H2 and h2
that cannot be estimated directly, but can be inferred
from the incidents of the trait among individuals and
their relatives
(Refer to the slides) # (30 -34)
Analyzing multifactorial traits:
it's difficult and requires multiple techniques they use
human genome sequences, population and family
studies.
 Empiric risk – incidence or rate an event occurs in a
population. (The chance that a disease will occur in a family,
based on experience with the diagnosis, past history, and
medical records rather than theory.)
 Prevalence - proportion of the population that has a
disorder at a specific time. (The proportion of
individuals in a population having a disease or
characteristic. Prevalence is a statistical concept referring
to the number of cases of a disease that are present in a
particular population at a given time, whereas incidence
refers to the number of new cases that develop in a given
period of time).
 Empiric Risk – increases with the severity, more
family members affected and the closer the
relationship to an affected individual.
• The closer the relationship; increased
probability, since increase in genes in common.
• Based on observations so it can be used even
in difficult transmission patterns.( based on
observation not study because we don’t know
that one gene that we should study)
 Heritability- Measurement of genetic.( How much of
this condition is related to genetic factor)
• Blood relationship and the coefficient of
relatedness (genes 2 related people share.
• Designate 10, 20,30
• Pedigrees (a document to record ancestry, used
by genealogists in study of human family lines,
and in selective breeding of animals)
50 % chance of inheriting genes from parents and
between siblings
Empiric risks:
• Recurrence risks are empiric risks derived from
population studies. So they are observational and do
not depend on theory as the Mendelian characters.
• Empiric risks vary according to several factors.
1- The incidence of the condition is
greatest among relatives of the most
severely affected patients
** Presumably because they are the most extreme
deviants along the liability curve. For example, in
cleft lip/palate the proportion of affected firstdegree relatives (parents, siblings, and offspring) is
6% if the index patient has bilateral cleft lip and
palate, but only 2% if the index patient has a
unilateral cleft lip
( fe jadwal bl slides ) #38
2- Recurrence risk increases with increasing
number of previously affected children
** If a couple have a baby with neural tube defect, •
recurrence risk is about 2-4%. If they have 2
children with neural tube defects, the recurrence
risk rises to 10%. It is not that having a second baby
caused their recurrence risk to increase, but it
makes them a couple who always had been at a
high risk. For MF disorders, bad luck in the past is a
predictor of bad luck in the future.
3- The risk is greatest among close relatives of
the index case and decreases rapidly in
more distant relatives
**In spina bifida the risks to first-, second- and third
degree relatives of the index case are approximately
4%, 1% and less than 0.5%, respectively.
Heritability (H) – Genetic Component
• Estimates the proportion of the phenotypic
variation in a population due to genetic
differences
– Value between 0 and 1: higher number
= greater genetic component
• Differs from Empiric Risk (includes
environmental component)
– Both vary with environment and time –
different reasons
• Estimated from: proportion of those
showing trait/those expected to show trait
•
4- If the condition is more common in
individuals of one particular sex, recurrence
risk varies according to sex of index case
** If the condition is more common in
individuals of one sex, then relatives of an
affected individual of the less frequently
affected sex will be at higher risk than relatives
of an affected individual of the more frequently
affected sex. This is illustrated by the condition
pyloric stenosis. Pyloric stenosis shows a male
to female ratio of 5 to 1.
( the threshold must be higher for girls than boys )
Relatives of an affected girl must have a higher
Susceptibility than relatives of an affected boy.
Offspring of male index patients are 6.4% risk for sons
and 2.5% risk for daughters. The risks to the offspring of
female index patients are 22.9% for sons and 11.4% for
daughters.
………..
Heritability Measures the Genetic
Contribution to Phenotypic Variation
** Heritability is measured by estimating the relative
contributions of genetic and non-genetic differences to the
total phenotypic variation in a population. Heritability is an
important concept in quantitative genetics, particularly
in selective breeding and behavior genetics (for
instance, twin studies), but is less widely used
in population genetics.
** Heredity has nothing to do with incidence in
population** (mesh eza Kan el heritability 3ali m3nato
incidence kteer)
Slides 45-46
………………………
Analyzing multifactorial traits:
**Comparisons between and within families
 Twins dizygotic and monozygotic
 Twins raised apart ( same gene different
environment)
 Adopted children(different gene same
environment )
**Association studies – compare SNP patterns between
affected and unaffected groups, identify important DNA
regions
• Concordance (( the presence of the same trait in
both members of a pair of twins. However, the strict
definition is the probability that a pair of individuals
will both have a certain characteristic, given that one
of the pair has the characteristic. For example, twins
are concordant when both have or both lack a given
trait.[1]The ideal example of concordance is that
of identical twins.))
• Used to determine heritability
• Has limitations, assumes both type of twins share
similar environments
• MZ twins often share more similar
environments
• Monozygotic twins

Single fertilization

Genetically identical
• Dizygotic twins

Independent fertilizations

Share approximately half their genes
Twin studies ** reveal the absolute and relative
importance of environmental and genetic influences on
individuals in a sample. Twin research is considered a key
tool in behavioral genetics and in content fields, from
biology to psychology. Twin studies are part of the
methods used in behavior genetics, which includes all
data that are genetically informative –siblings, adoptees,
pedigree data etc.
………..
slide 50 for calculation of relative risk of disease
association.
………..
Slides 51-52
Concordance % of pairs of individuals that share the
trait (both affected or both unaffected)
Fe jadwal bl slides shofo.
Separating genes and environment :
• Dizygotic twins: Shared environment and 50% of
genes
• Monozygotic twins: Identical genotype, and shared
environmen
• Twins raised apart: Shared genotype but not
environment
• Adopted individuals: Shared environment but not
genes
• Disease concordance less than 100% in MZ twins is
strong evidence that non-genetic factors play a role
in the disease.
• Greater concordancy in MZ versus DZ twins is
strong evidence of a genetic component to the
disease.
• An important exception is X-linked diseases. In
females, discordancy could also be due to
differences in the proportion of maternal versus
paternal X that is inactivated.
Ascertainment bias can also affect twin studies
(refer to the slides 55-56)
……..
Correlation :
 Correlation coefficient
The fraction of genes shared by two relatives
Identical twins have 100% of their genes in
common (correlation coefficient = 1.0)
When raised in separate environments identical
twins provide an estimate of the degree of
environmental influence on gene expression
Association Studies :
 Studies which compare a group of interest (cases)
to a control group for the presence of a gene or
SNP.
 Controls are matched to cases for characteristics
that may confound results: age, ethnicity, gender,
environment.
 If the SNP is present more often in cases than
controls, it is associated with the trait and implies
that the SNP may be near a gene impacting the
trait.
SNP (single nucleotide polymorphism) :
Nucleotide site with more than one allele is a
polymorphism
• On average between two random individuals, there
is one SNP every 1000 bases => 3 million
differences!
Genetic linkage and linkage analysis :
** Genetic linkage analysis is a powerful tool to detect
the chromosomal location of disease genes. It is based
on the observation that genes that reside physically
close on a chromosome remain linked during meiosis.
For most neurologic diseases for which the underlying
biochemical defect was not known, the identification of
the chromosomal location of the disease gene was the
first step in its eventual isolation. By now, genes that
have been isolated in this way include examples from all
types of neurologic diseases, from neurodegenerative
diseases such as Alzheimer, Parkinson, or ataxias, to
diseases of ion channels leading to periodic paralysis or
hemiplegic migraine, to tumor syndromes such as
neurofibromatosis types 1 and 2.
 Two loci are linked if they appear closseby in the
same chromosome.
 The task of linkage analysis is to find markers that
are linked to the hypothetical disease locus
 Complex diseases in focus  usually need to
search for one gene at a time
 Requires mathematical modelling of meiosis
• One of the two main approaches in gene
mapping.
Uses pedigree data
Farah Ode'h