Multifactorial or Polygenic

Inheritance

Hanan Hamamy
Department of Genetic Medicine and Development
Geneva University Hospital

Training Course in Sexual and Reproductive Health Research

Geneva 2010
 Spectrum of Human Disease
Human diseases are caused by a multitude of
genetic and environmental factors acting
together.
In certain conditions such as Down syndrome ,
genetic factors predominate, while in infections
for example, environmental factors predominate.
Most chronic non-communicable conditions such as
schizophrenia and diabetes as well as congenital
malformations are caused by an interaction of
both genetic and environmental factors.
 Multifactorial inheritance

Diseases that show familial clustering

but do not conform to any recognized
pattern of single gene inheritance are
termed multifactorial disorders.
They are determined by the additive
effects of many genes at different
loci together with the effect of
environmental factors.
 Multifactorial disorders
These conditions show a definite
familial tendency but the incidence in
close relatives of affected individuals is
usually around 2-4%, instead of the
much higher figures that would be seen
if these conditions were caused by
mutations in single genes (25-50%).
 Examples of disorders of
multifactorial inheritance
Congenital malformations:
congenital heart defects
neural tube defects
cleft lip/palate
pyloric stenosis
congenital hip dysplasia
Common non-communicable diseases:
asthma
schizophrenia
diabetes mellitus
hypertension
 Polygenic inheritance
This involves the inheritance and
expression of a phenotype being
determined by many genes at different
loci, with each gene exerting a small
additive effect.
Additive implies that the effects of
the genes are cumulative, i.e. no one
gene is dominant or recessive to
another.
 Multifactorial traits
Several human characteristics show a
continuous distribution in the general
population, which closely resembles a
normal distribution. This takes the form
of a symmetrical bell-shaped curve
distributed evenly about a mean.
 Polygenic / Multifactorial traits
A normal distribution
(Gaussian or bell shaped
curve) is generated by many
genes, known as polygenes,
each acting in an additive
fashion.
Human characteristics that show a continuous
normal distribution

Height
Intelligence
Blood pressure
Skin colour
 Heritability
Heritability of a trait or disease is the
proportion of the total variance that is
genetic.
The overall variance of the phenotype is
the sum of the environmental and genetic
variance.
Heritability provides information of the
importance of genetic factors in the
causation of the disease.
Examples of heritability estimates

Schizophrenia 85
Asthma 80
Pyloric stenosis 75
Ischaemic heart disease 65
Essential hypertension 60
Spina bifida 60
Diabetes mellitus 40
 Liability curve and threshold
According to the
liability/threshold model, all of
the factors which influence the
development of a multifactorial
disorder, whether genetic or
environmental, can be
considered as a single entity
known as liability.

The liabilities of all individuals

in a population form a
continuous variable, which can
be exemplified by a bell shaped
curve.

Individuals on the right side of

the threshold line represent
those affected by the disorder.
 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. In the general
population the proportion beyond the
threshold is the population incidence, and
among relatives the proportion beyond the
threshold is the familial incidence.
Liability curves of affected and their
relatives
The curve for
relatives of
affected will be
shifted to the right;
so the familial
incidence is higher
than the general
population incidence.
 Familial incidence versus general
population incidence
The risk of recurrence for first-degree
relatives, i.e. siblings and offspring of
an index case approximates to the
square root of the general population
incidence.
Thus if the incidence in the general
population is 1 in 1000, the sibling and
offspring risk will equal approximately 1
in 32 or 3% (square root of 1/1000).
 Population and recurrence risks for
Type 2 diabetes mellitus

If incidence in the general

population is 4-5%, then possible
rate of affection in first degree
relatives (brothers, sisters, sons
and daughters) is around 10-15%.
Liability curve and threshold
 Liability or susceptibility for a
certain disorder
For example : every embryo has a certain
susceptibility to cleft palate.
The susceptibility is low or high and follows a
Gaussian distribution in the population.
Embryos whose susceptibility exceeds a critical
threshold value develop cleft palate, those whose
susceptibility is below the threshold develop a normal
palate.
Susceptibility is the product of interaction of many
genes with environmental factors in utero.
 Characteristics of multifactorial
inheritance
Polygenic threshold characters tend to run in
families because affected individuals have
relatives who share their genes with them.
Parents who have several affected children
will have more high risk alleles than parents
with only one affected child.
Thus recurrence risk increases with
increasing number of previously affected
children.
 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.

 If the index patient

has bilateral cleft lip
and palate, the risk to
future sibling is 6%.
 If the index patient
has unilateral cleft lip,
the risk to future
sibling is 2%.
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.
4- If the condition is more common in individuals of one
particular sex, recurrence risk varies according to sex
of index case

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.
 To be affected or not depends on a balance
between the number and function of good and
bad genes and environmental factors
 Conclusions

Multifactorial disorders are more

common than single gene and
chromosomal disorders
They are caused by the interaction of
many genes with environmental factors
 Conclusions
Optimum preventive measures rely on
avoidance of the bad environmental
factors since avoidance of inheriting
the bad genes is at present not possible.
These measures can be explained
through counseling such as
periconception and chronic non-
communicable diseases counseling.