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MULTIFACTORIAL DISORDERS
Learning Objectives
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Define multifactorial inheritance
Define polygenic inheritance
Enlist common diseases with multifactorial causes
Terms
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Polygenic traits are determined by two or more genes
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Multifactorial traits are controlled by two or more genes and show
significant interaction with the environment
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Complex traits are ones where relative contribution of genes and
environment are not yet established
Polygenic Inheritance
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Traits are usually quantified by measurement
Two or more genes contribute to the phenotype
Phenotypic variation varies across a wide range
Better analyzed in populations than in individuals
Example: human eye color
As the number of loci increases, the number of classes
increases
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As classes increase, phenotypic difference between classes decreases
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Averaging out of the phenotype is called regression to the mean.
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Multifactorial Traits
Genotype does not change after fertilization (except by mutation)
Phenotype is the sum of the observable characteristics and may change
throughout life
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Environment includes all genetic and nongenetic factors
Characteristics of Multifactorial Traits
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Polygenic
Genes controlling trait act additively
Environmental factors interact with the genotype to produce the
phenotype
Assessing interactions can be difficult
Methods Used to Study Multifactorial Traits
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Threshold model
Frequency of disorder among relatives is compared with the frequency
of the disorder in the general population
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Recurrence risk
Estimates the risk that the disease will recurrance
Threshold Model
Familial Risk
Phenotypic Variation
Sources of phenotypic variation
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Genotypes in the population
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Variation in the environment
Heritability – how much of the observed phenotypic variation is due to
differences in genotype
Factors that Contribute to Phenotypic Variance
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Genetic variance
Variance attributed to the genotypic differences
Environmental variance
Variance attributed to differences in the environment
Correlation coefficients
Measure the degree to which variables vary together
Heritability of Fingerprints
Twin Studies
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Monozygotic twins
– Single fertilization
– Genetically identical
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Dizygotic twins
– Independent fertilizations
– Share approximately half their genes
Multifactorial inheritance
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Inheritance controlled by many genes with small additive effects
(polygenic) plus the effects of the environment
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Clinical clue:
One organ system affected
Multifactorial inheritance
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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 inheritance:
Factors increasing probability of recurrence in a particular family
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Close relationship to proband
High heritability of disorder
Proband of more rarely affected sex
Severe or early onset disease
Multiple family members affected
Multifactorial inheritance as a mode of inheritance for a condition is more
likely if……
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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
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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
Multifactorial traits
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Genetic predisposition likely to be due to a particular
combination of genes
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The genes and environmental factors causing a
particular multifactorial trait may vary from person to
person
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Most diseases with a genetic component are not inherited in Mendelian
fashion but display multifactorial inheritance
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Multifactorial disease usually polygenic -many genes each with small
additive effects
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Major effort to identify common disease susceptibility genes underway
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Identification of SNPs associated with disease susceptibility.
Examples of disorders of
multifactorial inheritance
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A. Congenital malformations:
congenital heart defects
neural tube defects
cleft lip/palate
pyloric stenosis
congenital hip dysplasia
B. Common non-communicable diseases:
asthma
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schizophrenia
diabetes mellitus
hypertension
Common diseases
• Congenital malformations
Cleft lip/palate
Congenital hip dislocation Congenital heart defects
Neural tube defects
Pyloric stenosis
Talipes
Multifactorial
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Examples include some cases of cleft lip and palate; neural tube defects;
diabetes and hypertension
Caused by a combination of genetic predisposition and environmental
influences
Pattern – more affected people in family than expected from incidence
in population but doesn’t fit dominant, recessive or X-linked
inheritance patterns.
How can the probability of recurrence be determined for multifactorial
disorders?
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The recurrence risk for multifactorial disorders has to be determined
through family studies
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Observe the number of affected siblings in many families (empiric risk)
How evidence is gathered for genetic factors in complex diseases
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Familial risks
(what is the incidence of a disorder in relatives compared with the
incidence in the general population?)
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Twin studies
(what is the incidence in monozygotic compared with dizygotic twins?)
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Adoption studies
(what is the incidence in adopted children of the disorders which their
parent had?)
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Population and Migration studies
(what is the incidence in people from a particular ancestry group when
they move to a different geographical area?)
Multifactorial traits
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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 inheritance
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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.
Polygenic / Multifactorial traits
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A normal distribution (Gaussian or bell shaped curve) is generated by
many genes, known as polygenes, each acting in an additive fashion.
Conclusions
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Multifactorial disorders are more common than single gene and
chromosomal disorders
They are caused by the interaction of many genes with environmental
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factors.
Optimum preventive measures rely on avoidance of the bad
environmental factors since avoidance of inheriting the bad genes is
at present not possible.
4. These measures can be explained through counseling such as
periconception and chronic noncommunicable diseases counseling.
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Reference
Kaplan Biochemistry and medical genetics