Multifactorial or Polygenic
Inheritance
Hanan Hamamy
Department of Genetic Medicine and Development
Geneva University Hospital
Training Course in Sexual and Reproductive Health Research
Geneva 2011
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Multifactorial Inheritance and Human Diseases: Genetic and Environmental Factors - Prof. G, Study notes of Biochemistry
An overview of multifactorial inheritance, a complex genetic concept that explains how human diseases are caused by the interaction of multiple genes and environmental factors. The spectrum of human disease, multifactorial disorders, polygenic inheritance, heritability, and the liability/threshold model. Examples of multifactorial disorders and diseases with high heritability are given, along with the risks for relatives and population incidence.
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Multifactorial or Polygenic
Inheritance
Hanan Hamamy Department of Genetic Medicine and Development Geneva University Hospital
Training Course in Sexual and Reproductive Health Research Geneva 2011
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 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
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.
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
- Asthma
- Pyloric stenosis
- Ischaemic heart disease
- Essential hypertension
- Spina bifida
- Diabetes mellitus
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.
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.