chapter_8 - Multifactorial inheritance Mendelian polygenic...

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Mendelian, polygenic and multifactorial The contribution of hereditary factors to disease is a continuum. On one side of the spectrum reside the Mendelian conditions, on the other side we find the complex or multifactorial conditions. In between are the oligo- and polygenic conditions. Mendelian conditions are monogenic and are characterized by segregation and a clear inheritance pattern. Multifactorial diseases are caused by genetic as well as environmental factors. For these conditions, there usually is no clear inheritance pattern, although the family history is usually positive. The distinction between these conditions is based on the number of loci that affect the phenotype and their penetrance. As the number of loci that affects a particular phenotype increases, the phenotype adopts a Gaussian distribution. Well known examples of multifactorial conditions are: asthma, hypertension, diabetes and auto-immune diseases. Although the genetic basis for these diseases is less pronounced than for the Mendelian conditions, they are vastly more important for health care. Only recently, with the introduction of high throughput genotyping systems, the knowledge on genetic variation in man and the outgrowth of bioinformatics, studying these conditions became a feasible objective. the liability model In analogy to the distribution of the phenotypes, the risk of developing a polygenic or multifactorial condition (liability, susceptibility) is distributed normally. The liability model hypothesizes that a particular phenotype will emerge when the risk of an individual exceeds a certain threshold. This model explains the variation of the recurrence risk within families. When an individual develops a multifactorial disease, this will be the result from carrying a critical number a susceptibility alleles. Relatives of this affected individual will share a number of risk alleles with this person: therefore their risk curve shifts to the right. As the threshold remains the same, the same condition will be present in a larger number of family members as compared to the general population. The increase in risk for relatives will depend on the number of shared genes with the affected individual and therefore on the degree of kinship. A large number of conditions for which a similar threshold is assumed have a different incidence in males and females. Arguably, this is the consequence of a sex specific critical threshold. As an example: congenital pyloric stenosis is a polygenic condition that occurs 5 times more frequently in boys, the threshold should therefore by higher in girls. heritability
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chapter_8 - Multifactorial inheritance Mendelian polygenic...

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