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Polygenic Disorders 5 Notes

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Polygenic Disorders, population genetics, prenatal diagnosis Polygenic inheritance and normal distribution Polygenic inheritance: inheritance and expression of a phenotype being determined by many genes at different loci with each gene exerting a small additive effect (effects of genes are cumulative-no one gene is recessive or dominant)
-Polygenic inheritance generates a phenotype with normal distribution due to multigene effect- genes generate a continuous trait when they act together -each gene has varying effects on trait occurrence and development

-Most of the polygenic phenotypes are also influenced by the environment and by genes that don't have an additive effect E.g of human characteristics showing continous normal distributions: Height, blood pressure, intelligence, waist size
-mutations casuing single gene diseases have a major impact on the function of the gene product so are rare. Mutations causing polygenic disease/multifactorial have a more moderate effect- so are relatively common Multi-factorial inheritance - the liability/threshold model
-The liability/threshold model- discontinuous traits all of the factors which influence the development of a discontinuous multifactorial disorder, genetic/environmental is considered as a liability
-the liability of all individuals in a population forms a continous variableforms a normal distribution in the general distribution and affected relatives of affected individuals (here curve shifted right)
-discontinuous phenotype: affected/ not affected - if threshold of liability is exceeded, phenotype is expressed- determined by the combination of genes

one has inherited and the exposure one has had to environmental risk factors
-general population, the proportion beyond the threshold is the population incidence and the relatives the proportion beyond the threshold is the familial incidence
-This model is a hypothesis for inheriting conditions such as spina bifida, cleft lip Recurrence risk- greater risk in exceeding the threshold risk that a disease will occur elsewhere in a pedigree given that at least one member of the pedigree exhibits the disease. The recurrence risk increases as the number affected family members increase and also depends on the severity of the disease
-if there is a multiple consanguineous family and the child is affected with a rare syndrome and there is unknown gene, homozygosity mapping is done to find out areas of the genome that are commonly inherited between affected individuals E.g
-In Cleft lip and palate- the proportion of first degree relative affected is 6% if index patient has bilateral cleft lip and palate
-Proportion of first degree releatives affected is 2% if index patient has only unilateral cleft lip
-in Spina Bifida, risks to first degree relative is 4%, second degree relative 1% and third degree relative 0.5%. If more than one close relative is affected, risks increase. If 2 siblings are affected next child- 10%
-it is not possible to measure an individual's liability for a particular disorder it is possible to estimate what proportion of the aetiology can be due to genetic factors as opposed to environmental factors Definition: total of the phenotypic variance of a condition that is caused by additive genetic variance
-symbol for heritability is h2 and is expressed as a proportion of 1 or as a percentage- greater the value the more genetic the condition

E.g Schizoprenia- 85%
Spina Bifida-60%
-Heritability is measured from the degree of resemblance between relatives and is expressed in the form of a correlation coefficient. Assesing if the disease has a genetic component
-Identifying genetic factors identifies people who are susceptible to a particular disorder
- some diseases genetic susceptibility is the main determinant of development of disease (Coronary heart disease) but can be modified by environmental alteration
-Some diseases environmental factors are the main determinant of development of disease Population and immigration studies?

Difference in Incidence of particular disease in different populations suggests the possibility of genetic factors- may be explained by environmental factors Study a low incidence immigrant group moving to new group with high incidence.
- If incidence rises then more likely to be environmental.
- Maintenance of low incidence would suggest genetic factors are important.

Family studies?

Higher frequency of disease in family relatives than in general population. Proportion of affected relatives of a specific relationship- 1 st degree, 2nd degreeempirical recurrence risks in genetic counselling
- However, families often share a common environment, so may not be genetic.
- Spouses (different genetic background) but share common environment can serve as controls for environment
- look at % of affected relatives of specific relationship e.g. 1o / 2o risks



risk to siblings of patients

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