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Genetics of complex diseases


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What are some characteristics of complex genetic diseases?
-show no clear pattern of mendelian inheritance
-are influenced by multiple gens and environmental factors
-are often common diseases
Define genetic heterogeneity.
Different genes causes simiiar disease in different families
Define decreased penetrance.
not all persons with the susceptibility genotype are affected
Define polygenic inheritance
Several genes acting together. (Instead of having 1 gene that causes the disease, you may need 10 to 20 risk alleles to really increase the risk)
BRCA1, BRCA2, and bipolar affective disorder are examples of ?
susceptibility genes - rare, high penetrance
Mild vs. Severe sickle cell and adrenoleukodystrophy vs. adremomyeloneuropathy are examples of ?.
Modifiers of severity
Modifiers of severity can be described as ?:? interaction.
Define 'multifactorial trait' and tell which method is best used in analysis.
Definition: a trait that is caused by both genetic and enviromental risk components

Since it is difficult to model in segregation analysis and linkage analysis, it is best to use non parametric anaylsis
What is the one the first questions asked?
Is there evidence of clustering of disease in families?
What would serve as epidemiological evidence of familial aggregation?
1. The incidence of the disease is higher in relatives of cases than relatives of controls.
2. A higher proportion of cases than controls have a family history of the disease.
What is λ(r)?
the recurrence risk ratio (aka relative risk)
-risk of disease in relatives of probands/risk in population
-risk of disease in relatives of probands/risk to relatives of controls
what does a relative risk in closer family members suggest?
It implies a genetic component (not proven though)
What is the threshold of λ(r) that implies a significant genetic component?
In general, any λ>2.0 is believed to indicate a significant genetic component.
What is the purpose of segregation analysis?
-to study how a disease or trait is transmitted from one generation to the next
-to determine whether there is evidence for major gene effects on the susceptibility to the disease or variability of the trait
How is segregation analysis generally performed?
-fitting probability models to observed family data
-compare the OBSERVED pattern of affected individuals in the families to the EXPECTED patterns based on particular genetic models
-determine if any models can be rejected
What is implied with a genetic model is not rejected?
That a major locus may be involved in causation of the disease, but it is NOT PROOF.
What is linkage disequilibrium?
The tendency of specific combinations of alleles at two or more linked loci to occur together on the same chromosome more frequently than would be expected by chance.
What are candidate gene studies used for?
to determine whether a polymorphism in a known gene is associated with:
the presence of the disease (susceptib.)
with the phenotypic expression of the disease (disease modifier/severity gene)
What are some criteria for choosing a candidate gene?
-biologic plausibility
-specific polymorphism in exon or regulatory region (protein change)
-candidate in chromosomal region showing evidence for linkage from previous study
-frequence of polymorphism high enough to detect in the population sample
The risk of breast cancer to women with an affected first degree relative is ? to ? times the risk to women without such a first degree relative.
2 to 3
What percentage of lung cancers are directly attributed to smoking?
80 to 90%

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