Deck 14: Molecular and Genetic Epidemiology

Question 1

One of the potential limitations of case-control studies of the biological basis of disease is that the disease process may alter the exposure of interest. Is that a concern for germline DNA?

Answer 1

No. Our germline DNA does not change. We may acquire mutations in specific tissues, but collection of a blood sample for extraction of DNA will result in the procurement of DNA that we inherited and have possessed since birth.

Question 2

For some rare autosomal dominant diseases, it is possible that the dominant homozygote has never been seen. One reason is that the fetus with this genotype may die early in development and be spontaneously aborted. In fact, roughly 25% of all women will have a pregnancy end in spontaneous abortion at some point during their lifetimes. Consider a situation in which
Q/Q dies as an early fetus; Q/q lives to reproduce but is unaffected; q/q lives and is unaffected. What genotypes are possible among live-born children of the mating Q/q × Q/q? (Hint: Construct a 2-by-2 table to reflect the genotypes of the parents.)

Answer 2

1/4 of the potential offspring will be Q/Q and die in utero. Therefore, only Q/q and q/q will be observed. 2/3 will be Q/q and 1/3 will be q/q.

Question 3

Cancer of the kidney constitutes about 2% of all human cancers, and renal cell carcinoma comprises about 85% of all kidney cancers. Although the etiology is largely unknown, a quick review of the literature reveals nearly 30 case reports of familial aggregates. Can one conclude that renal cell carcinoma is hereditary?

Answer 3

No. There may be a hereditary component, but common environmental exposure must be considered, as well as the role of chance.

Question 4

Family history of disease is often used as a surrogate marker of genetic susceptibility. For a common disease with a late and variable age at onset, what two factors play a significant role in your interpretation of a case-control study of family history?

Question 5

A segregation analysis of a large set of randomly selected families suggests weak evidence for a genetic influence on obesity. The investigators split their families into two groups, based on the median age of the probands. Results indicate a substantial genetic influence on obesity among the late-onset group of families, but no significant genetic influence on obesity among the early-onset group of families. You intend to map the genes (or gene) that influence(s) risk of obesity. Would you measure risk factors among family members? If so, which risk factors would you measure?

Question 6

Genetic linkage studies can be either based on a model of inheritance or parameter free. For the former, one needs to know the mode of inheritance and the penetrance (age-risk function). How are penetrance values obtained for presumed genetic susceptibles?

Question 7

Twelve families are selected for a genetic linkage study because of a high prevalence of disease. A genome screen is performed, using anonymous DNA markers on all autosomes. Significant evidence is observed for linkage to a marker on chromosome 2 (D2S123) in four families. The LOD score for the remaining families at this locus is significantly negative. How do you interpret this finding?

Question 8

You are interested in identifying the role of genetic factors in alcoholism. A case-control study is done of patients with alcoholism and age- and sex-matched controls. After DNA is obtained, the alcohol dehydrogenase-3 gene is analyzed for a common genetic polymorphism. The frequency of the polymorphism is found to be significantly higher among cases than controls. The polymorphism results in a silent amino acid substitution, and functional studies indicate that the variant and the normal allele have similar activity. How do you interpret your finding?