Chat with AIExam 14: Molecular and Genetic Epidemiology
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.)
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Verified1/4 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.
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?
(70) VerifiedA number of possibilities should be explored. If the allele frequency differs by race and ethnicity, the study groups should be examined for comparability (confounding). Also, the genetic variant under study may be a case of simple linkage (linkage disequilibrium) to a functional mutation either in another exon or in some part of the gene that regulates transcription (enhancer or promoter region). Finally, one must acknowledge that the findings simply could reflect chance.
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?
(73) VerifiedYou would certainly need to have measures of obesity from the family members (from either height and weight, underwater weighing, body circumferences, or skinfolds). Because age appears to be important, you will need to know their ages. Besides genetics, a number of other risk factors for obesity exist (e.g., physical disability and co-morbidities); these risk factors may preclude exercise, diet, and other interventions for obesity. Such measures of risk are helpful in fitting "nongenetic" models to the family data.
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?
(78) 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?
(76) 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?
(78) 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?
(74) 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?
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