The existence of two or more different chromosomal sites where mutations result in the same clinical expression is called:
B. Locus heterogeneity refers to the existence of mutations in different chromosomal loci resulting in the same disease phenotype. It is an important clinical phenomenon when attempting to test for the presence of a carrier state or mutation for a specific disease. For example, early-onset Alzheimer’s disease could be caused by presenilin 1 or 2 mutations or by β amyloid precursor mutations. These mutations occur in chromosomes 14, 1, and 21, respectively. (Pleiotropy and allelic heterogeneity are explained below.)
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Which of the following factors is often corrected for when ascertaining probands and unaffected relatives for family genetic studies?
A. When ascertaining cases for genetic family studies it is possible to miss certain cases as the disease has not occurred as yet in some members of the family. For example if a disease presents at age 40 on average, and if the studied family has three ‘normal’ members aged 50, 30, and 18, there is still the possibility that the latter two may become ‘cases’ in the future. Various methods of age correction have been employed to ascertain the morbid risk precisely in such cases. Weinberger’s weighted age method is a popular approach. Life tables can also be used for age correction. In most genetic disorders, birth order does not play a role in disease expression as each birth is an independent genetic event. Duration or severity of illness does not complicate the issues in most family studies.
A researcher studying the genetic explanation for delusional disorder detects genes at two different loci in the sample studied. One gene modifies the expression of the other in producing the delusional disorder phenotype. This phenomenon is called:
A. Epistasis is the term used to describe gene interactions. Epistasis specifically refers to interaction between alleles at different genetic loci. This interaction is evident in the protein production and function of the involved genes. It can occur at the same step or at different stages of the same biochemical pathway. Variable expression refers to the variation in the degree of phenotypic expression seen in certain genetic disorders. Some individuals carrying the phenotype may be severely affected while others will only be mildly affected. This may be due to the effect of environment on a phenotype, allelic heterogeneity (different mutations causing a phenotype, leading to variation in expressed severity), or epistatic influences (another genetic loci conferring protection against severe expression by modifying the biochemical pathway at a distant site). Incomplete penetrance refers to the phenomenon where some individuals with the disease genotype do not display any signs of the disease at all. If the number of obligate carriers of a genotype (individuals who possess a genotype) is 100, and the number showing disease expression is 80, then the penetrance rate is 80%. Codominance refers to simultaneous expression of two alleles at a chromosomal locus, for example AB blood group when one chromosome has genotype A and the other has genotype B.
The population distribution curve of a multifactorial trait is such that when it crosses a threshold disease becomes manifest.
A similar distribution curve for relatives of affected individuals will be:
A. Multifactorial diseases could be defined by a threshold model. Considering psychiatric disorders, the families of affected individual often show substantially higher risk than the general population. These disorders can be described as quasicontinuous as the affected portion (defined categorically) of the population can be differentiated as mild to severe in the spectrum (continuous dimensions). This could be described as having a continuously distributed liability to develop the disease that is inherited, while the actual expression is multifactorial. If the liability crosses a particular threshold then disease expression could occur. This liability distribution curve is shifted to the right if relatives of a patient are considered, as, for the given threshold, more affected individuals are found in the families than in the general population.
In spite of accumulating evidence for the role played by genetic factors in various psychiatric illnesses, this is not translated to clinical genetic approaches in psychiatry.
This paucity is most probably related to:
B. The odds ratio in most psychiatric genetic association studies are in the order of 1 to 2, the median being 1.3. This is insufficient to prove a genetic cause for most disorders. To demonstrate a more significant odds ratio, very large sample sizes are required; this methodological problem is being surmounted, at least partially, by meta-analyses that are providing evidence for the role of certain genes in psychiatric disorders. Non-contingent gene–disorder association refers to the fact that the relationship is not influenced by other factors such as environment or presence of other genes, that is not polygenic or multifactorial. But most psychiatric disorders do not follow non-contingent association models. The causal pathway from an identified genetic abnormality to actual disease expression is too complex and not fully explored in most known genetic markers of psychiatric diseases. For example it is unclear how a mutant dysbindin gene can lead to a belief that aliens are invading earth. There are few notable exceptions to this; for example the role of the serotonin transporter polymorphism in mediating the effects of life events on the risk of depression. For a long time, much genetic research was guided by the assumption that genes cause diseases, but the expectation that direct paths will be found from gene to disease has not proven fruitful for complex psychiatric disorders. Gene × environment interaction models of disease causation appear promising, as in Caspi’s work, and may possibly throw more light on the causal chains from gene to disease.
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