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What is a candidate gene study?

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One method of studying the nature of the expression specific gene is called the "candidate gene" method. This allows researchers to take educated guesses about the genetic basis of this or that trait. The "educated" part has to do with hypothetical inferences based on what we know or think we know about the role of a specific gene in a specific biological function or disease. For example, a candidate gene study of aggression might involve the study of genes which mediate or regulate expressions of testosterone, based on what we know about the biological pathway of an underlying biological pathway, or its function in the brain.

Since men are more predisposed to aggression, and testosterone is more common in men, and testosterone is known to have a profound effect on brain development and function, then the neuroscientist might suggest that testosterone is somehow involved in aggression, and might therefore seek to locate genes which mediate testosterone, and with it, aggression. Linkage studies, genome wide association studies (GWAS) or expression studies may all be involved in an attempt to identify candidate genes.

The researcher proceeds by testing different variants of the proposed vandidate gene. The implication is that the gene variant is responsible for certain trait variants. For example, if a variant of a gene involved in regulating serotonin is associated with a certain mood disorder, this increases the likelihood that it is this variant that produces a protein whose trait manifests itself differently from the norm. It is in this way that the researcher is able to generate and test hypotheses concerning which variants may result in which differences or deviationts in trait expression.

This method of study is useful in attempting to determine whether or not certain disorders may have common genetic roots, and therefore, perhaps, similar biological pathways. Family studies may be helpful in determining whether or not a candidate gene hypothesized to be responsible for a specific syndrome or disease really is repsonsible for it, since relatives tend to share a large number of genes and may thus share the candidate gene in question.

Multiple family groupings (e.g., parents and child, siblings) may be used to increase the likelihood of finding an association. Using relatives takes advantage of the fact that a certain percentage of genes are shared between parents and children.

Researchers tend to search for gene variants which may be causally associated with the transmission of the candidate gene which they believe are responsible for a particular disease or syndrome. The operative assumption in such studies is that of the truth of 'linkage disequilibrium,' which refers to the belief that if the transmission of a specific genetic variant tends to be associated with the transmission of the candidate gene, this increases the probability of the genetic marker being a causative factor in that trait.

The essence of linkage disequilibrium refers to the non-randomness of the association between the co-ordinate transmission of two alleles. While alleles tend to be transmitted independently of one another, some alleles exhibit a tendency to be co-ordinately transmitted, or transmitted with one another.

Thus, when we find the transmission of a specific gene variant correlated with the transmission of the candidate gene we are studying, it increases the odds of that gene variant being causally responsible for that trait along with the candidate gene.

Of course, there are limitations to such a study. The identification of such candidate genes assumes that we understand the relationship between the candidate gene and the biological pathway for which it is supposedly responsible. Most traits, however, are the result of numerous genes, each of which individually contributes a small amount to the trait's emergence.

Identification the independent contribution of a single gene may therefore be quite difficult and fraught with uncertainties. There may therefore be a highly subjective element to such a study. Assumptions about the function of the gene among researchers may vary and may be circumscribed by that researcher's field of interest, causing him to ignore causative variants external to that genetic region.

Furthermore, findings in such association studies are frequently not replicated in other independent studies. This causes some to believe that the candidate gene approach is therefore unreliable. Furthermore, independent studies which do attempt to replicate findings of other independent studies oftentimes yield contradictory results, sometimes due to study design variations.

For example, a subsequent candidate gene study that attempts to replicate findings of a previous one may differ in its results because it chooses a different study population or a different definition of phenotype. This is especially true of complex diseases involving several biological pathways which may result in various phenotypical expressions. Researchers may therefore identify the same disease in a different manner in individuals.

Furthermore, relying too much on linkage disequilibrium may produce inaccuracies in studies. Physical distance between genes is correlated with the likelihood of their being transmitted together. However, the assumption of linkage disequilibrium between two genes is not always justified and may prove problematic in attempting to find a relevant association between genes and trait expression. In other words, the two genes may not be in linkage disequilibrium at all.

Lastly, it is important to supplement candidate gene studies with other methods of analysis such as genome-wide association studies and linkage analysis. Relying on candidate gene studies alone may be inadequate and fail to account for converging lines of evidence (or lack thereof) from other methods of studying.