![]() ![]() The biological justification for the choice of the genetic contrasts (which may not necessarily present the genetic model of inheritance) to be tested is, however, seldom available and lack of a priori assumption for the specific genetic model is customary practice. Note that this contrast does not correspond to the conventionally examined "additive model" which is tested using the Armitage's test for trend ) (ii) the recessive contrast, which compares genotype mtmt with the merged genotypes wtwt + wtmt (iii) the dominant contrast, which merges genotypes mtmt + wtmt and compares them with genotype wtwt and (iv) the co-dominant contrast, which compares genotype wtmt against the merged genotypes mtmt + wtwt. wtwt- (in this contrast the heterozygotes are ignored. Thus, in view of a significant association, the following contrasts of genotypes are defined by merging information of the genotype distribution, and estimated with the odds ratio (OR) and its 95% confidence interval (CI): (i) the additive contrast, which is defined as the comparison between the extreme genotypes - mtmt vs. However, besides evaluating the overall statistical significance, the clinical relevance of a genetic association depends on the magnitude of risk conferred to the carriers of allele mt. ![]() For a bi-allelic candidate gene with alleles wild-type wt and mutant-type mt in a case-control study, where mt is thought to be associated with a disease, the association is usually assessed using a chi-squared test for the 3 × 2 contingency table with genotype entries n 11( wtwt), n 21( wtmt) and n 31( mtmt) for the control subjects, and n 12( wtwt), n 22( wtmt) and n 32( mtmt) for the diseased subjects. Genetic association studies (GAS), candidate-gene and genome-wide association studies assess the association between a disease and genetic variants (gene polymorphisms) in a population. The introduction of the degree of dominance provides useful insights into the mode of inheritance in GAS. ![]() In addition, power for detecting significance of h when the study conforms to HWE rule increases with the degree of dominance and to some extent is related to the mutant allele frequency. Simulations show that h may capture the real mode of inheritance and it is affected by deviations from Hardy-Weinberg equilibrium (HWE). ![]() Otherwise, dominance (including over- and under-dominance) is present and the direction of dominance depends on the value of h. Non-dominance exists when the co-dominant contrast is non-significant and, hence, the risk effect of heterozygotes lies in the middle of the risk of the two homozygotes. We propose to define the mode of inheritance by the significance of the deviance of the co-dominant contrast and the degree of dominance ( h), which is a function of two orthogonal contrasts (the co-dominant and additive). Then, the mode of inheritance is approximated by investigating a number of non-orthogonal genetic contrasts making the interpretation of results difficult. The biological justification for the choice of the genetic mode in genetic association studies (GAS) is seldom available. ![]()
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