FIG. 1.

This figure illustrates the inherent paradox with the dogma that numerous genes with small effect can cause an additive strong genetic effect on susceptibility to disease. We simulated five genetic variants predisposing to autoimmune thyroid diseases, each giving an odds ratio (OR) of 1.2 individually. Therefore, the combined OR if an individual inherited all five variants, assuming an additive effect is 1.2 × 1.2 × 1.2 × 1.2 × 1.2 = 2.5. However, the calculated frequency in the population of the combined genotype including all five susceptible variants (assuming no linkage disequilibrium exists between them), assuming the frequency of each variant alone is 0.2 (20%) would be 0.2 × 0.2 × 0.2 × 0.2 × 0.2 = 0.00032 or 0.032%. Such a low frequency of the combined genotype is not consistent with the strong genetic influence on highly prevalent complex diseases, such as autoimmune thyroid diseases.