Contribution of rare variants to heritability of a disease is much greater than conventionally estimated: modification of allele distribution model.

"Missing heritability" is a current problem in human genetics. I previously reported a method to estimate heritability of a polymorphism (h_p²) for a common disease without calculating the genetic variance under dominant and the recessive models. Here, I extend the method to the co-dominant model and carry out trial calculations of h_p². I also calculate h_p² applying the allele distribution model originally reported by Pawitan et al. for comparison as a conventional method. But unexpectedly, h_p² calculated for rare variants with high odds ratios was much higher than the calculated values with the allele distribution model. Also, while examining the basis for the difference in calculated h_p², I noticed that conventional methods use the allele frequency (AF) of a variant in the general population to calculate the genetic variance of that variant. However, this implicitly assumes that the unaffected are included among the phenotypes of the disease - an assumption that is inconsistent with case-control studies in which unaffected individuals belong to the control (unaffected) group. Therefore, I modified the allele distribution model by using the AF in the patient population. Consequently, the h_p² of rare variants calculated with the modified allele distribution model was quite high. Recalculating h_p² of several rare variants reported in the literature with the modified allele distribution model yielded results were 3.2 - 53.7 times higher than the h_p² calculated with the original allele distribution model. These results suggest that the contribution of rare variants to heritability of a disease has been considerably underestimated.