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 p 2 ) for a common disease without calculating the genetic variance under dominant and the recessive models. Here, I extended the method to the co-dominant model and carry out trial calculations of h p 2 . I also calculated h p 2 applying the allele distribution model originally reported by Pawitan et al. for a comparison. Unexpectedly, h p 2 calculated for rare variants with high odds ratios was much higher. I noticed that conventional methods use the allele frequency (AF) of a variant in the general population. However, this implicitly assumes that the unaffected are included among the phenotypes: an assumption that is inconsistent with case-control studies in which unaffected individuals belong to the control group. Therefore, I modified the allele distribution model by using the AF in the patient population. Consequently, the h p 2 of rare variants was quite high. Recalculating h p 2 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 original model. These results suggest that the contribution of rare variants to heritability of a disease has been considerably underestimated.