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

Abstract

Missing heritability is a current problem in human genetics. I previously reported a method to estimate heritability of a polymorphism (hp2) 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 hp2. I also calculated hp2applying the allele distribution model originally reported by Pawitan et al. for a comparison. Unexpectedly, hp2calculated 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 hp2of rare variants was quite high. Recalculating hp2of 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.