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

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 9808008 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1435-232X (Electronic) Linking ISSN: 14345161 NLM ISO Abbreviation: J Hum Genet Subsets: MEDLINE

Publication: 2009- : London : Nature Pub. Group
Original Publication: Tokyo : Springer-Verlag, c1998-

Gene Frequency* ; Models, Genetic* ; Genetic Predisposition to Disease* ; Alleles*; Humans ; Genetic Variation ; Phenotype ; Odds Ratio ; Case-Control Studies ; Polymorphism, Genetic

"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 extend the method to the co-dominant model and carry out trial calculations of h p ² . I also calculate h p ² applying the allele distribution model originally reported by Pawitan et al. for comparison as a conventional method. But unexpectedly, h p ² 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 p ² , 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 p ² of rare variants calculated with the modified allele distribution model 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 h p ² 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

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