The mystery of missing heritability: Genetic interactions create phantom heritability
Name
Zuk-2012-The mystery of missi.pdf
Size
261.35 KB
Format
Adobe PDF
Checksum (MD5)
bbd529e5a81b314ccbaa4ba08637d860
Author(s)
Sunyaev, Shamil R.
Lander, Eric Steven
Date Issued
January 2012
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
Zuk, O. et al. “The Mystery of Missing Heritability: Genetic Interactions Create Phantom Heritability.” Proceedings of the National Academy of Sciences 109.4 (2012): 1193–1198. Copyright ©2012 by the National Academy of Sciences
Version
Final published version
Abstract
Human genetics has been haunted by the mystery of “missing heritability” of common traits. Although studies have discovered >1,200 variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. The proportion of heritability explained by a set of variants is the ratio of (i) the heritability due to these variants (numerator), estimated directly from their observed effects, to (ii) the total heritability (denominator), inferred indirectly from population data. The prevailing view has been that the explanation for missing heritability lies in the numerator—that is, in as-yet undiscovered variants. While many variants surely remain to be found, we show here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating “phantom heritability.” Specifically, (i) estimates of total heritability implicitly assume the trait involves no genetic interactions (epistasis) among loci; (ii) this assumption is not justified, because models with interactions are also consistent with observable data; and (iii) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn's disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/pnas.1119675109
