mystery of missing heritability: Genetic interactions create phantom heritability

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (4), p.1193-1198
• Main Authors: Zuk, Or, Hechter, Eliana, Sunyaev, Shamil R, Lander, Eric S
• Format: Article
• Language: English
• Subjects: Biological Sciences; Crohn disease; Crohn's disease; Disease models; Epistasis; Genetic Diseases, Inborn - genetics; Genetic disorders; Genetic loci; Genetic Predisposition to Disease - genetics; genetic traits; Genetic Variation; Genetics; Genetics, Population; Heritability; Human genetics; Humans; loci; mathematics and statistics; Medical genetics; Models, Genetic; Multifactorial Inheritance - genetics; Phenotypic traits; Physical Sciences; Population genetics; Quantitative genetics; Quantitative traits
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1119675109

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.