Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models

Abstract

In order to further illuminate the potential role of dominant genetic variation in the "missing heritability" debate, we investigated the additive (narrow-sense heritability, h(2)) and dominant (δ(2)) genetic variance for 18 human complex traits. Within the same study base (10,682 Swedish twins), we calculated and compared the estimates from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood [GREML(d)] method. Contributions of δ(2) were evident for 14 traits in twin models (average δ(2)twin = 0.25, range 0.14-0.49), two of which also displayed significant δ(2) in the GREMLd analyses (triglycerides δ(2)SNP = 0.28 and waist circumference δ(2)SNP = 0.19). On average, the proportion of h(2)SNP/h(2)twin was 70% for ADE-fitted traits (for which the best-fitting model included additive and dominant genetic and unique environmental components) and 31% for AE-fitted traits (for which the best-fitting model included additive genetic and unique environmental components). Independent evidence for contribution from shared environment, also in ADE-fitted traits, was obtained from self-reported within-pair contact frequency and age at separation. We conclude that despite the fact that additive genetics appear to constitute the bulk of genetic influences for most complex traits, dominant genetic variation might often be masked by shared environment in twin and family studies and might therefore have a more prominent role than what family-based estimates often suggest. The risk of erroneously attributing all inherited genetic influences (additive and dominant) to the h(2) in too-small twin studies might also lead to exaggerated "missing heritability" (the proportion of h(2) that remains unexplained by SNPs).

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“…Underrepresentation of more severe disease may underestimate the contribution of CFTR if more severe disease is secondary to underrepresented mutations within the study population or overestimate the contribution of CFTR if more severe disease is a function of specific environmental factors. It is also possible that common environmental effects may mask modest effects of modifier genes (44). Furthermore, the current methods do not allow us to detect potential effects of modifier gene-CFTR interactions, gene-environment interactions, or intragenic CFTR modifiers.…”

Genetic Loci and Novel Discrimination Measures Associated with Blood Pressure Variation in African Americans Living in Tallahassee

“…Multiple studies have discussed the “missing heritability” of complex phenotypes [30–32]. While most studies focus on the need for more samples, more genetic markers, better genetic models or analytic methods, the consistent factor is that heritability is “missing” only for complex diseases.…”

“…the discrepancy between the estimated heritability of a phenotype and the total variation explained by specific genetic variants [30–32]. The missing heritability of complex disease may partially be due to the lack of inclusion of environmental stressors in standard genetic association studies [33].…”

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“…[3][4][5] For a quantitative trait such as height, the estimated heritability was about 0.5 using variance component methods. Compared with the empirical upper bound of the heritability of height, 6,7 which was thought to be approximately 0.8, the gap of 'missing heritability' has been much narrowed using variance component methods. However, 'true heritability ' has not yet been attained.…”