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

Chen X, Kuja-Halkola R, Rahman I, Arpegård J, Viktorin A, Karlsson R, Hägg S, Svensson P, Pedersen NL, Magnusson PK

Am. J. Hum. Genet. 97 (5) 708-714 [2015-11-05; online 2015-11-07]

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).

NGI Uppsala (SNP&SEQ Technology Platform)

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PubMed 26544805

DOI 10.1016/j.ajhg.2015.10.004

Crossref 10.1016/j.ajhg.2015.10.004

S0002-9297(15)00406-1

pmc PMC4667127