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Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models
Authors:Xu Chen  Ralf Kuja-Halkola  Iffat Rahman  Johannes Arpeg?rd  Alexander Viktorin  Robert Karlsson  Sara H?gg  Per Svensson  Nancy?L Pedersen  Patrik?KE Magnusson
Institution:1.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden;2.Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden;3.Department of Medicine-Solna, Karolinska Institutet, Stockholm 17177, Sweden;4.Department of Emergency Medicine, Karolinska University Hospital, Stockholm 17177, Sweden
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, h2) and dominant (δ2) 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 δ2 were evident for 14 traits in twin models (average δ2twin = 0.25, range 0.14–0.49), two of which also displayed significant δ2 in the GREMLd analyses (triglycerides δ2SNP = 0.28 and waist circumference δ2SNP = 0.19). On average, the proportion of h2SNP/h2twin 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 h2 in too-small twin studies might also lead to exaggerated “missing heritability” (the proportion of h2 that remains unexplained by SNPs).
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