Abstract
High levels of liver enzymes GGT, ALT and AST are predictive of disease and all-cause mortality and can reflect liver injury, fatty liver and/or oxidative stress. Variation in GGT, ALT and AST levels is heritable. Moderation of the heritability of these liver enzymes by age and sex has not often been explored, and it is not clear to what extent non-additive genetic and shared environmental factors may play a role. To examine the genetic architecture of GGT, ALT and AST, plasma levels were assessed in a large sample of twins, their siblings, parents and spouses (N = 8,371; age range 18–90). For GGT and ALT, but not for AST, genetic structural equation modeling showed evidence for quantitative sex differences in the genetic architecture. There was no evidence for qualitative sex differences, i.e. the same genes were expressed in males and females. Both additive and non-additive genetic factors were important for GGT in females (total heritability h2 60 %) and AST in both sexes (total h2 43 %). The heritability of GGT in males and ALT for both sexes was due to additive effects only (GGT males 30 %; ALT males 40 %, females 22 %). Evidence emerged for shared environmental factors influencing GGT in the male offspring generation (variance explained 28 %). Thus, the same genes influence liver enzyme levels across sex and age, but their relative contribution to the variation in GGT and ALT differs in males and females and for GGT across age. Given adequate sample sizes these results suggest that genome-wide association studies may result in the detection of new susceptibility loci for liver enzyme levels when pooling results over sex and age.
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Acknowledgments
This work has been executed in the Mental Health research program of the EMGO Institute for Health and Care Research and was supported by grants from the Netherlands Organization for Scientific Research (NWO) (ZonMW Addiction 31160008; NWO/SPI 56-464-14192; NWO 016-115-035; NWO-MW 904-61-193) and the European Research Council (Genetics of Mental Illness: ERC-230374; ERC starting grant 284167). We thank Professor J.B. Whitfield for useful discussions and the twin families for their participation in the NTR research.
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van Beek, J.H.D.A., de Moor, M.H.M., de Geus, E.J.C. et al. The Genetic Architecture of Liver Enzyme Levels: GGT, ALT and AST. Behav Genet 43, 329–339 (2013). https://doi.org/10.1007/s10519-013-9593-y
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DOI: https://doi.org/10.1007/s10519-013-9593-y