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Evidence for sex-specific genetic architectures across a spectrum of human complex traits

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    Rights statement: © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Original languageEnglish
Article number166
JournalGenome Biology
Issue number1
Early online date29 Jul 2016
Publication statusE-pub ahead of print - 29 Jul 2016


Background: Sex differences are a common feature of human traits; however, the role sex determination plays in human genetic variation remains unclear. The presence of Gene-by- Sex (GxS) interactions implies that trait genetic architecture differs between men and women. Here, we show that GxS interactions and genetic heterogeneity among sexes, are small but common features of a range of high-level complex traits.

Results: We analyzed 19 complex traits measured in 54,040 unrelated men and 59,820 unrelated women from the UK Biobank cohort, to estimate autosomal genetic correlations, and heritability differences between men and women. In 13 of the 19 traits examined, there is evidence that the trait measured is genetically different between males and females. We find that estimates of genetic correlations, based on ~114,000 unrelated individuals and~19,000 related individuals from the same cohort, are largely consistent. Genetic predictors using a sex-specific model that incorporated GxS interactions, led to a relative improvement of up to 4% (mean 1.4% across all relevant phenotypes) over those provided by a sex-agnostic model. This further supports the hypothesis of the presence of sexual genetic heterogeneity across high-level phenotypes.

Conclusions: The sex-specific environment seems to play a role in changing genotype expression across a range of human complex traits. Further studies of sex by genotype interactions for high-level human traits may shed light on the molecular mechanisms that lead to biological differences between men and women. However, this may be a challenging endeavour due to the likely small effects of the interactions at individual loci.

    Research areas

  • gene-by-sex interactions, sex specific genetic architecture, genomic prediction

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