Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The sex-specific genetic architecture of quantitative traits in humans

Abstract

Mapping genetically complex traits remains one of the greatest challenges in human genetics today. In particular, gene-environment and gene-gene interactions, genetic heterogeneity and incomplete penetrance make thorough genetic dissection of complex traits difficult, if not impossible. Sex could be considered an environmental factor that can modify both penetrance and expressivity of a wide variety of traits. Sex is easily determined and has measurable effects on recognizable morphology; neurobiological circuits; susceptibility to autoimmune disease, diabetes, asthma, cardiovascular and psychiatric disease; and quantitative traits like blood pressure, obesity and lipid levels, among others. In this study, we evaluated sex-specific heritability and genome-wide linkages for 17 quantitative traits in the Hutterites. The results of this study could have important implications for mapping complex trait genes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Heritability estimates for 17 quantitative traits.
Figure 2: Genome-wide significant linkages.

Similar content being viewed by others

References

  1. Carrel, L. & Willard, H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005).

    Article  CAS  Google Scholar 

  2. Rinn, J.L. & Snyder, M. Sexual dimorphism in mammalian gene expression. Trends Genet. 21, 298–305 (2005).

    Article  CAS  Google Scholar 

  3. Mackay, T.F. The genetic architecture of quantitative traits: lessons from Drosophila. Curr. Opin. Genet. Dev. 14, 253–257 (2004).

    Article  CAS  Google Scholar 

  4. Korstanje, R. et al. Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population. J. Lipid Res. 45, 881–888 (2004).

    Article  CAS  Google Scholar 

  5. Ueno, T. et al. Rat model of familial combined hyperlipidemia as a result of comparative mapping. Physiol. Genomics 17, 38–47 (2004).

    Article  CAS  Google Scholar 

  6. Woods, S.C., Gotoh, K. & Clegg, D.J. Gender differences in the control of energy homeostasis. Exp. Biol. Med. (Maywood) 228, 1175–1180 (2003).

    Article  CAS  Google Scholar 

  7. Cairney, J. & Wade, T.J. The influence of age on gender differences in depression: further population-based evidence on the relationship between menopause and the sex difference in depression. Soc. Psychiatry Psychiatr. Epidemiol. 37, 401–408 (2002).

    Article  Google Scholar 

  8. Williams, A.J. et al. The prevalence of insulin autoantibodies at the onset of Type 1 diabetes is higher in males than females during adolescence. Diabetologia 46, 1354–1356 (2003).

    Article  CAS  Google Scholar 

  9. Chen, Y., Stewart, P., Johansen, H., McRae, L. & Taylor, G. Sex difference in hospitalization due to asthma in relation to age. J. Clin. Epidemiol. 56, 180–187 (2003).

    Article  Google Scholar 

  10. Stromberg, A. & Martensson, J. Gender differences in patients with heart failure. Eur. J. Cardiovasc. Nurs. 2, 7–18 (2003).

    Article  Google Scholar 

  11. Towne, B., Siervogel, R.M. & Blangero, J. Effects of genotype-by-sex interaction on quantitative trait linkage analysis. Genet. Epidemiol. 14, 1053–1058 (1997).

    Article  CAS  Google Scholar 

  12. Stone, J.L. et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am. J. Hum. Genet. 75, 1117–1123 (2004).

    Article  CAS  Google Scholar 

  13. Fullerton, J. et al. Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am. J. Hum. Genet. 72, 879–890 (2003).

    Article  CAS  Google Scholar 

  14. Zubenko, G.S. et al. Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am. J. Med. Genet. 123, 1–18 (2003).

    Article  Google Scholar 

  15. Fisher, S.A. et al. Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6. Eur. J. Hum. Genet. 10, 259–265 (2002).

    Article  CAS  Google Scholar 

  16. Loughlin, J. et al. Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology (Oxford) 39, 377–381 (2000).

    Article  CAS  Google Scholar 

  17. Weiss, L.A., Abney, M., Cook, E.H. & Ober, C. Sex-specific genetic architecture of whole blood serotonin levels. Am. J. Hum. Genet. 76, 33–41 (2005).

    Article  CAS  Google Scholar 

  18. Kurina, L.M. et al. Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women. J. Clin. Endocrinol. Metab. 90, 4747–4752 (2005).

    Article  CAS  Google Scholar 

  19. Ober, C., Abney, M. & McPeek, M.S. The genetic dissection of complex traits in a founder population. Am. J. Hum. Genet. 69, 1068–1079 (2001).

    Article  CAS  Google Scholar 

  20. Abney, M., Ober, C. & McPeek, M.S. Homozygosity mapping of quantitative trait loci in complex inbred pedigrees. Am. J. Hum. Genet. 67, 327 (2000).

    Google Scholar 

  21. Weiss, L.A. et al. Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin. Eur. J. Hum. Genet. 12, 949–954 (2004).

    Article  CAS  Google Scholar 

  22. Abney, M., McPeek, M. & Ober, C. Estimation of variance components of quantitative traits in inbred populations. Am. J. Hum. Genet. 66, 629–650 (2000).

    Article  CAS  Google Scholar 

  23. Newman, D.L. et al. Are common disease susceptibility alleles the same in outbred and founder populations? Eur. J. Hum. Genet. 12, 584–590 (2004).

    Article  CAS  Google Scholar 

  24. Bourgain, C. et al. Novel case-control test in a founder population identifies P-selectin as an atopy-susceptibility locus. Am. J. Hum. Genet. 73, 612–626 (2003).

    Article  CAS  Google Scholar 

  25. Ober, C., Tsalenko, A., Parry, R. & Cox, N.J. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am. J. Hum. Genet. 67, 1154–1162 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Weiss, L.A. et al. Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample. Hum. Genet. 117, 81–87 (2005).

    Article  CAS  Google Scholar 

  27. Abney, M., McPeek, M.S. & Ober, C. Broad and narrow heritabilities of quantitative traits in a founder population. Am. J. Hum. Genet. 68, 1302–1307 (2001).

    Article  CAS  Google Scholar 

  28. Schwarz, G. Estimating the dimension of a model. Ann. Stat. 6, 461–464 (1978).

    Article  Google Scholar 

  29. Abney, M., Ober, C. & McPeek, M.S. Quantitative trait homozygosity and association mapping and empirical genome-wide significance in large complex pedigrees: Fasting serum insulin levels in the Hutterites. Am. J. Hum. Genet. 70, 920–934 (2002).

    Article  CAS  Google Scholar 

  30. Newman, D.L. et al. Major loci influencing serum triglyceride levels on 2q14 and 9p21 localized by homozygosity-by-descent mapping in a large Hutterite pedigree. Hum. Mol. Genet. 12, 137–144 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge assistance from N. Phillips, R. Anderson, H. Dytch and L. Kurina. This work was supported by grants from the US National Institutes of Health to M.A. and C.O. and a grant from Hoffmann-LaRoche, Inc. to C.O. L.A.W. was supported by a US National Science Foundation graduate research fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carole Ober.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weiss, L., Pan, L., Abney, M. et al. The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 38, 218–222 (2006). https://doi.org/10.1038/ng1726

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1726

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing