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.
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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).
- 2.
Rinn, J.L. & Snyder, M. Sexual dimorphism in mammalian gene expression. Trends Genet. 21, 298–305 (2005).
- 3.
Mackay, T.F. The genetic architecture of quantitative traits: lessons from Drosophila. Curr. Opin. Genet. Dev. 14, 253–257 (2004).
- 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).
- 5.
Ueno, T. et al. Rat model of familial combined hyperlipidemia as a result of comparative mapping. Physiol. Genomics 17, 38–47 (2004).
- 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).
- 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).
- 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).
- 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).
- 10.
Stromberg, A. & Martensson, J. Gender differences in patients with heart failure. Eur. J. Cardiovasc. Nurs. 2, 7–18 (2003).
- 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).
- 12.
Stone, J.L. et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am. J. Hum. Genet. 75, 1117–1123 (2004).
- 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).
- 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).
- 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).
- 16.
Loughlin, J. et al. Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology (Oxford) 39, 377–381 (2000).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 28.
Schwarz, G. Estimating the dimension of a model. Ann. Stat. 6, 461–464 (1978).
- 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).
- 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).
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
Author notes
- Lauren A Weiss
Current address: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Affiliations
Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637, USA.
- Lauren A Weiss
- , Lin Pan
- , Mark Abney
- & Carole Ober
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Competing interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to Carole Ober.
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