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Genome scan for quantitative trait loci influencing HDL levels: evidence for multilocus inheritance in familial combined hyperlipidemia

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Abstract

Several genome scans in search of high-density lipoprotein (HDL) quantitative trait loci (QTLs) have been performed. However, to date the actual identification of genes implicated in the regulation of common forms of HDL abnormalities remains unsuccessful. This may be due, in part, to the oligogenic and multivariate nature of HDL regulation, and potentially, pleiotropy affecting HDL and other lipid-related traits. Using a Bayesian Markov Chain Monte Carlo (MCMC) approach, we recently provided evidence of linkage of HDL level variation to the APOA1–C3–A4–A5 gene complex, in familial combined hyperlipidemia pedigrees, with an estimated number of two to three large QTLs remaining to be identified. We also presented results consistent with pleiotropy affecting HDL and triglycerides at the APOA1–C3–A4–A5 gene complex. Here we use the same MCMC analytic strategy, which allows for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. We now present results from a genome scan in search for the additional HDL QTLs in these pedigrees. We provide evidence of linkage for additional HDL QTLs on chromosomes 3p14 and 13q32, with results on chromosome 3 further supported by maximum parametric and variance component LOD scores of 3.0 and 2.6, respectively. Weaker evidence of linkage was also obtained for 7q32, 12q12, 14q31–32 and 16q23–24.

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Acknowledgements

We are thankful to the families for their participation in the study. We are grateful for the meticulous technical assistance of Andy Louie. Computer support was provided by Hiep D. Nguyen. The database was constructed and maintained by Ted Holzman. Genotyping for the FCHL pedigrees was provided by the NHLBI mammalian genotyping service. Supported by National Institute of Health grants HL30086 and GM46255. F. Gagnon was the recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research. G. Jarvik was a Pew Biomedical Scholar during the analysis of these data.

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Authors and Affiliations

  1. Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada

    France Gagnon

  2. Division of Medical Genetics, Department of Medicine, University of Washington, BOX 357720, Seattle, WA, 98195-7720, USA

    France Gagnon, Gail P. Jarvik, Michael D. Badzioch, Arno G. Motulsky & Ellen M. Wijsman

  3. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Gail P. Jarvik, Arno G. Motulsky & Ellen M. Wijsman

  4. Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington, USA

    John D. Brunzell

  5. Department of Biostatistics, University of Washington, Seattle, Washington, USA

    Ellen M. Wijsman

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  1. France Gagnon
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Correspondence to Ellen M. Wijsman.

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Gagnon, F., Jarvik, G.P., Badzioch, M.D. et al. Genome scan for quantitative trait loci influencing HDL levels: evidence for multilocus inheritance in familial combined hyperlipidemia. Hum Genet 117, 494–505 (2005). https://doi.org/10.1007/s00439-005-1338-4

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