Original Article

Tests for the presence of two linked disease susceptibility genes

  1. Joanna M. Biernacka1,2,†,
  2. Lei Sun1,3,
  3. Shelley B. Bull1,2,*

Article first published online: 28 SEP 2005

DOI: 10.1002/gepi.20094

Issue

Genetic Epidemiology

Genetic Epidemiology

Volume 29, Issue 4, pages 389–401, December 2005

Additional Information

How to Cite

Biernacka, J. M., Sun, L. and Bull, S. B. (2005), Tests for the presence of two linked disease susceptibility genes. Genetic Epidemiology, 29: 389–401. doi: 10.1002/gepi.20094

Author Information

  1. 1

    Department of Public Health Sciences, University of Toronto, Toronto, Canada

  2. 2

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

  3. 3

    The Hospital for Sick Children, Toronto, Canada

  1. †

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

*Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Lebovic Building, 5th Floor, 600 University Avenue, Toronto, Ontario, M5G 1X5 Canada

Publication History

  1. Issue published online: 17 NOV 2005
  2. Article first published online: 28 SEP 2005
  3. Manuscript Accepted: 6 JUL 2005
  4. Manuscript Received: 22 APR 2005

Funded by

  • Samuel Lunenfeld Research Institute
  • Mathematics for Information Technology and Complex Systems (MITACS) Network of Centres of Excellence (NCE-Canada)
  • Natural Sciences and Engineering Research Council of Canada

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Keywords:

  • generalized estimating equations;
  • affected sib pairs;
  • identity by descent;
  • complex disease;
  • hypothesis test;
  • multi-locus linkage analysis;
  • empirical p values

Abstract

For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Under explicit assumptions about the number of disease genes in a region, generalized estimating equations (GEE) can be used to estimate the putative disease gene location(s) and expected identical-by-descent allele sharing in affected sib pairs at these gene(s). Extending the work of Liang et al. ([2001] Hum. Hered. 51:64–78), Biernacka et al. ([2005] Genet. Epidemiol. 28:33–47) developed a method for simultaneous localization of two susceptibility genes in one region using marker identical-by-descent (IBD) sharing in affected sib pairs. Here we propose methods to evaluate the evidence for two versus one disease loci in a region in a quasi-likelihood/GEE framework. We describe tests based on approximate quasi-likelihood ratio and generalized score test statistics. Because of difficulties in determining the asymptotic null distributions of these statistics and the small sample sizes that can be available in genetic studies, we recommend that significance be evaluated empirically. Application of the described methods to data from a genome scan for type 1 diabetes (Mein et al. [1998] Nat. Genet. 19:297–300) yielded some evidence for two linked disease genes on chromosome 6, approximately 20 cM apart (p value for an approximate quasi-likelihood ratio test=0.049). In simulation studies, we found that both tests performed quite well for a range of scenarios. Power to detect the presence of two linked disease genes increased with the number of affected sib pairs, greater IBD sharing at the two loci, and larger distance between the two loci. Genet Epidemiol. 2005. © 2005 Wiley-Liss, Inc.

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