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A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases
  1. P-Y Liu1,
  2. Y-Y Zhang1,
  3. Y Lu1,
  4. J-R Long1,
  5. H Shen1,2,
  6. Lan-J Zhao1,2,
  7. F-H Xu1,2,
  8. P Xiao1,2,
  9. D-H Xiong1,2,
  10. Y-J Liu1,2,
  11. R R Recker1,
  12. H-W Deng1,2,3
  1. 1Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA
  2. 2Department of Biomedical Sciences, Creighton University, Omaha, NE 68131, USA
  3. 3Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China
  1. Correspondence to:
 Dr H-W Deng
 Osteoporosis Research Center, Creighton University Medical Center, 601 N. 30th St., Suite 6787, Omaha, NE 68131, USA;


Background: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies.

Methods: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence.

Results: Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 × 10−6 and p = 1.6 × 10−4, respectively). Large phenotypic differences (4.0∼5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution.

Conclusions: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.

  • BMD, bone mineral density
  • CD-CV, common diseases common variants
  • LD, linkage disequilibrium
  • PTH, parathyroid hormone
  • PTHR1, parathyroid hormone receptor 1
  • VDR, vitamin D receptor
  • association
  • complex diseases
  • haplotype
  • rare variants

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  • Competing interests: none declared