Abstract | 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 x 10(-6) and p = 1.6 x 10(-4), respectively). Large phenotypic differences (4.0 approximately 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.
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Authors | P-Y Liu, Y-Y Zhang, Y Lu, J-R Long, H Shen, Lan-J Zhao, F-H Xu, P Xiao, D-H Xiong, Y-J Liu, R R Recker, H-W Deng |
Journal | Journal of medical genetics
(J Med Genet)
Vol. 42
Issue 3
Pg. 221-7
(Mar 2005)
ISSN: 1468-6244 [Electronic] England |
PMID | 15744035
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Apolipoproteins E
- Collagen Type I
- Estrogen Receptor alpha
- Parathyroid Hormone
- Receptor, Parathyroid Hormone, Type 1
- Receptors, Calcitriol
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Topics |
- Apolipoproteins E
(genetics)
- Bone Density
(genetics)
- Collagen Type I
(genetics)
- Estrogen Receptor alpha
(genetics)
- Female
- Genetic Testing
(methods)
- Haplotypes
- Humans
- Male
- Middle Aged
- Osteoporosis
(genetics)
- Parathyroid Hormone
(genetics)
- Phenotype
- Polymorphism, Single Nucleotide
- Receptor, Parathyroid Hormone, Type 1
(genetics)
- Receptors, Calcitriol
(genetics)
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