Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes

BMC Genet. 2004 May 24;5:11. doi: 10.1186/1471-2156-5-11.


Background: The adequacy of association studies for complex diseases depends critically on the existence of linkage disequilibrium (LD) between functional alleles and surrounding SNP markers.

Results: We examined the patterns of LD and haplotype distribution in eight candidate genes for osteoporosis and/or obesity using 31 SNPs in 1,873 subjects. These eight genes are apolipoprotein E (APOE), type I collagen alpha1 (COL1A1), estrogen receptor-alpha (ER-alpha), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-beta1 (TGF-beta1), uncoupling protein 3 (UCP3), and vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR). Yin yang haplotypes, two high-frequency haplotypes composed of completely mismatching SNP alleles, were examined. To quantify LD patterns, two common measures of LD, D' and r2, were calculated for the SNPs within the genes. The haplotype distribution varied in the different genes. Yin yang haplotypes were observed only in PTHR1 and UCP3. D' ranged from 0.020 to 1.000 with the average of 0.475, whereas the average r2 was 0.158 (ranging from 0.000 to 0.883). A decay of LD was observed as the intermarker distance increased, however, there was a great difference in LD characteristics of different genes or even in different regions within gene.

Conclusion: The differences in haplotype distributions and LD patterns among the genes underscore the importance of characterizing genomic regions of interest prior to association studies.

Publication types

  • 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.

MeSH terms

  • Apolipoproteins E / genetics
  • Carrier Proteins / genetics
  • Collagen Type I / genetics
  • Estrogen Receptor alpha
  • Family Health
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Haplotypes / genetics*
  • Humans
  • Ion Channels
  • Linkage Disequilibrium / genetics*
  • Male
  • Mitochondrial Proteins
  • Obesity / genetics*
  • Osteoporosis / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Receptor, Parathyroid Hormone, Type 1 / genetics
  • Receptors, Calcitriol / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, Estrogen / genetics
  • Receptors, Leptin
  • Statistics as Topic
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1
  • Uncoupling Protein 3


  • Apolipoproteins E
  • Carrier Proteins
  • Collagen Type I
  • Estrogen Receptor alpha
  • Ion Channels
  • Mitochondrial Proteins
  • Receptor, Parathyroid Hormone, Type 1
  • Receptors, Calcitriol
  • Receptors, Cell Surface
  • Receptors, Estrogen
  • Receptors, Leptin
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • UCP3 protein, human
  • Uncoupling Protein 3
  • collagen type I, alpha 1 chain