Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes

BMC Genetics

Hong-Wen Deng¹  Peng Xiao²  Dong-Hai Xiong²  Yuan-Yuan Zhang³  Yong-Jun Liu²  Hui Shen²  Volodymyr Dvornyk³  Yan Lu³  Peng-Yuan Liu³  Lan-Juan Zhao²  Ji-Rong Long³ 

[1] Laboratory of Molecular and Statistical Genetics, College of Life Sciences Hunan Normal University, Changsha, Hunan 410081, P. R. China;Department of Biomedical Sciences, Creighton University, Omaha, NE 68131, USA;Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA

关键词: single nucleotide polymorphism (SNP);    haplotype;    linkage disequilibrium (LD);   

Others  :  1143838
DOI  :  10.1186/1471-2156-5-11

 received in 2004-01-29, accepted in 2004-05-24,  发布年份 2004

【 摘 要 】

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 α1 (COL1A1), estrogen receptor-α (ER-α), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-β1 (TGF-β1), 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.

【 授权许可】

   
2004 Long et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Ardlie KG, Kruglyak L, Seielstad M: Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 2002, 3:299-309.
• [2]Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES: Linkage disequilibrium in the human genome. Nature 2001, 411:199-204.
• [3]Wall JD, Pritchard JK: Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 2003, 4:587-597.
• [4]Moffatt MF, Traherne JA, Abecasis GR, Cookson WO: Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus. Hum Mol Genet 2000, 9:1011-1019.
• [5]Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, Jiang R, Messer CJ, Chew A, Han JH, Duan J, Carr JL, Lee MS, Koshy B, Kumar AM, Zhang G, Newell WR, Windemuth A, Xu C, Kalbfleisch TS, Shaner SL, Arnold K, Schulz V, Drysdale CM, Nandabalan K, Judson RS, Ruano G, Vovis GF: Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001, 293:489-493.
• [6]Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI, Anderson GG, Zhang Y, Lench NJ, Carey A, Cardon LR, Moffatt MF, Cookson WO: Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001, 68:191-197.
• [7]Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996, 273:1516-1517.
• [8]Weiss KM, Clark AG: Linkage disequilibrium and the mapping of complex human traits. Trends Genet 2002, 18:19-24.
• [9]Jorde LB: Linkage disequilibrium and the search for complex disease genes. Genome Res 2000, 10:1435-1444.
• [10]Teare MD, Dunning AM, Durocher F, Rennart G, Easton DF: Sampling distribution of summary linkage disequilibrium measures. Ann Hum Genet 2002, 66:223-233.
• [11]Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001, 68:978-989.
• [12]Bonnen PE, Wang PJ, Kimmel M, Chakraborty R, Nelson DL: Haplotype and linkage disequilibrium architecture for human cancer-associated genes. Genome Res 2002, 12:1846-1853.
• [13]Zhu X, Yan D, Cooper RS, Luke A, Ikeda MA, Chang YP, Weder A, Chakravarti A: Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program. Genome Res 2003, 13:173-181.
• [14]Croucher PJ, Mascheretti S, Hampe J, Huse K, Frenzel H, Stoll M, Lu T, Nikolaus S, Yang SK, Krawczak M, Kim WH, Schreiber S: Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet 2003, 11:6-16.
• [15]Zhang J, Rowe WL, Clark AG, Buetow KH: Genomewide Distribution of High-Frequency, Completely Mismatching SNP Haplotype Pairs Observed To Be Common across Human Populations. Am J Hum Genet 2003, 73:1073-1081.
• [16]Kruglyak L: Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999, 22:139-144.
• [17]Tiret L, Poirier O, Nicaud V, Barbaux S, Herrmann SM, Perret C, Raoux S, Francomme C, Lebard G, Tregouet D, Cambien F: Heterogeneity of linkage disequilibrium in human genes has implications for association studies of common diseases. Hum Mol Genet 2002, 11:419-429.
• [18]Nakajima T, Jorde LB, Ishigami T, Umemura S, Emi M, Lalouel JM, Inoue I: Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet 2002, 70:108-123.
• [19]Weale ME, Depondt C, Macdonald SJ, Smith A, Lai PS, Shorvon SD, Wood NW, Goldstein DB: Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. Am J Hum Genet 2003, 73:551-565.
• [20]Guo SW: Linkage disequilibrium measures for fine-scale mapping: a comparison. Hum Hered 1997, 47:301-314.
• [21]Peterson RJ, Goldman D, Long JC: Effects of worldwide population subdivision on ALDH2 linkage disequilibrium. Genome Res 1999, 9:844-852.
• [22]Albagha OM, Tasker PN, McGuigan FE, Reid DM, Ralston SH: Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women. Hum Mol Genet 2002, 11:2289-2295.
• [23]Devlin B, Risch N: A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995, 29:311-322.
• [24]Taillon-Miller P, Bauer-Sardina I, Saccone NL, Putzel J, Laitinen T, Cao A, Kere J, Pilia G, Rice JP, Kwok PY: Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nat Genet 2000, 25:324-328.
• [25]Ardlie K, Liu-Cordero SN, Eberle MA, Daly M, Barrett J, Winchester E, Lander ES, Kruglyak L: Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. Am J Hum Genet 2001, 69:582-589.
• [26]Zabetian CP, Buxbaum SG, Elston RC, Kohnke MD, Anderson GM, Gelernter J, Cubells JF: The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine beta-hydroxylase activity. Am J Hum Genet 2003, 72:1389-1400.
• [27]Dawson E, Abecasis GR, Bumpstead S, Chen Y, Hunt S, Beare DM, Pabial J, Dibling T, Tinsley E, Kirby S, Carter D, Papaspyridonos M, Livingstone S, Ganske R, Lohmussaar E, Zernant J, Tonisson N, Remm M, Magi R, Puurand T, Vilo J, Kurg A, Rice K, Deloukas P, Mott R, Metspalu A, Bentley DR, Cardon LR, Dunham I: A first-generation linkage disequilibrium map of human chromosome 22. Nature 2002, 418:544-548.
• [28]Liu YZ, Liu YJ, Recker RR, Deng HW: Molecular studies of identification of genes for osteoporosis: the 2002 update. J Endocrinol 2003, 177:147-196.
• [29]Chagnon YC, Rankinen T, Snyder EE, Weisnagel SJ, Perusse L, Bouchard C: The human obesity gene map: the 2002 update. Obes Res 2003, 11:313-367.
• [30]O'Connell JR, Weeks DE: PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998, 63:259-266.
• [31]Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES: Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996, 58:1347-1363.
• [32]Lewontin RC: The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 1964, 49:49-67.