Abstract
There is presently much interest in utilizing patterns of linkage disequilibrium (LD) to further genetic association studies. This is particularly pertinent in the class III region of the human major histocompatibility complex (MHC), which has been extensively studied as a disease susceptibility locus in a number of ethnic groups. To date, however, few studies of LD in the MHC have considered non-Caucasian populations. With the advent of large-scale haplotyping of the human genome, the question of utilizing LD patterns across populations has come to the fore. We have previously used LD mapping to direct an MHC class III association study in a UK Caucasian population. As an extension of this, we sought to determine to what extent the pattern of LD observed in that study could be used to conduct a similar study in a West African Gambian population. We found that broad patterns of LD were similar in the two populations, resulting in similar candidate region delineations, but at a higher resolution, marker-specific patterns of LD and population-dependent allele frequencies confounded the choice of regional tagging SNPs. Our results have implications for the applicability of large-scale haplotype maps such as the HapMap to complex regions like the MHC.
References
Ackerman H, Usen S, Mott R, Richardson A, Sisay-Joof F, Katundu P, Taylor T, Ward R, Molyneux M, Pinder M, Kwiatkowski DP (2003a) Haplotypic analysis of the TNF locus by association efficiency and entropy. Genome Biol 4(4):R24
Ackerman HC, Ribas G, Jallow M, Mott R, Neville M, Sisay-Joof F, Pinder M, Campbell RD, Kwiatkowski DP (2003b) Complex haplotypic structure of the central MHC region flanking TNF in a West African population. Genes Immun 4(7):476–486
Ahmad T, Neville M, Marshall SE, Armuzzi A, Mulcahy-Hawes K, Crawshaw J, Sato H, Ling KL, Barnardo M, Goldthorpe S, Walton R, Bunce M, Jewell DP, Welsh KI (2003) Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum Mol Genet 12(6):647–656
Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P (2005) A haplotype map of the human genome. Nature 437(7063):1299–12320
Conway DJ, Holland MJ, Bailey RL, Campbell AE, Mahdi OS, Jennings R, Mbena E, Mabey DC (1997) Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid. Infect Immun 65(3):1003–1006
Degli-Esposti MA, Leaver AL, Christiansen FT, Witt CS, Abraham LJ, Dawkins RL (1992) Ancestral haplotypes: conserved population MHC haplotypes. Hum Immunol 34(4):242–252
Evans DM, Cardon LR (2005) A comparison of linkage disequilibrium patterns and estimated population recombination rates across multiple populations. Am J Hum Genet 76(4):681–687
Goldstein DB, Weale ME (2001) Population genomics: linkage disequilibrium holds the key. Curr Biol 11(14):R576–R579
Hanchard N, Rockett K, Udalova I, Wilson J, Keating B, Koch O, Nijnik A, Diakite M, Herbert M, Kwiatkowski D (2006) An investigation of transmission ratio distortion in the central region of the human MHC. Genes Immun 7(1):51–58
Hull J, Ackerman H, Isles K, Usen S, Pinder M, Thomson A, Kwiatkowski D (2001) Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus. Am J Hum Genet 69(2):413–419
Luoni G, Forton J, Jallow M, Akha ES, Sisay-Joof F, Pinder M, Hanchard N, Herbert M, Kimber M, Mott R, Hull J, Rockett K, Kwiatkowski D (2005) Population-specific patterns of linkage disequilibrium in the human 5q31 region. Genes Immun
Miretti MM, Walsh EC, Ke X, Delgado M, Griffiths M, Hunt S, Morrison J, Whittaker P, Lander ES, Cardon LR, Bentley DR, Rioux JD, Beck S, Deloukas P (2005) A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 76(4):634–646
Mueller JC, Lohmussaar E, Magi R, Remm M, Bettecken T, Lichtner P, Biskup S, Illig T, Pfeufer A, Luedemann J, Schreiber S, Pramstaller P, Pichler I, Romeo G, Gaddi A, Testa A, Wichmann HE, Metspalu A, Meitinger T (2005) Linkage disequilibrium patterns and tagSNP transferability among European populations. Am J Hum Genet 76(3):387–398
Okamoto K, Makino S, Yoshikawa Y, Takaki A, Nagatsuka Y, Ota M, Tamiya G, Kimura A, Bahram S, Inoko H (2003) Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet 72(2):303–312
Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES (2001) Linkage disequilibrium in the human genome. Nature 411(6834):199–204
Stenzel A, Lu T, Koch WA, Hampe J, Guenther SM, De La Vega FM, Krawczak M, Schreiber S (2004) Patterns of linkage disequilibrium in the MHC region on human chromosome 6p. Hum Genet 114(4):377–385
Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989
Walsh EC, Mather KA, Schaffner SF, Farwell L, Daly MJ, Patterson N, Cullen M, Carrington M, Bugawan TL, Erlich H, Campbell J, Barrett J, Miller K, Thomson G, Lander ES, Rioux JD (2003) An integrated haplotype map of the human major histocompatibility complex. Am J Hum Genet 73(3):580–590
Wei J, Hemmings GP (2004) TNXB locus may be a candidate gene predisposing to schizophrenia. Am J Med Genet 125B(1):43–49
Wilson JN, Rockett K, Jallow M, Pinder M, Sisay-Joof F, Newport M, Newton J, Kwiatkowski D (2005) Analysis of IL10 haplotypic associations with severe malaria. Genes Immun 6(6):462–466
Yu HX, Chia JM, Bourque G, Wong MV, Chan SH, Ren EC (2005) A population-based LD map of the human chromosome 6p. Immunogenetics 57(8):559–565
Acknowledgements
NH was supported through a scholarship from the Rhodes Trust. This work was financially supported by the Medical Research Council, UK. The Joint Gambian Government/MRC Ethics Committee granted permission for the collection, storage and use of Gambian samples for malaria research (family trios) and genetic research (cord blood). Permission to recruit and sample Caucasian families in Oxford, UK was granted by the local ethical committee (COREC no. C01.059).
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Hanchard, N., Diakite, M., Koch, O. et al. Implications of inter-population linkage disequilibrium patterns on the approach to a disease association study in the human MHC class III. Immunogenetics 58, 465–470 (2006). https://doi.org/10.1007/s00251-006-0118-1
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DOI: https://doi.org/10.1007/s00251-006-0118-1