Abstract
For haplotype analysis of the X chromosome, haplotype-sharing (HS) statistics with sliding windows are defined for males and females separately, which are then combined to a single HS test for the X chromosome. When independent replication samples are not available, the training-testing sets approach is used to validate this procedure and a permutation method is used to obtain its P-value. We applied this method to the X chromosome (with 1804 SNPs) for age-related macular degeneration (AMD). We found a window of five SNPs over a 272 kb region associated with AMD after Bonferroni correction. An examination of the odds ratio and the population attributable risks revealed a disease-preventive haplotype, ATGAC, on these five SNPs. For elderly females without this haplotype, the likelihood of AMD is increased by a factor of 4.75 with a 95% confidence interval (1.43, 15.82). The frequency of ATGAC in HapMap CEU is 0.276. These five SNPs are covered by the gene DIAPH2, which is known to cause premature ovarian failure (POF) in females. Our results indicated that DIAPH2 may be a polygenic pleiotropy for POF and AMD.
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References
Zheng G, Joo J, Zhang C, Geller NL : Testing association for markers on the X chromosome. Genet Epidemiol 2007; 31: 834–843.
Clayton DG : Testing for association on the X chromosome. Biostatistics 2008; 9: 593–600.
Tzeng JY, Devlin B, Wasserman L, Roeder K : On the identification of disease mutations by the analysis of haplotype similarity and goodness of fit. Am J Hum Genet 2003; 72: 891–902.
Zhang SL, Sha Q, Chen H, Dong J, Jiang R : Transmission/disequilibrium test based on haplotype sharing for tightly linked markers. Am J Hum Genet 2003; 73: 566–579.
Excoffier L, Slatkin M : Maximum likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.
Li Y, Sung WK, Liu JJ : Association mapping via regularized regression analysis of single-nucleotide-polymorphism haplotypes in variable-sized sliding windows. Am J Hum Genet 2007; 80: 705–715.
Clayton DG, Jones H : Transmission/disequilibrium tests for extended marker haplotypes. Am J Hum Genet 1999; 65: 1161–1169.
Bourgain C, Genin E, Quesneville H, Clerget-Darpoux F : Search for multifactorial disease susceptibility genes in founder populations. Ann Hum Genet 2000; 64: 255–265.
Toivonen HT, Onkamo P, Vasko K et al: Data mining applied to linkage disequilibrium mapping. Am J Hum Genet 2000; 67: 133–145.
Frieman DS, O’Colmain BJ, Munoz B et al: Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564–572.
Klein RJ, Zeiss C, Chew EY et al: Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385–389.
Schaffner SF : The X chromosome in population genetics. Nat Rev Genet 2004; 5: 43–51.
Laan M, Wiebe V, Khusnutdinove E, Remm M, Paabo S : X chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations. Eur J Hum Genet 2005; 13: 452–462.
Smith JA, Vitale S, Reed GF et al: Dry eye signs and symptoms in women with premature ovarian failure. Arch Ophthalmol 2004; 122: 151–156.
de Jong PTVM : Age-related macular degeneration. N Engl J Med 2007; 355: 1474–1485.
Thorisson GA, Smith AV, Krishnan L, Stein LD : The International HapMap Project Web site. Genome Res 2005; 15: 1591–1593.
Acknowledgements
The use of NEI AREDS GWAS data was approved by the Data Access Committee of NEI through dbGap. We would like to thank a reviewer for the helpful comments and suggestions, especially on the two-stage analysis. We would also like to thank Dr James Troendle on discussion of multiple testing issues.
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Jiang, R., Dong, J., Joo, J. et al. Simple strategies for haplotype analysis of the X chromosome with application to age-related macular degeneration. Eur J Hum Genet 19, 801–806 (2011). https://doi.org/10.1038/ejhg.2011.35
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DOI: https://doi.org/10.1038/ejhg.2011.35
