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Independent Replication and Meta-Analysis for Endometriosis Risk Loci

  • Yadav Sapkota (a1), Amelie Fassbender (a2) (a3), Lisa Bowdler (a1), Jenny N. Fung (a1), Daniëlle Peterse (a2) (a3), Dorien O (a2) (a3), Grant W. Montgomery (a1), Dale R. Nyholt (a1) (a4) and Thomas M. D'Hooghe (a2) (a3) (a5)...

Abstract

Endometriosis is a complex disease that affects 6–10% of women in their reproductive years and 20–50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with ‘All’ (p = .066) and ‘Grade_B’ (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.

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Corresponding author

address for correspondence: Yadav Sapkota, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston 4006 Queensland, Australia. E-mail: Yadav.Sapkota@qimrberghofer.edu.au

References

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Adachi, S., Tajima, A., Quan, J., Haino, K., Yoshihara, K., Masuzaki, H., . . . Tanaka, K. (2010). Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. Journal of Human Genetics, 55, 816821.
Albertsen, H. M., Chettier, R., Farrington, P., & Ward, K. (2013). Genome-wide association study link novel loci to endometriosis. PLoS One, 8, e58257.
American Society for Reproductive Medicine. (1997). Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertility and Sterility, 67, 817821.
Cochran, W. G. (1954). The combination of estimates from different experiments. Biometrics, 10, 101129.
Delaneau, O., Marchini, J., & Zagury, J. F. (2012). A linear complexity phasing method for thousands of genomes. Nature Methods, 9, 179181.
Fung, J. N., Holdsworth-Carson, S. J., Sapkota, Y., Zhao, Z. Z., Jones, L., Girling, J.E., . . . Montgomery, G. W. (2015). Functional evaluation of genetic variants associated with endometriosis near GREB1. Human Reproduction, 30, 12631275.
Gao, X., Outley, J., Botteman, M., Spalding, J., Simon, J. A., & Pashos, C. L. (2006). Economic burden of endometriosis. Fertility and Sterility, 86, 15611572.
Goldstein, J. I., Crenshaw, A., Carey, J., Grant, G. B., Maguire, J., Fromer, M., . . . Neale, B. M. (2012). zCall: A rare variant caller for array-based genotyping: Genetics and population analysis. Bioinformatics, 28, 25432545.
Han, B., & Eskin, E. (2011). Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. American Journal of Human Genetics, 88, 586598.
Hata, Y., Nakaoka, H., Yoshihara, K., Adachi, S., Haino, K., Yamaguchi, M., . . . Tanaka, K. (2013). A non-synonymous variant of IL1A is associated with endometriosis in Japanese population. Journal of Human Genetics, 58, 517520.
Ioannidis, J. P., Patsopoulos, N. A., & Evangelou, E. (2007). Heterogeneity in meta-analyses of genome-wide association investigations. PLoS One, 2, e841.
Li, Y., Willer, C. J., Ding, J., Scheet, P., & Abecasis, G. R. (2010). MaCH: Using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genetic Epidemiology, 34, 816834.
Li, Y., Willer, C., Sanna, S., & Abecasis, G. (2009). Genotype imputation. Annual Review of Genomics and Human Genetics, 10, 387406.
Magi, R., & Morris, A. P. (2010). GWAMA: Software for genome-wide association meta-analysis. BMC Bioinformatics, 11, 288.
Nyholt, D. R., Low, S. K., Anderson, C. A., Painter, J. N., Uno, S., Morris, A. P., . . . Montgomery, G. W. (2012). Genome-wide association meta-analysis identifies new endometriosis risk loci. Nature Genetics, 44, 13551359.
Pagliardini, L., Gentilini, D., Sanchez, A. M., Candiani, M., Vigano, P., & Di Blasio, A. M. (2015). Replication and meta-analysis of previous genome-wide association studies confirm vezatin as the locus with the strongest evidence for association with endometriosis. Human Reproduction, 30, 987993.
Pagliardini, L., Gentilini, D., Vigano, P., Panina-Bordignon, P., Busacca, M., Candiani, M., . . . Di Blasio, A. M. (2013). An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis. Journal of Medical Genetics, 50, 4346.
Painter, J. N., Anderson, C. A., Nyholt, D. R., Macgregor, S., Lin, J., Lee, S. H., . . . Zondervan, K. T. (2011). Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nature Genetics, 43, 5154.
Purcell, S., Cherny, S. S., & Sham, P. C. (2003). Genetic power calculator: Design of linkage and association genetic mapping studies of complex traits. Bioinformatics, 19, 149150.
Rahmioglu, N., Nyholt, D. R., Morris, A. P., Missmer, S. A., Montgomery, G. W., & Zondervan, K. T. (2014). Genetic variants underlying risk of endometriosis: Insights from meta-analysis of eight genome-wide association and replication datasets. Human Reproduction Update, 20, 702716.
Sapkota, Y., Attia, J., Gordon, S. D., Henders, A. K., Holliday, E. G., Rahmioglu, N., . . . Nyholt, D. R. (2015a). Genetic burden associated with varying degrees of disease severity in endometriosis. Molecular Human Reproduction, 21, 594602.
Sapkota, Y., Low, S. K., Attia, J., Gordon, S. D., Henders, A. K., Holliday, E. G., . . . Nyholt, D. R. (2015b). Association between endometriosis and the interleukin 1A (IL1A) locus. Human Reproduction, 30, 239248.
Sundqvist, J., Xu, H., Vodolazkaia, A., Fassbender, A., Kyama, C., Bokor, A., . . . Falconer, H. (2013). Replication of endometriosis-associated single-nucleotide polymorphisms from genome-wide association studies in a Caucasian population. Human Reproduction, 28, 835839.
Treloar, S. A., O'Connor, D. T., O'Connor, V. M., & Martin, N. G. (1999). Genetic influences on endometriosis in an Australian twin sample. Fertility and Sterility, 71, 701710.
Uno, S., Zembutsu, H., Hirasawa, A., Takahashi, A., Kubo, M., Akahane, T., . . . Nakamura, Y. (2010). A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nature Genetics, 42, 707710.
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Twin Research and Human Genetics
  • ISSN: 1832-4274
  • EISSN: 1839-2628
  • URL: /core/journals/twin-research-and-human-genetics
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