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Parental origin of sequence variants associated with complex diseases

Abstract

Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five—one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes—have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.

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Figure 1: An example of determination of parental origin.
Figure 2: Chromosome 11p15 locus.
Figure 3: Chromosome 7q32 locus.

References

  1. Rampersaud, E., Mitchell, B. D., Naj, A. C. & Pollin, T. I. Investigating parent of origin effects in studies of type 2 diabetes and obesity. Curr. Diabetes Rev. 4, 329–339 (2008)

    Article  CAS  Google Scholar 

  2. Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nature Genet. 40, 1068–1075 (2008)

    Article  CAS  Google Scholar 

  3. Luedi, P. P. et al. Computational and experimental identification of novel human imprinted genes. Genome Res. 17, 1723–1730 (2007)

    Article  CAS  Google Scholar 

  4. Morison, I. M., Paton, C. J. & Cleverley, S. D. The imprinted gene and parent-of-origin effect database. Nucleic Acids Res. 29, 275–276 (2001)

    Article  CAS  Google Scholar 

  5. Morison, I. M., Ramsay, J. P. & Spencer, H. G. A census of mammalian imprinting. Trends Genet. 21, 457–465 (2005)

    Article  CAS  Google Scholar 

  6. Hindorff, L. A., Junkins, H. A., Mehta, J. P. & Manolio, T. A. A Catalog of Published Genome-Wide Association Studies. OPG: Catalog Published Genome-Wide Assoc. Studieshttp://www.genome.gov/gwastudies〉 (2009)

  7. Stacey, S. N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nature Genet. 41, 909–914 (2009)

    Article  CAS  Google Scholar 

  8. Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007)

    Article  ADS  CAS  Google Scholar 

  9. Thomas, G. et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nature Genet. 41, 579–584 (2009)

    Article  CAS  Google Scholar 

  10. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nature Genet. 39, 906–913 (2007)

    Article  CAS  Google Scholar 

  11. Yasuda, K. et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature Genet. 40, 1092–1097 (2008)

    Article  CAS  Google Scholar 

  12. Unoki, H. et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nature Genet. 40, 1098–1102 (2008)

    Article  CAS  Google Scholar 

  13. Storey, J. D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl Acad. Sci. USA 100, 9440–9445 (2003)

    Article  ADS  MathSciNet  CAS  Google Scholar 

  14. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999)

    Article  CAS  Google Scholar 

  15. Georges, M., Charlier, C. & Cockett, N. The callipyge locus: evidence for the trans interaction of reciprocally imprinted genes. Trends Genet. 19, 248–252 (2003)

    Article  CAS  Google Scholar 

  16. Ideraabdullah, F. Y., Vigneau, S. & Bartolomei, M. S. Genomic imprinting mechanisms in mammals. Mutat. Res. 647, 77–85 (2008)

    Article  CAS  Google Scholar 

  17. Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007)

    Article  ADS  CAS  Google Scholar 

  19. Goldberg, M., Wei, M., Yuan, L., Murty, V. V. & Tycko, B. Biallelic expression of HRAS and MUCDHL in human and mouse. Hum. Genet. 112, 334–342 (2003)

    CAS  PubMed  Google Scholar 

  20. Authier, F., Metioui, M., Fabrega, S., Kouach, M. & Briand, G. Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D. J. Biol. Chem. 277, 9437–9446 (2002)

    Article  CAS  Google Scholar 

  21. Parker-Katiraee, L. et al. Identification of the imprinted KLF14 transcription factor undergoing human-specific accelerated evolution. PLoS Genet. 3, e65 (2007)

    Article  Google Scholar 

  22. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008)

    Article  ADS  CAS  Google Scholar 

  23. Kim, T. H. et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231–1245 (2007)

    Article  CAS  Google Scholar 

  24. Cuddapah, S. et al. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res. 19, 24–32 (2009)

    Article  CAS  Google Scholar 

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Acknowledgements

Acknowledgements This project was funded in part by FP7-MC-IAPP Grant agreement no. 218071 (CancerGene) to deCODE genetics.

Author Contributions A.K. and K.S. planned and directed the research. A.K. wrote the first draft of the paper and, together with K.S., V.S., G.M., G.T. and U.T., wrote most of the final version. A.K. and G.M. designed the method to determine parental origin. G.M., with assistance from P.I.O., implemented the algorithm. D.F.G. wrote the code for association analysis taking parental origin into account and performed some initial analyses. P.S., S.B. and S.S. tabulated the established disease-associated variants and the regions known to harbour imprinted genes. V.S. and G.T. contributed to the analysis of the diabetes data and, together with A.K. and U.T., planned the follow-up association and functional studies. A.G., A.K. and M.L.F. imputed the untyped SNPs. S.N.S. and P.S. were responsible for the breast cancer and basal-cell carcinoma data. A.B.H., G.S. and R.B. provided clinical data for T2D, O.Th.J., T.J. and H.S. provided clinical data for breast cancer, and J.H.O., B.S. and K.R.B. provided clinical data for basal-cell carcinoma. The DIAGRAM Consortium provided the novel T2D-associated variants that are close to imprinted genes. Aslaug J., A.S., Adalbjorg J., K.Th.K. and S.A.G. performed the methylation and expression studies. A.C.F.-S. assisted in the interpretation of the results from the association and functional studies.

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Correspondence to Augustine Kong, Augustine Kong, Kari Stefansson or Kari Stefansson.

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The authors from Decode Genetics Inc. own stocks and stock options in the company.

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Kong, A., Steinthorsdottir, V., Masson, G. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009). https://doi.org/10.1038/nature08625

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