Parental origin of sequence variants associated with complex diseases


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.


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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 or Augustine Kong or Kari Stefansson or Kari Stefansson.

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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).

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