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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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)
Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nature Genet. 40, 1068–1075 (2008)
Luedi, P. P. et al. Computational and experimental identification of novel human imprinted genes. Genome Res. 17, 1723–1730 (2007)
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)
Morison, I. M., Ramsay, J. P. & Spencer, H. G. A census of mammalian imprinting. Trends Genet. 21, 457–465 (2005)
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. Studies 〈http://www.genome.gov/gwastudies〉 (2009)
Stacey, S. N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nature Genet. 41, 909–914 (2009)
Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007)
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)
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)
Yasuda, K. et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature Genet. 40, 1092–1097 (2008)
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)
Storey, J. D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl Acad. Sci. USA 100, 9440–9445 (2003)
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999)
Georges, M., Charlier, C. & Cockett, N. The callipyge locus: evidence for the trans interaction of reciprocally imprinted genes. Trends Genet. 19, 248–252 (2003)
Ideraabdullah, F. Y., Vigneau, S. & Bartolomei, M. S. Genomic imprinting mechanisms in mammals. Mutat. Res. 647, 77–85 (2008)
Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000)
Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007)
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)
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)
Parker-Katiraee, L. et al. Identification of the imprinted KLF14 transcription factor undergoing human-specific accelerated evolution. PLoS Genet. 3, e65 (2007)
Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008)
Kim, T. H. et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231–1245 (2007)
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)
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.
The authors from Decode Genetics Inc. own stocks and stock options in the company.
Lists of participants and affiliations appear at the end of the paper.
About this article
Cite this article
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
Quantitative genome-wide association analyses of receptive language in the Danish High Risk and Resilience Study
BMC Neuroscience (2020)
Pflügers Archiv - European Journal of Physiology (2020)
Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis
Scientific Reports (2020)
Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans
Brain and Behavior (2020)
Epigenome-wide association study of DNA methylation and microRNA expression highlights novel pathways for human complex traits