Parental origin of sequence variants associated with complex diseases

Augustine Kong (), Valgerdur Steinthorsdottir, Gisli Masson, Gudmar Thorleifsson, Patrick Sulem, Soren Besenbacher, Aslaug Jonasdottir, Asgeir Sigurdsson, Kari Th. Kristinsson, Adalbjorg Jonasdottir, Michael L. Frigge, Arnaldur Gylfason, Pall I. Olason, Sigurjon A. Gudjonsson, Sverrir Sverrisson, Simon N. Stacey, Bardur Sigurgeirsson, Kristrun R. Benediktsdottir, Helgi Sigurdsson, Thorvaldur Jonsson, Rafn Benediktsson, Jon H. Olafsson, Oskar Th. Johannsson, Astradur B. Hreidarsson, Gunnar Sigurdsson, Anne C. Ferguson-Smith, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir and Kari Stefansson ()
Additional contact information
Augustine Kong: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Valgerdur Steinthorsdottir: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Gisli Masson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Gudmar Thorleifsson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Patrick Sulem: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Soren Besenbacher: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Aslaug Jonasdottir: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Asgeir Sigurdsson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Kari Th. Kristinsson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Adalbjorg Jonasdottir: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Michael L. Frigge: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Arnaldur Gylfason: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Pall I. Olason: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Sigurjon A. Gudjonsson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Sverrir Sverrisson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Simon N. Stacey: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Bardur Sigurgeirsson: Department of Dermatology,
Kristrun R. Benediktsdottir: Department of Pathology,
Helgi Sigurdsson: Department of Oncology,
Thorvaldur Jonsson: Department of Surgery,
Rafn Benediktsson: Landspitali-University Hospital, 101 Reykjavik, Iceland
Jon H. Olafsson: Department of Dermatology,
Oskar Th. Johannsson: Department of Oncology,
Astradur B. Hreidarsson: Landspitali-University Hospital, 101 Reykjavik, Iceland
Gunnar Sigurdsson: Landspitali-University Hospital, 101 Reykjavik, Iceland
Anne C. Ferguson-Smith: Development and Neuroscience, University of Cambridge
Daniel F. Gudbjartsson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Unnur Thorsteinsdottir: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland
Kari Stefansson: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland

Nature, 2009, vol. 462, issue 7275, 868-874

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature08625

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