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Kong, A.* ; Steinthorsdottir, V.* ; Masson, G.* ; Thorleifsson, G.* ; Sulem, P.* ; Besenbacher, S.* ; Jonasdottir, A.* ; Sigurdsson, A.* ; Kristinsson, K.T.* ; Frigge, M.L.* ; Gylfason, A. Olason, P.I.* ; Gudjonsson, S.A.* ; Sverrisson, S.* ; Stacey, S.N.* ; Sigurgeirsson, B.* ; Benediktsdottir, K.R.* ; Sigurdsson, H.* ; Jonsson, T.* ; Benediktsson, R.* ; Olafsson, J.H.* ; Johannsson, O.T.* ; Hreidarsson, A.B.* ; Sigurdsson, G.* ; DIAGRAM Consortium (Huth, C. ; Grallert, H. ; Gieger, C. ; Klopp, N. ; Meitinger, T. ; Petersen, A.-K. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T.) ; Ferguson-Smith, A.C.* ; Gudbjartsson, D.F.* ; Thorsteinsdottir, U.* ; Stefansson, K.

Parental origin of sequence variants associated with complex diseases.

Nature 462, 868-874 (2009)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords genome-wide association; imprinted genes; susceptibility; expression; imputation; kcnq1
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 462, Issue: 7275, Pages: 868-874 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)