Publication Date:
2009-12-18
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746295/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746295/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kong, Augustine -- Steinthorsdottir, Valgerdur -- Masson, Gisli -- Thorleifsson, Gudmar -- Sulem, Patrick -- Besenbacher, Soren -- Jonasdottir, Aslaug -- Sigurdsson, Asgeir -- Kristinsson, Kari Th -- Jonasdottir, Adalbjorg -- Frigge, Michael L -- Gylfason, Arnaldur -- Olason, Pall I -- Gudjonsson, Sigurjon A -- Sverrisson, Sverrir -- Stacey, Simon N -- Sigurgeirsson, Bardur -- Benediktsdottir, Kristrun R -- Sigurdsson, Helgi -- Jonsson, Thorvaldur -- Benediktsson, Rafn -- Olafsson, Jon H -- Johannsson, Oskar Th -- Hreidarsson, Astradur B -- Sigurdsson, Gunnar -- DIAGRAM Consortium -- Ferguson-Smith, Anne C -- Gudbjartsson, Daniel F -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- 077016/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- G9723500/Medical Research Council/United Kingdom -- K08 AR055688/AR/NIAMS NIH HHS/ -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106179474/Medical Research Council/United Kingdom -- MC_U127592696/Medical Research Council/United Kingdom -- R01 DK029867/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Dec 17;462(7275):868-74. doi: 10.1038/nature08625.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland. kong@decode.is〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20016592" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Binding Sites
;
Breast Neoplasms/genetics
;
Carcinoma, Basal Cell/genetics
;
Chromosomes, Human, Pair 11/genetics
;
Chromosomes, Human, Pair 7/genetics
;
DNA Methylation/genetics
;
Diabetes Mellitus, Type 2/genetics
;
*Fathers
;
Female
;
Genetic Predisposition to Disease/*genetics
;
Genome, Human/genetics
;
Genomic Imprinting/genetics
;
Haplotypes
;
Humans
;
Iceland
;
Male
;
*Mothers
;
Pedigree
;
Polymorphism, Single Nucleotide/*genetics
;
Repressor Proteins/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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