Parental origin of sequence variants associated with complex diseases

被引：406

作者：

Kong, Augustine ^{[1
]}

Steinthorsdottir, Valgerdur ^{[1
]}

Masson, Gisli ^{[1
]}

Thorleifsson, Gudmar ^{[1
]}

Sulem, Patrick ^{[1
]}

Besenbacher, Soren ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Kristinsson, Kari Th.

Jonasdottir, Adalbjorg ^{[1
]}

Frigge, Michael L. ^{[1
]}

Gylfason, Arnaldur ^{[1
]}

Olason, Pall I. ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Sverrisson, Sverrir ^{[1
]}

Stacey, Simon N. ^{[1
]}

Sigurgeirsson, Bardur ^{[2
]}

Benediktsdottir, Kristrun R. ^{[3
]}

Sigurdsson, Helgi ^{[4
]}

Jonsson, Thorvaldur ^{[5
]}

Benediktsson, Rafn ^{[6
]}

Olafsson, Jon H. ^{[2
]}

Johannsson, Oskar Th. ^{[4
]}

Hreidarsson, Astradur B. ^{[6
]}

Sigurdsson, Gunnar ^{[6
]}

Ferguson-Smith, Anne C. ^{[7
]}

Gudbjartsson, Daniel F. ^{[1
]}

Thorsteinsdottir, Unnur ^{[1
,8
]}

Stefansson, Kari ^{[1
,8
]}

机构：

[1] deCODE Genet, IS-101 Reykjavik, Iceland

[2] Landspitali Univ Hosp, Dept Dermatol, IS-101 Reykjavik, Iceland

[3] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland

[4] Landspitali Univ Hosp, Dept Oncol, IS-101 Reykjavik, Iceland

[5] Landspitali Univ Hosp, Dept Surg, IS-101 Reykjavik, Iceland

[6] Landspitali Univ Hosp, Dept Endocrinol & Metab, IS-101 Reykjavik, Iceland

[7] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England

[8] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

来源：

NATURE | 2009年 / 462卷 / 7275期

基金：

芬兰科学院;

关键词：

GENOME-WIDE ASSOCIATION; IMPRINTED GENES; SUSCEPTIBILITY; EXPRESSION; IMPUTATION; KCNQ1;

D O I：

10.1038/nature08625

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：868 / U59

页数：8

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