Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-03

AUTHORS

Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Patrick Sulem, Hannes Helgason, Niels Grarup, Asgeir Sigurdsson, Hafdis T Helgadottir, Hrefna Johannsdottir, Olafur T Magnusson, Sigurjon A Gudjonsson, Johanne M Justesen, Marie N Harder, Marit E Jørgensen, Cramer Christensen, Ivan Brandslund, Annelli Sandbæk, Torsten Lauritzen, Henrik Vestergaard, Allan Linneberg, Torben Jørgensen, Torben Hansen, Maryam S Daneshpour, Mohammad-Sadegh Fallah, Astradur B Hreidarsson, Gunnar Sigurdsson, Fereidoun Azizi, Rafn Benediktsson, Gisli Masson, Agnar Helgason, Augustine Kong, Daniel F Gudbjartsson, Oluf Pedersen, Unnur Thorsteinsdottir, Kari Stefansson

ABSTRACT

Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)). More... »

PAGES

294-298

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.2882

    DOI

    http://dx.doi.org/10.1038/ng.2882

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1006024989

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24464100


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