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

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)).

journal_name

Nat Genet

journal_title

Nature genetics

authors

Steinthorsdottir V,Thorleifsson G,Sulem P,Helgason H,Grarup N,Sigurdsson A,Helgadottir HT,Johannsdottir H,Magnusson OT,Gudjonsson SA,Justesen JM,Harder MN,Jørgensen ME,Christensen C,Brandslund I,Sandbæk A,Lauritzen T,Ve

doi

10.1038/ng.2882

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

294-8

issue

3

eissn

1061-4036

issn

1546-1718

pii

ng.2882

journal_volume

46

pub_type

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