Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 612.4 Hematopoietic, lymphatic, glandular, urinary systems
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: Article No. 5897 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261229
• Chủ đề: 1. 60 applied life sciences; 2. Science & technology - other topics

Tóm tắt

 Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T
  rs10305492
  MAF=1.4%) with lower FG (?=-0.09�0.01 mmol l<
 sup>
 -1<
 /sup>
 , P=3.4 � 10<
 sup>
 -12<
 /sup>
 ), T2D risk (OR[95%CI]=0.86[0.76?0.96], P=0.010), early insulin secretion (?=-0.07�0.035 pmol<
 sub>
 insulin<
 /sub>
  mmol<
 sub>
 glucose<
 /sub>
 <
 sup>
 -1<
 /sup>
 , P=0.048), but higher 2-h glucose (?=0.16�0.05 mmol l<
 sup>
 -1<
 /sup>
 , P=4.3 � 10<
 sup>
 -4<
 /sup>
 ). We identify a gene-based association with FG at G6PC2 (p<
 sub>
 SKAT<
 /sub>
 =6.8 � 10<
 sup>
 -6<
 /sup>
 ) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (?=0.02�0.004 mmol l<
 sup>
 -1<
 /sup>
 , P=1.3 � 10<
 sup>
 -8<
 /sup>
 ). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.