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 (β=-0.09±0.01 mmol l-1, P=3.4 × 10-12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10-6) 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 (β=0.02±0.004 mmol l-1, P=1.3 × 10-8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Wessel, Jennifer, Chu, Audrey Y., Willems, Sara M., Wang, Shuai, Yaghootkar, Hanieh, Brody, Jennifer A., Dauriz, Marco, Hivert, Marie-France, Raghavan, Sridharan, Lipovich, Leonard, Hidalgo, Bertha, Fox, Keolu, Huffman, Jennifer E., An, Ping, Lu, Yingchang, Rasmussen-Torvik, Laura J., Grarup, Niels, Ehm, Margaret G., ... Goodarzi, Mark O. (2015). Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nature Communications, 6(1). https://doi.org/10.1038/ncomms6897
Wessel, Jennifer, Chu, Audrey Y., Willems, Sara M., et al., "Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility," Nature Communications 6, no. 1 (2015), https://doi.org/10.1038/ncomms6897
@article{osti_1623962,
author = {Wessel, Jennifer and Chu, Audrey Y. and Willems, Sara M. and Wang, Shuai and Yaghootkar, Hanieh and Brody, Jennifer A. and Dauriz, Marco and Hivert, Marie-France and Raghavan, Sridharan and Lipovich, Leonard and others},
title = {Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility},
annote = {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 (β=-0.09±0.01 mmol l-1, P=3.4 × 10-12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10-6) 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 (β=0.02±0.004 mmol l-1, P=1.3 × 10-8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.},
doi = {10.1038/ncomms6897},
url = {https://www.osti.gov/biblio/1623962},
journal = {Nature Communications},
issn = {ISSN 2041-1723},
number = {1},
volume = {6},
place = {United States},
publisher = {Nature Publishing Group},
year = {2015},
month = {01}}
Lawrence Berkeley National Lab (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
American Recovery and Reinvestment Act (ARRA); Atherosclerosis Risk in Communities (ARIC) Study; Baylor Genome Center; National Institutes of Health (NIH); National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI); USDOE Office of Science (SC)