TY - JOUR
T1 - Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization
AU - EPIC-InterAct Consortium
AU - Understanding Society Scientific Group
AU - Willems, Sara M.
AU - Ng, Natasha H.J.
AU - Fernandez, Juan
AU - Fine, Rebecca S.
AU - Wheeler, Eleanor
AU - Wessel, Jennifer
AU - Kitajima, Hidetoshi
AU - Marenne, Gaelle
AU - Sim, Xueling
AU - Yaghootkar, Hanieh
AU - Wang, Shuai
AU - Chen, Sai
AU - Chen, Yuning
AU - Chen, Yii Der Ida
AU - Grarup, Niels
AU - Li-Gao, Ruifang
AU - Varga, Tibor V.
AU - Asimit, Jennifer L.
AU - Feng, Shuang
AU - Strawbridge, Rona J.
AU - Kleinbrink, Erica L.
AU - Ahluwalia, Tarunveer S.
AU - An, Ping
AU - Appel, Emil V.
AU - Arking, Dan E.
AU - Auvinen, Juha
AU - Bielak, Lawrence F.
AU - Bihlmeyer, Nathan A.
AU - Bork-Jensen, Jette
AU - Brody, Jennifer A.
AU - Campbell, Archie
AU - Chu, Audrey Y.
AU - Davies, Gail
AU - Demirkan, Ayse
AU - Floyd, James S.
AU - Giulianini, Franco
AU - Guo, Xiuqing
AU - Gustafsson, Stefan
AU - Jackson, Anne U.
AU - Jakobsdottir, Johanna
AU - Järvelin, Marjo Riitta
AU - Jensen, Richard A.
AU - Kanoni, Stavroula
AU - Keinanen-Kiukaanniemi, Sirkka
AU - Li, Man
AU - Lu, Yingchang
AU - Luan, Jian'an
AU - Manning, Alisa K.
AU - Marten, Jonathan
AU - Pankow, James S.
N1 - Publisher Copyright:
Copyright: © 2023 Willems SM et al.
PY - 2023
Y1 - 2023
N2 - Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
AB - Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
KW - effector genes
KW - exome chip
KW - genetic discovery
KW - glycaemic traits
KW - summary statistics resources
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U2 - 10.12688/wellcomeopenres.18754.1
DO - 10.12688/wellcomeopenres.18754.1
M3 - Article
AN - SCOPUS:85204904115
SN - 2398-502X
VL - 8
JO - Wellcome Open Research
JF - Wellcome Open Research
M1 - 483
ER -