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Lookup NU author(s): Emeritus Professor Mark Walker
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright: © 2023 Willems SM et al. 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.
Author(s): Willems SM, Ng NHJ, Fernandez J, Fine RS, Wheeler E, Wessel J, Kitajima H, Marenne G, Sim X, Yaghootkar H, Wang S, Chen S, Chen Y, Chen Y-DI, Grarup N, Li-Gao R, Varga TV, Asimit JL, Feng S, Strawbridge RJ, Kleinbrink EL, Ahluwalia TS, An P, Appel EV, Arking DE, Auvinen J, Bielak LF, Bihlmeyer NA, Bork-Jensen J, Brody JA, Campbell A, Chu AY, Davies G, Demirkan A, Floyd JS, Giulianini F, Guo X, Gustafsson S, Jackson AU, Jakobsdottir J, Jarvelin M-R, Jensen RA, Kanoni S, Keinanen-Kiukaanniemi S, Li M, Lu Y, Luan J, Manning AK, Marten J, Meidtner K, Mook-Kanamori DO, Muka T, Pistis G, Prins B, Rice KM, Sanna S, Smith AV, Smith JA, Southam L, Stringham HM, Tragante V, van der Laan SW, Warren HR, Yao J, Yiorkas AM, Zhang W, Zhao W, Graff M, Highland HM, Justice AE, Marouli E, Medina-Gomez C, Afaq S, Alhejily WA, Amin N, Asselbergs FW, Bonnycastle LL, Bots ML, Brandslund I, Chen J, Danesh J, de Mutsert R, Dehghan A, Ebeling T, Elliott P, Farmaki A-E, Faul JD, Franks PW, Franks S, Fritsche A, Gjesing AP, Goodarzi MO, Gudnason V, Hallmans G, Harris TB, Herzig K-H, Hivert M-F, Jorgensen T, Jorgensen ME, Jousilahti P, Kajantie E, Karaleftheri M, Kardia SLR, Kinnunen L, Koistinen HA, Komulainen P, Kovacs P, Kuusisto J, Laakso M, Lange LA, Launer LJ, Leong A, Lindstrom J, Manning Fox JE, Mannisto S, Maruthur NM, Moilanen L, Mulas A, Nalls MA, Neville M, Pankow JS, Pattie A, Petersen ERB, Puolijoki H, Rasheed A, Redmond P, Renstrom F, Roden M, Saleheen D, Saltevo J, Savonen K, Sebert S, Skaaby T, Small KS, Stancakova A, Stokholm J, Strauch K, Tai E-S, Taylor KD, Thuesen BH, Tonjes A, Tsafantakis E, Tuomi T, Tuomilehto J, Uusitupa M, Vaarasmaki M, Vaartjes I, Zoledziewska M, Abecasis G, Balkau B, Bisgaard H, Blakemore AI, Bluher M, Boeing H, Boerwinkle E, Bonnelykke K, Bottinger EP, Caulfield MJ, Chambers JC, Chasman DI, Cheng C-Y, Collins FS, Coresh J, Cucca F, de Borst GJ, Deary IJ, Dedoussis G, Deloukas P, den Ruijter HM, Dupuis J, Evans MK, Ferrannini E, Franco OH, Grallert H, Hansen T, Hattersley AT, Hayward C, Hirschhorn JN, Ikram A, Ingelsson E, Karpe F, Kaw K-T, Kiess W, Kooner JS, Korner A, Lakka T, Langenberg C, Lind L, Lindgren CM, Linneberg A, Lipovich L, Liu C-T, Liu J, Liu Y, Loos RJF, MacDonald PE, Mohlke KL, Morris AD, Munroe PB, Murray A, Padmanabhan S, Palmer CNA, Pasterkamp G, Pedersen O, Peyser PA, Polasek O, Porteous D, Province MA, Psaty BM, Rauramaa R, Ridker PM, Rolandsson O, Rorsman P, Rosendaal FR, Rudan I, Salomaa V, Schulze MB, Sladek R, Smith BH, Spector TD, Starr JM, Stumvoll M, van Duijn CM, Walker M, Wareham NJ, Weir DR, Wilson JG, Wong TY, Zeggini E, Zonderman AB, Rotter JI, Morris AP, Boehnke M, Florez JC, McCarthy MI, Meigs JB, Mahajan A, Scott RA, Gloyn AL, Barroso I
Publication type: Article
Publication status: Published
Journal: Wellcome Open Research
Year: 2023
Volume: 8
Online publication date: 20/08/2023
Acceptance date: 20/08/2023
Date deposited: 08/10/2024
ISSN (electronic): 2398-502X
Publisher: F1000 Research Ltd
URL: https://doi.org/10.12688/wellcomeopenres.18754.1
DOI: 10.12688/wellcomeopenres.18754.1
Data Access Statement: Open Science Framework (OSF): Underlying data for 'Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization' https://doi.org/10.17605/OSF.IO/K6W3B. For the full list of the underlying data and their accession numbers please see the article.
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