101. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization.
- Author
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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 YI, 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, Järvelin MR, 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 AE, Faul JD, Franks PW, Franks S, Fritsche A, Gjesing AP, Goodarzi MO, Gudnason V, Hallmans G, Harris TB, Herzig KH, Hivert MF, Jørgensen T, Jørgensen 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, Lindström J, Manning Fox JE, Männistö S, Maruthur NM, Moilanen L, Mulas A, Nalls MA, Neville M, Pankow JS, Pattie A, Petersen ERB, Puolijoki H, Rasheed A, Redmond P, Renström F, Roden M, Saleheen D, Saltevo J, Savonen K, Sebert S, Skaaby T, Small KS, Stančáková A, Stokholm J, Strauch K, Tai ES, Taylor KD, Thuesen BH, Tönjes A, Tsafantakis E, Tuomi T, Tuomilehto J, Uusitupa M, Vääräsmäki M, Vaartjes I, Zoledziewska M, Abecasis G, Balkau B, Bisgaard H, Blakemore AI, Blüher M, Boeing H, Boerwinkle E, Bønnelykke K, Bottinger EP, Caulfield MJ, Chambers JC, Chasman DI, Cheng CY, 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 KT, Kiess W, Kooner JS, Körner A, Lakka T, Langenberg C, Lind L, Lindgren CM, Linneberg A, Lipovich L, Liu CT, 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, and Barroso I
- Abstract
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., Competing Interests: Competing interests: Rebecca S. Fine: Rebecca S. Fine is currently employed by Vertex Pharmaceuticals Incorporated. Audrey Y Chu: Currently employed by GlaxoSmithkline. Dennis O. Mook-Kanamori: Dennis Mook-Kanamori is working as a part-time clinical research consultant for Metabolon, Inc. Paul W. Franks: PWF has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project. Mike A. Nalls: Dr. Mike A. Nalls is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. Dr. Nalls also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. Mark J. Caulfield: MJC is Chief Scientist for Genomics England, a UK government company. Joel N. Hirschhorn: JHN is on the scientific advisory board of Camp4 Therapeutics. Erik Ingelsson: Erik Ingelsson is now an employee of GlaxoSmithKline. Anubha Mahajan: Anubha Mahajan is an employee of Genentech since January 2020, and a holder of Roche stock. Mark I McCarthy: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MMcC has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock. Inês Barroso: IB and spouse declare stock ownership in GlaxoSmithkline and Incyte Ltd. James B. Meigs: JBM serves as an Academic Associate for Quest Diagnostics R&D Bruce M Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr. Sander W. van der Laan has received Roche funding for unrelated work. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. Vinicius Tragante: VT became an employee of deCODE genetics/Amgen Inc. after the conclusion of this work Dr Franco is employed by ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.) and Metagenics., (Copyright: © 2023 Willems SM et al.)
- Published
- 2023
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