用于血糖性状的大规模外显子阵列汇总统计资源，以协助效应基因的优先级排序。
Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization.
作者信息
Willems Sara M, Ng Natasha H J, Fernandez Juan, Fine Rebecca S, Wheeler Eleanor, Wessel Jennifer, Kitajima Hidetoshi, Marenne Gaelle, Sim Xueling, Yaghootkar Hanieh, Wang Shuai, Chen Sai, Chen Yuning, Chen Yii-Der Ida, Grarup Niels, Li-Gao Ruifang, Varga Tibor V, Asimit Jennifer L, Feng Shuang, Strawbridge Rona J, Kleinbrink Erica L, Ahluwalia Tarunveer S, An Ping, Appel Emil V, Arking Dan E, Auvinen Juha, Bielak Lawrence F, Bihlmeyer Nathan A, Bork-Jensen Jette, Brody Jennifer A, Campbell Archie, Chu Audrey Y, Davies Gail, Demirkan Ayse, Floyd James S, Giulianini Franco, Guo Xiuqing, Gustafsson Stefan, Jackson Anne U, Jakobsdottir Johanna, Järvelin Marjo-Riitta, Jensen Richard A, Kanoni Stavroula, Keinanen-Kiukaanniemi Sirkka, Li Man, Lu Yingchang, Luan Jian'an, Manning Alisa K, Marten Jonathan, Meidtner Karina, Mook-Kanamori Dennis O, Muka Taulant, Pistis Giorgio, Prins Bram, Rice Kenneth M, Sanna Serena, Smith Albert Vernon, Smith Jennifer A, Southam Lorraine, Stringham Heather M, Tragante Vinicius, van der Laan Sander W, Warren Helen R, Yao Jie, Yiorkas Andrianos M, Zhang Weihua, Zhao Wei, Graff Mariaelisa, Highland Heather M, Justice Anne E, Marouli Eirini, Medina-Gomez Carolina, Afaq Saima, Alhejily Wesam A, Amin Najaf, Asselbergs Folkert W, Bonnycastle Lori L, Bots Michiel L, Brandslund Ivan, Chen Ji, Danesh John, de Mutsert Renée, Dehghan Abbas, Ebeling Tapani, Elliott Paul, Farmaki Aliki-Eleni, Faul Jessica D, Franks Paul W, Franks Steve, Fritsche Andreas, Gjesing Anette P, Goodarzi Mark O, Gudnason Vilmundur, Hallmans Göran, Harris Tamara B, Herzig Karl-Heinz, Hivert Marie-France, Jørgensen Torben, Jørgensen Marit E, Jousilahti Pekka, Kajantie Eero, Karaleftheri Maria, Kardia Sharon L R, Kinnunen Leena, Koistinen Heikki A, Komulainen Pirjo, Kovacs Peter, Kuusisto Johanna, Laakso Markku, Lange Leslie A, Launer Lenore J, Leong Aaron, Lindström Jaana, Manning Fox Jocelyn E, Männistö Satu, Maruthur Nisa M, Moilanen Leena, Mulas Antonella, Nalls Mike A, Neville Matthew, Pankow James S, Pattie Alison, Petersen Eva R B, Puolijoki Hannu, Rasheed Asif, Redmond Paul, Renström Frida, Roden Michael, Saleheen Danish, Saltevo Juha, Savonen Kai, Sebert Sylvain, Skaaby Tea, Small Kerrin S, Stančáková Alena, Stokholm Jakob, Strauch Konstantin, Tai E-Shyong, Taylor Kent D, Thuesen Betina H, Tönjes Anke, Tsafantakis Emmanouil, Tuomi Tiinamaija, Tuomilehto Jaakko, Uusitupa Matti, Vääräsmäki Marja, Vaartjes Ilonca, Zoledziewska Magdalena, Abecasis Goncalo, Balkau Beverley, Bisgaard Hans, Blakemore Alexandra I, Blüher Matthias, Boeing Heiner, Boerwinkle Eric, Bønnelykke Klaus, Bottinger Erwin P, Caulfield Mark J, Chambers John C, Chasman Daniel I, Cheng Ching-Yu, Collins Francis S, Coresh Josef, Cucca Francesco, de Borst Gert J, Deary Ian J, Dedoussis George, Deloukas Panos, den Ruijter Hester M, Dupuis Josée, Evans Michele K, Ferrannini Ele, Franco Oscar H, Grallert Harald, Hansen Torben, Hattersley Andrew T, Hayward Caroline, Hirschhorn Joel N, Ikram Arfan, Ingelsson Erik, Karpe Fredrik, Kaw Kay-Tee, Kiess Wieland, Kooner Jaspal S, Körner Antje, Lakka Timo, Langenberg Claudia, Lind Lars, Lindgren Cecilia M, Linneberg Allan, Lipovich Leonard, Liu Ching-Ti, Liu Jun, Liu Yongmei, Loos Ruth J F, MacDonald Patrick E, Mohlke Karen L, Morris Andrew D, Munroe Patricia B, Murray Alison, Padmanabhan Sandosh, Palmer Colin N A, Pasterkamp Gerard, Pedersen Oluf, Peyser Patricia A, Polasek Ozren, Porteous David, Province Michael A, Psaty Bruce M, Rauramaa Rainer, Ridker Paul M, Rolandsson Olov, Rorsman Patrik, Rosendaal Frits R, Rudan Igor, Salomaa Veikko, Schulze Matthias B, Sladek Robert, Smith Blair H, Spector Timothy D, Starr John M, Stumvoll Michael, van Duijn Cornelia M, Walker Mark, Wareham Nick J, Weir David R, Wilson James G, Wong Tien Yin, Zeggini Eleftheria, Zonderman Alan B, Rotter Jerome I, Morris Andrew P, Boehnke Michael, Florez Jose C, McCarthy Mark I, Meigs James B, Mahajan Anubha, Scott Robert A, Gloyn Anna L, Barroso Inês
机构信息
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
General Medicine Center, Saarland University Faculty of Medicine, Homburg, 66421, Germany.
出版信息
Wellcome Open Res. 2023 Oct 20;8:483. doi: 10.12688/wellcomeopenres.18754.1. eCollection 2023.
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.
背景
针对血糖性状的全基因组关联研究已经确定了数百个与这些葡萄糖稳态生物标志物相关的基因座。尽管取得了这一成功，但将变异关联与基因以及潜在的生物学途径联系起来的挑战依然存在。
方法
为了识别可能在新的和先前已确定的全基因组关联基因座上确定效应基因的编码变异关联，我们对四种血糖性状的外显子阵列研究进行了荟萃分析：糖化血红蛋白（HbA1c，多达144,060名参与者）、空腹血糖（FG，多达129,665名参与者）、空腹胰岛素（FI，多达104,140名）和口服葡萄糖耐量试验后2小时血糖（2hGlu，多达57,878名）。此外，我们还进行了网络和途径分析。
结果
单变异和基于基因的关联分析确定了60多个基因的编码变异关联，与其他数据集结合时可能有助于确定效应基因。网络和途径分析确定了与胰岛素分泌、锌转运和脂肪酸代谢相关的途径。HbA1c关联在与血细胞生物学相关的途径中高度富集。
结论
我们的结果提供了新的血糖性状关联，并突出了与血糖调节相关的途径。外显子阵列汇总统计结果已提供给科学界，以促进进一步的发现。
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