Faculty, Staff and Student Publications
Publication Date
1-1-2023
Journal
Wellcome Open Research
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.
Keywords
exome chip, glycaemic traits, genetic discovery, effector genes, summary statistics resources
DOI
10.12688/wellcomeopenres.18754.1
PMID
39280063
PMCID
PMC11399760
PubMedCentral® Posted Date
10-20-2023
PubMedCentral® Full Text Version
Post-print
Recommended Citation
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; EPIC-Interact Consortium; 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; Understanding Society Scientific Group;; 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; and Barroso, Inês, "Large-Scale Exome Array Summary Statistics Resources for Glycemic Traits to Aid Effector Gene Prioritization" (2023). Faculty, Staff and Student Publications. 105.
https://digitalcommons.library.tmc.edu/uthdb_docs/105
Published Open-Access
yes