Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization
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; Keinänen-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; 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; Barroso, Inês (2023-10-20)
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
Keinänen-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
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
Barroso, Inês
Wellcome Trust
20.10.2023
Willems SM, Ng NHJ, Fernandez J et al. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization [version 1; peer review: 2 approved] Wellcome Open Research 2023, 8:483, https://doi.org/10.12688/wellcomeopenres.18754.1
https://creativecommons.org/licenses/by/4.0/
© 2023 Willems SM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
https://creativecommons.org/licenses/by/4.0/
© 2023 Willems SM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
https://creativecommons.org/licenses/by/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202409175901
https://urn.fi/URN:NBN:fi:oulu-202409175901
Tiivistelmä
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.
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.
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