Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Ng, N; Willems, SM; Fernandez, J; Fine, RS; Wheeler, E; Wessel, J; Kitajima, H; Marenne, G; Rundle, JK; Sim, X; Yeghootkar, H; Vääräsmäki, M; Vaartjes, I; Evans, MK; Zoledziewska, M; Chen, S; Hansen, T; Abecasis, G; Balkau, B; Scott, RA; Fritsche, A; Justice, AE; Bisgaard, H; Hattersley, AT; Elliott, P; de Haan, HG; Hayward, C; Hirschhorn, JN; Bonnycastle, LL; Gjesing, AP; Ikram, MA; Ingelsson, E; Lo, KS; de Mutsert, R; Karpe, F; Kaw, K-T; Kiess, W; Kooner, JS; Körner, A; Consortium, E-I; Lakka, T; Bots, ML; Grarup, N; Herzig, K-H; Chasman, DI; Blakemore, AI; Langenberg, C; Lind, L; Lindgren, CM; Linneberg, A; Lipovich, L; Liu, C-T; Liu, J; Liu, Y; Marouli, E; Brandslund, I; Farmaki, A-E; Rotter, JI; Loos, RJF; Barroso, I; MacDonald, PE; Li-Gao, R; Mohlke, KL; Morris, AD; Munroe, PB; Medina-Gomez, C; Murray, A; Padmanabhan, S; Chen, J; Arking, DE; Palmer, CNA; Pasterkamp, G; Faul, JD; Kleinbrink, EL; Pedersen, O; Peyser, PA; Jørgensen, ME; Polasek, O; Varga, TV; Porteous, D; Province, MA; Auvinen, J; Hivert, M-F; Psaty, BM; Rauramaa, R; Ridker, PM; Rolandsson, O; Afaq, S; Ahluwalia, TS; Franks, PW; Rorsman, P; Rosendaal, F; Rudan, I; Bielak, LF; Salomaa, V; Christensen, C; Asimit, JL; Schulze, MB; Alhejily, WA; Sladek, R; Smith, BH; Spector, TD; An, P; Starr, JM; Franks, S; Bihlmeyer, NA; Stumvoll, M; van Duijn, CM; Danesh, J; Deary, IJ; Walker, M; Bork-Jensen, J; Cheng, C-Y; Goodarzi, MO; Brody, JA; Campbell, A; Blüher, M; Dedoussis, G; Chu, AY; Davies, G; Chen, Y; Demirkan, A; Floyd, JS; Giulianini, F; Guo, X; Gustafsson, S; Clark, A; Hastoy, B; Boeing, H; Beer, NL; Morris, AP; Wareham, NJ; Jackson, AU; Jakobsdottir, J; Järvelin, M-R; Jensen, RA; Kanoni, S; Keinanen-Kiukaanniemi, S; Li, J; Li, M; Boerwinkle, E; Collins, FS; Amin, N; Lohman, K; Dehghan, A; Lu, Y; Gudnason, V; Luan, JA; Manning, AK; Marten, J; Marzi, C; Meidtner, K; Bønnelykke, K; Jousilahti, P; Mook-Kanamori, DO; Muka, T; Coresh, J; Jansson, J-H; Pistis, G; Prins, B; Rice, KM; Hallmans, G; Robertson, N; Sanna, S; Raimondo, A; Ferrannini, E; Shi, Y; Smith, AV; Smith, JA; Southam, L; Jhun, MA; Cucca, F; Stringham, HM; Tajuddin, SM; Tragante, V; Kajantie, E; van der Laan, SW; Bottinger, EP; Harris, TB; Warren, HR; Yao, J; Yiorkas, AM; Zhang, W; Beck Jørgensen, T; Zhao, W; de Borst, GJ; Karaleftheri, M; Ahlqvist, E; Graff, M; Caulfield, MJ; Highland, HM; Kardia, SLR; Boehnke, M; Chen, Y-DI; Kinnunen, L; Koistinena, HA; Weir, DR; Gloyn, AL; Komulainen, P; Kovacs, P; Kuusisto, J; Laakso, M; Lange, LA; Tarasov, AI; Launer, LJ; Florez, J; Lee, J-J; Feng, S; Ebeling, T; Asselbergs, FW; Leong, A; Lindström, J; Fox, JEM; Männistö, S; Maruthur, NM; Moilanen, L; Mulas, A; Nalls, MA; Wilson, JG; McCarthy, MI; Thomsen, SK; Chambers, JC; Neville, M; Deloukas, P; Pankow, JS; Pattie, A; Petersen, ERB; Puolijoki, H; Rasheed, A; Wong, TY; Redmond, P; Renström, F; Meigs, JB; Franco, OH; Roden, M; Saleheen, D; van de Bunt, M; den Ruijter, HM; Saltevo, J; Savonen, K; Appel, EV; Sébert, SP; Skaaby, T; Small, KS; Stančáková, A; Grallert, H; Strawbridge, RJ; Stokholm, J; Strauch, K; Tai, E-S; Taylor, KD; Zeggini, E; Dupuis, J; Wang, S; Thuesen, BH; Tönjes, A; Tsafantakis, E; Groop, L; Tuomi, T; Mahajan, A; Tuomilehto, J; Group, USS; Zonderman, AB; Uusitupa, MI

Please use this identifier to cite or link to this item: http://bura.brunel.ac.uk/handle/2438/21693

Title:	Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation
Authors:	Ng, N Willems, SM Fernandez, J Fine, RS Wheeler, E Wessel, J Kitajima, H Marenne, G Rundle, JK Sim, X Yeghootkar, H Vääräsmäki, M Vaartjes, I Evans, MK Zoledziewska, M Chen, S Hansen, T Abecasis, G Balkau, B Scott, RA Fritsche, A Justice, AE Bisgaard, H Hattersley, AT Elliott, P de Haan, HG Hayward, C Hirschhorn, JN Bonnycastle, LL Gjesing, AP Ikram, MA Ingelsson, E Lo, KS de Mutsert, R Karpe, F Kaw, K-T Kiess, W Kooner, JS Körner, A Consortium, E-I Lakka, T Bots, ML Grarup, N Herzig, K-H Chasman, DI Blakemore, AI Langenberg, C Lind, L Lindgren, CM Linneberg, A Lipovich, L Liu, C-T Liu, J Liu, Y Marouli, E Brandslund, I Farmaki, A-E Rotter, JI Loos, RJF Barroso, I MacDonald, PE Li-Gao, R Mohlke, KL Morris, AD Munroe, PB Medina-Gomez, C Murray, A Padmanabhan, S Chen, J Arking, DE Palmer, CNA Pasterkamp, G Faul, JD Kleinbrink, EL Pedersen, O Peyser, PA Jørgensen, ME Polasek, O Varga, TV Porteous, D Province, MA Auvinen, J Hivert, M-F Psaty, BM Rauramaa, R Ridker, PM Rolandsson, O Afaq, S Ahluwalia, TS Franks, PW Rorsman, P Rosendaal, F Rudan, I Bielak, LF Salomaa, V Christensen, C Asimit, JL Schulze, MB Alhejily, WA Sladek, R Smith, BH Spector, TD An, P Starr, JM Franks, S Bihlmeyer, NA Stumvoll, M van Duijn, CM Danesh, J Deary, IJ Walker, M Bork-Jensen, J Cheng, C-Y Goodarzi, MO Brody, JA Campbell, A Blüher, M Dedoussis, G Chu, AY Davies, G Chen, Y Demirkan, A Floyd, JS Giulianini, F Guo, X Gustafsson, S Clark, A Hastoy, B Boeing, H Beer, NL Morris, AP Wareham, NJ Jackson, AU Jakobsdottir, J Järvelin, M-R Jensen, RA Kanoni, S Keinanen-Kiukaanniemi, S Li, J Li, M Boerwinkle, E Collins, FS Amin, N Lohman, K Dehghan, A Lu, Y Gudnason, V Luan, JA Manning, AK Marten, J Marzi, C Meidtner, K Bønnelykke, K Jousilahti, P Mook-Kanamori, DO Muka, T Coresh, J Jansson, J-H Pistis, G Prins, B Rice, KM Hallmans, G Robertson, N Sanna, S Raimondo, A Ferrannini, E Shi, Y Smith, AV Smith, JA Southam, L Jhun, MA Cucca, F Stringham, HM Tajuddin, SM Tragante, V Kajantie, E van der Laan, SW Bottinger, EP Harris, TB Warren, HR Yao, J Yiorkas, AM Zhang, W Beck Jørgensen, T Zhao, W de Borst, GJ Karaleftheri, M Ahlqvist, E Graff, M Caulfield, MJ Highland, HM Kardia, SLR Boehnke, M Chen, Y-DI Kinnunen, L Koistinena, HA Weir, DR Gloyn, AL Komulainen, P Kovacs, P Kuusisto, J Laakso, M Lange, LA Tarasov, AI Launer, LJ Florez, J Lee, J-J Feng, S Ebeling, T Asselbergs, FW Leong, A Lindström, J Fox, JEM Männistö, S Maruthur, NM Moilanen, L Mulas, A Nalls, MA Wilson, JG McCarthy, MI Thomsen, SK Chambers, JC Neville, M Deloukas, P Pankow, JS Pattie, A Petersen, ERB Puolijoki, H Rasheed, A Wong, TY Redmond, P Renström, F Meigs, JB Franco, OH Roden, M Saleheen, D van de Bunt, M den Ruijter, HM Saltevo, J Savonen, K Appel, EV Sébert, SP Skaaby, T Small, KS Stančáková, A Grallert, H Strawbridge, RJ Stokholm, J Strauch, K Tai, E-S Taylor, KD Zeggini, E Dupuis, J Wang, S Thuesen, BH Tönjes, A Tsafantakis, E Groop, L Tuomi, T Mahajan, A Tuomilehto, J Group, USS Zonderman, AB Uusitupa, MI
Keywords:	genetics;Genomics;glycemic traits;type 2 diabetes;tissue;pathways;effector transcript
Issue Date:	3-Oct-2019
Publisher:	Cell Press
Citation:	Cell, [submitted version under consideration at Cell Press and has not been peer-reviewed.]
Abstract:	Metabolic dysregulation in multiple tissues influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits we investigated associations of exome-array variants in up to 144,060 nondiabetic individuals of multiple ancestries. Single-variant analyses identified 21 novel coding variant associations (18 loci), whilst gene-based tests revealed novel signals at TF (HbA1c) and G6PC [(Fasting Glucose (FG), Fasting Insulin (FI)]. Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and islets for FG, implicated adipose tissue in FI and gut in 2hGlu, and a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that the liver-enriched G6PC and the islet-specific G6PC2 were driven by multiple rare variants, with G6PC2 including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.
Description:	bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
URI:	https://bura.brunel.ac.uk/handle/2438/21693 https://europepmc.org/article/ppr/ppr94720 https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3469835
ISSN:	0092-8674
Appears in Collections:	Dept of Life Sciences Research Papers

Files in This Item:

File	Description	Size	Format
Perprint.pdf		10.13 MB	Adobe PDF	View/Open

Show full item record