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1. Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target

Author

Ye, S M, Huang, Y D, Mullendorff, K, Dong, L M, Giedt, G, Meng, E C, Cohen, F E, Kuntz, I D, Weisgraber, Karl H, and Mahley, R W

Subjects
Alzheimer's disease, neurodegeneration
Abstract

Apolipoprotein (apo) E4 is a major risk factor for Alzheimer's disease, and many studies have suggested that apoE has isoform-specific effects on the deposition or clearance of amyloid beta (A beta) peptides. We examined the effects of apoE isoforms on the processing of amyloid precursor protein (APP) and on A beta production in rat neuroblastoma B103 cells stably transfected with human wild-type APP695 (B103-APP). Lipid-poor apoE4 increased A beta production in B103-APP cells to a greater extent than lipid-poor apoE3 (60% vs. 30%) due to more pronounced stimulation of APP recycling by apoE4 than apoE3. The difference in A beta production was abolished by preincubating the cells with the receptor-associated protein (25 nM), which blocks the low-density lipoprotein receptor-related protein (LRP) pathway, or by reducing LRP expression by small interference RNA. The differences were also attenuated by replacing Arg-61 with threonine in apoE4 or pretreating apoE4 with small molecules, both of which abolish apoE4 intramolecular domain interaction. Thus, apoE4 appears to modulate APP processing and A beta production through both the LRP pathway and domain interaction. These findings provide insights into why apoE4 is associated with increased risk for Alzheimer's disease and may represent a potential target for drug development.

Published
2005

18. Receptor Interactions of Human Apolipoprotein E

Author

Weisgraber, K. H., Rall, S. C., Jr., Innerarity, T. L., Mahley, R. W., Schettler, F. Gotthard, editor, Gotto, Antonio M., Jr., editor, Middelhoff, Gert, editor, Habenicht, Andreas J. R., editor, and Jurutka, Klara R., editor

Published
1983
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19. Apolipoprotein E and Cholesterol Metabolsim

Author

Mahley, R. W., Rall, S. C., Jr., Innerarity, T. L., Weisgraber, K. H., Schettler, F. Gotthard, editor, Gotto, Antonio M., Jr., editor, Middelhoff, Gert, editor, Habenicht, Andreas J. R., editor, and Jurutka, Klara R., editor

Published
1983
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22. The Lin28/let-7 axis regulates glucose metabolism

Author

Zhu H, Shyh Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, Urbach A, Thornton JE, Triboulet R, Gregory RI, DIAGRAM Consortium, MAGIC Investigators, Altshuler D, Daley G.Q. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Boehnke M, McCarthy MI, Soranzo N, Wheeler E, Glazer NL, Bouatia Naji N, Mägi R, Randall J, Johnson T, Elliott P, Rybin D, Henneman P, Dehghan A, Hottenga JJ, Song K, Goel A, Egan JM, Lajunen T, Doney A, Voight BF, Kanoni S, Cavalcanti Proença C, Kumari M, Timpson NJ, Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, Roccasecca RM, Pattou F, Sethupathy P, Ariyurek Y, Barter P, Beilby JP, Ben Shlomo Y, Bergmann S, Bochud M, Bonnefond A, Borch Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L, Day IN, de Geus EJ, Delplanque J, Fedson AC, Fischer Rosinsky A, Forouhi NG, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C, Heath SC, Hercberg S, Hicks AA, Hillman DR, Hingorani AD, Hui J, Hung J, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Mahley R, Mangino M, Manning AK, Martínez Larrad MT, McAteer JB, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Mukherjee S, Naitza S, Neville MJ, Oostra BA, Orrù M, Pakyz R, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rice K, Ripatti S, Rivadeneira F, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sigurðsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Tönjes A, Uitterlinden AG, van Dijk KW, Varma D, Visvikis Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Ward KL, Watkins H, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano Ríos M, Lind L, Palmer LJ, Franks PW, Ebrahim S, Marmot M, Wright AF, Stumvoll M, Hamsten A, Buchanan TA, Valle TT, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Ferrucci L, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Barroso I., PAOLISSO, Giuseppe, Zhu, H, Shyh Chang, N, Segrè, Av, Shinoda, G, Shah, Sp, Einhorn, W, Takeuchi, A, Engreitz, Jm, Hagan, Jp, Kharas, Mg, Urbach, A, Thornton, Je, Triboulet, R, Gregory, Ri, Diagram, Consortium, Magic, Investigator, Altshuler, D, Voight BF, Daley G. Q., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Voight, Bf, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sigurðsson, G, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, and Barroso, I.

Published
2011

23. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations

Author

Mallick, S, Li, H, Lipson, M, Mathieson, I, Gymrek, M, Racimo, F, Zhao, M, Chennagiri, N, Nordenfelt, S, Tandon, A, Skoglund, P, Lazaridis, I, Sankararaman, S, Fu, Q, Rohland, N, Renaud, G, Erlich, Y, Willems, T, Gallo, C, Spence, JP, Song, YS, Poletti, G, Balloux, F, van Driem, G, de Knijff, P, Romero, IG, Jha, AR, Behar, DM, Bravi, CM, Capelli, C, Hervig, T, Moreno-Estrada, A, Posukh, OL, Balanovska, E, Balanovsky, O, Karachanak-Yankova, S, Sahakyan, H, Toncheva, D, Yepiskoposyan, L, Tyler-Smith, C, Xue, Y, Abdullah, MS, Ruiz-Linares, A, Beall, CM, Di Rienzo, A, Jeong, C, Starikovskaya, EB, Metspalu, E, Parik, J, Villems, R, Henn, BM, Hodoglugil, U, Mahley, R, Sajantila, A, Stamatoyannopoulos, G, Wee, JTS, Khusainova, R, Khusnutdinova, E, Litvinov, S, Ayodo, G, Comas, D, Hammer, MF, Kivisild, T, Klitz, W, Winkler, CA, Labuda, D, Bamshad, M, Jorde, LB, Tishkoff, SA, Watkins, WS, Metspalu, M, Dryomov, S, Sukernik, R, Singh, L, Thangaraj, K, Paeaebo, S, Kelso, J, Patterson, N, Reich, D, Mallick, S, Li, H, Lipson, M, Mathieson, I, Gymrek, M, Racimo, F, Zhao, M, Chennagiri, N, Nordenfelt, S, Tandon, A, Skoglund, P, Lazaridis, I, Sankararaman, S, Fu, Q, Rohland, N, Renaud, G, Erlich, Y, Willems, T, Gallo, C, Spence, JP, Song, YS, Poletti, G, Balloux, F, van Driem, G, de Knijff, P, Romero, IG, Jha, AR, Behar, DM, Bravi, CM, Capelli, C, Hervig, T, Moreno-Estrada, A, Posukh, OL, Balanovska, E, Balanovsky, O, Karachanak-Yankova, S, Sahakyan, H, Toncheva, D, Yepiskoposyan, L, Tyler-Smith, C, Xue, Y, Abdullah, MS, Ruiz-Linares, A, Beall, CM, Di Rienzo, A, Jeong, C, Starikovskaya, EB, Metspalu, E, Parik, J, Villems, R, Henn, BM, Hodoglugil, U, Mahley, R, Sajantila, A, Stamatoyannopoulos, G, Wee, JTS, Khusainova, R, Khusnutdinova, E, Litvinov, S, Ayodo, G, Comas, D, Hammer, MF, Kivisild, T, Klitz, W, Winkler, CA, Labuda, D, Bamshad, M, Jorde, LB, Tishkoff, SA, Watkins, WS, Metspalu, M, Dryomov, S, Sukernik, R, Singh, L, Thangaraj, K, Paeaebo, S, Kelso, J, Patterson, N, and Reich, D

Abstract

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.

Published
2016

26. Erratum: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk (Nature Genetics (2010) 42 (105-116))

Author

Dupuis, J, Langenberg, C, Prokopenko, I, Saxena, R, Soranzo, N, Jackson, AU, Wheeler, E, Glazer, NL, Bouatia-Naji, N, Gloyn, AL, Lindgren, CM, Mägi, R, Morris, AP, Randall, J, Johnson, T, Elliott, P, Rybin, D, Thorleifsson, G, Steinthorsdottir, V, Henneman, P, Grallert, H, Dehghan, A, Hottenga, JJ, Franklin, CS, Navarro, P, Song, K, Goel, A, Perry, JRB, Egan, JM, Lajunen, T, Grarup, N, Sparsø, T, Doney, A, Voight, BF, Stringham, HM, Li, M, Kanoni, S, Shrader, P, Cavalcanti-Proença, C, Kumari, M, Qi, L, Timpson, NJ, Gieger, C, Zabena, C, Rocheleau, G, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, McCarroll, SA, Payne, F, Roccasecca, RM, Pattou, F, Sethupathy, P, Ardlie, K, Ariyurek, Y, Balkau, B, Barter, P, Beilby, JP, Ben-Shlomo, Y, Benediktsson, R, Bennett, AJ, Bergmann, S, Bochud, M, Boerwinkle, E, Bonnefond, A, Bonnycastle, LL, Borch-Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, SJ, Charpentier, G, Chen, Y-DI, Chines, P, Clarke, R, Coin, LJM, Cooper, MN, Cornelis, M, Crawford, G, Crisponi, L, Day, INM, De Geus, EJC, Delplanque, J, Dina, C, Erdos, MR, Fedson, AC, Fischer-Rosinsky, A, Forouhi, NG, Fox, CS, Frants, R, Franzosi, MG, Galan, P, Goodarzi, MO, Graessler, J, Groves, CJ, Grundy, S, Gwilliam, R, Gyllensten, U, Hadjadj, S, Hallmans, G, Hammond, N, Han, X, Hartikainen, A-L, Hassanali, N, Hayward, C, Heath, SC, Hercberg, S, Herder, C, Hicks, AA, Hillman, DR, Hingorani, AD, Hofman, A, Hui, J, Hung, J, Isomaa, B, Johnson, PRV, Jørgensen, T, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, YA, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, KO, Lathrop, GM, Lawlor, DA, Le Bacquer, O, Lecoeur, C, Li, Y, Lyssenko, V, Mahley, R, Mangino, M, Manning, AK, Martínez-Larrad, MT, McAteer, JB, McCulloch, LJ, McPherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, BD, Morken, MA, Mukherjee, S, Naitza, S, Narisu, N, Neville, MJ, Oostra, BA, Orr, M, Pakyz, R, Palmer, CNA, Paolisso, G, Pattaro, C, Pearson, D, Peden, JF, Pedersen, NL, Perola, M, Pfeiffer, AFH, Pichler, I, Polasek, O, Posthuma, D, Potter, SC, Pouta, A, Province, MA, Psaty, BM, Rathmann, W, Rayner, NW, Rice, K, Ripatti, S, Rivadeneira, F, Roden, M, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, AA, Scheet, P, Scott, LJ, Seedorf, U, Sharp, SJ, Shields, B, Sigursson, G, Sijbrands, EJG, Silveira, A, Simpson, L, Singleton, A, Smith, NL, Sovio, U, Swift, A, Syddall, H, Syvänen, A-C, Tanaka, T, Thorand, B, Tichet, J, Tönjes, A, Tuomi, T, Uitterlinden, AG, Van Dijk, KW, Van Hoek, M, Varma, D, Visvikis-Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, PJ, Walley, A, Walters, GB, Ward, KL, Watkins, H, Weedon, MN, Wild, SH, Willemsen, G, Witteman, JCM, Yarnell, JWG, Zeggini, E, Zelenika, D, Zethelius, B, Zhai, G, Zhao, JH, Zillikens, MC, Consortium, D, Consortium, G, Consortium, GB, Borecki, IB, Loos, RJF, Meneton, P, Magnusson, PKE, Nathan, DM, Williams, GH, Hattersley, AT, Silander, K, Salomaa, V, Smith, GD, Bornstein, SR, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, AR, Cooper, C, Dedoussis, GV, Serrano-Ríos, M, Morris, AD, Lind, L, Palmer, LJ, Hu, FB, Franks, PW, Ebrahim, S, Marmot, M, Kao, WHL, Pankow, JS, Sampson, MJ, Kuusisto, J, Laakso, M, Hansen, T, Pedersen, O, Pramstaller, PP, Wichmann, HE, Illig, T, Rudan, I, Wright, AF, Stumvoll, M, Campbell, H, Wilson, JF, Hamsten, A, Bergman, RN, Buchanan, TA, Collins, FS, Mohlke, KL, Tuomilehto, J, Valle, TT, Altshuler, D, Rotter, JI, Siscovick, DS, Penninx, BWJH, Boomsma, DI, Deloukas, P, Spector, TD, Frayling, TM, Ferrucci, L, Kong, A, Thorsteinsdottir, U, Stefansson, K, Van Duijn, CM, Aulchenko, YS, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, M-R, Waterworth, DM, Vollenweider, P, Peltonen, L, Mooser, V, Abecasis, GR, Wareham, NJ, Sladek, R, Froguel, P, Watanabe, RM, Meigs, JB, Groop, L, Boehnke, M, McCarthy, MI, Florez, JC, and Barroso, I

Published
2010

27. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk (vol 42, pg 105, 2010)

Author

Dupuis, J, Langenberg, C, Prokopenko, I, Saxena, R, Soranzo, N, Jackson, AU, Wheeler, E, Glazer, NL, Bouatia-Naji, N, Gloyn, AL, Lindgren, CM, Maegi, R, Morris, AP, Randall, J, Johnson, T, Elliott, P, Rybin, D, Thorleifsson, G, Steinthorsdottir, V, Henneman, P, Grallert, H, Dehghan, A, Hottenga, JJ, Franklin, CS, Navarro, P, Song, K, Goel, A, Perry, JRB, Egan, JM, Lajunen, T, Grarup, N, Sparso, T, Doney, A, Voight, BF, Stringham, HM, Li, M, Kanoni, S, Shrader, P, Cavalcanti-Proenca, C, Kumari, M, Qi, L, Timpson, NJ, Gieger, C, Zabena, C, Rocheleau, G, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, McCarroll, SA, Payne, F, Roccasecca, RM, Pattou, F, Sethupathy, P, Ardlie, K, Ariyurek, Y, Balkau, B, Barter, P, Beilby, JP, Ben-Shlomo, Y, Benediktsson, R, Bennett, AJ, Bergmann, S, Bochud, M, Boerwinkle, E, Bonnefond, A, Bonnycastle, LL, Borch-Johnsen, K, Boettcher, Y, Brunner, E, Bumpstead, SJ, Charpentier, G, Chen, Y-DI, Chines, P, Clarke, R, Coin, LJM, Cooper, MN, Cornelis, M, Crawford, G, Crisponi, L, Day, INM, de Geus, EJC, Delplanque, J, Dina, C, Erdos, MR, Fedson, AC, Fischer-Rosinsky, A, Forouhi, NG, Fox, CS, Frants, R, Franzosi, MG, Galan, P, Goodarzi, MO, Graessler, J, Groves, CJ, Grundy, S, Gwilliam, R, Gyllensten, U, Hadjadj, S, Hallmans, G, Hammond, N, Han, X, Hartikainen, A-L, Hassanali, N, Hayward, C, Heath, SC, Hercberg, S, Herder, C, Hicks, AA, Hillman, DR, Hingorani, AD, Hofman, A, Hui, J, Hung, J, Isomaa, B, Johnson, PRV, Jorgensen, T, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, YA, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, KO, Lathrop, GM, Lawlor, DA, Le Bacquer, O, Lecoeur, C, Li, Y, Lyssenko, V, Mahley, R, Mangino, M, Manning, AK, Martinez-Larrad, MT, McAteer, JB, McCulloch, LJ, McPherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, BD, Morken, MA, Mukherjee, S, Naitza, S, Narisu, N, Neville, MJ, Oostra, BA, Orru, M, Pakyz, R, Palmer, CNA, Paolisso, G, Pattaro, C, Pearson, D, Peden, JF, Pedersen, NL, Perola, M, Pfeiffer, AFH, Pichler, I, Polasek, O, Posthuma, D, Potter, SC, Pouta, A, Province, MA, Psaty, BM, Rathmann, W, Rayner, NW, Rice, K, Ripatti, S, Rivadeneira, F, Roden, M, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, AA, Scheet, P, Scott, LJ, Seedorf, U, Sharp, SJ, Shields, B, Sigurosson, G, Sijbrands, EJG, Silveira, A, Simpson, L, Singleton, A, Smith, NL, Sovio, U, Swift, A, Syddall, H, Syvaenen, A-C, Tanaka, T, Thorand, B, Tichet, J, Toenjes, A, Tuomi, T, Uitterlinden, AG, van Dijk, KW, van Hoek, M, Varma, D, Visvikis-Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, PJ, Walley, A, Walters, GB, Ward, KL, Watkins, H, Weedon, MN, Wild, SH, Willemsen, G, Witteman, JCM, Yarnell, JWG, Zeggini, E, Zelenika, D, Zethelius, B, Zhai, G, Zhao, JH, Zillikens, MC, Borecki, IB, Loos, RJF, Meneton, P, Magnusson, PKE, Nathan, DM, Williams, GH, Hattersley, AT, Silander, K, Salomaa, V, Smith, GD, Bornstein, SR, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, AR, Cooper, C, Dedoussis, GV, Serrano-Rios, M, Morris, AD, Lind, L, Palmer, LJ, Hu, FB, Franks, PW, Ebrahim, S, Marmot, M, Kao, WHL, Pankow, JS, Sampson, MJ, Kuusisto, J, Laakso, M, Hansen, T, Pedersen, O, Pramstaller, PP, Wichmann, HE, Illig, T, Rudan, I, Wright, AF, Stumvoll, M, Campbell, H, Wilson, JF, Hamsten, A, Bergman, RN, Buchanan, TA, Collins, FS, Mohlke, KL, Tuomilehto, J, Valle, TT, Altshuler, D, Rotter, JI, Siscovick, DS, Penninx, BWJH, Boomsma, DI, Deloukas, P, Spector, TD, Frayling, TM, Ferrucci, L, Kong, A, Thorsteinsdottir, U, Stefansson, K, van Duijn, CM, Aulchenko, YS, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, M-R, Waterworth, DM, Vollenweider, P, Peltonen, L, Mooser, V, Abecasis, GR, Wareham, NJ, Sladek, R, Froguel, P, Watanabe, RM, Meigs, JB, Groop, L, Boehnke, M, McCarthy, MI, Florez, JC, Consortium, DIAGRAM, Consortium, GIANT, Consortium, GB, Consortium, P, and Investigators, IBMAGIC

Published
2010

28. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels

Author

Richards, J.B., Waterworth, D., O'Rahilly, S., Hivert, M.-F., Loos, R.J.F., Perry, J.R.B., Tanaka, T., Timpson, N.J., Semple, R.K., Soranzo, N., Song, K., Rocha, N., Grundberg, E., Dupuis, J., Florez, J.C., Langenberg, C., Prokopenko, I., Saxena, R., Sladek, R., Aulchenko, Y., Evans, D., Waeber, G., Erdmann, J., Burnett, M.-S., Sattar, N., Devaney, J., Willenborg, C., Hingorani, A., Witteman, J.C.M., Vollenweider, P., Glaser, B., Hengstenberg, C., Ferrucci, L., Melzer, D., Stark, K., Deanfield, J., Winogradow, J., Grassl, M., Hall, A.S., Egan, J.M., Thompson, J.R., Ricketts, S.L., König, I.R., Reinhard, W., Grundy, S., Wichmann, H.-E., Barter, P., Mahley, R., Kesaniemi, Y.A., Rader, D.J., Reilly, M.P., Epstein, S.E., Stewart, A.F.R., Van Duijn, C.M., Schunkert, H., Burling, K., Deloukas, P., Pastinen, T., Samani, N.J., McPherson, R., Davey Smith, G., Frayling, T.M., Wareham, N.J., Meigs, J.B., Mooser, V., and Spector, T.D.

Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Published
2009

32. Prion clearance and plasma lipoproteins

Author

Safar, J. G., Wille, H., Geschwind, M. D., Deering, C., Latawiec, D., Serban, A., King, D. J., Legname, Giuseppe, Weisgraber, K. H., Mahley, R. W., Miller, B. L., Dearmond, S. J., and Prusiner, S. B.

Published
2006

33. A common biological basis of obesity and nicotine addiction

Author

Thorgeirsson, T.E. (Thorgeir), Gudbjartsson, D.F. (Daniel), Sulem, P. (Patrick), Besenbacher, S. (Søren), Styrkarsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Walters, G.B. (Bragi), Furberg, H. (Helena), Sullivan, P. (Patrick), Marchini, J. (Jonathan), McCarthy, M.I. (M.), Steinthorsdottir, V. (Valgerdur), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Surakka, I. (Ida), Vink, J.M. (Jacqueline), Amin, N. (Najaf), Geller, F. (Frank), Rafnar, T. (Thorunn), Esko, T. (Tõnu), Walter, S. (Stefan), Gieger, C. (Christian), Rawal, R. (Rajesh), Mangino, M. (Massimo), Prokopenko, I. (Inga), Mägi, R. (Reedik), Keskitalo, K. (Kaisu), Gudjonsdottir, I.H. (Iris), Gretarsdottir, S. (Solveig), Stefansson, H. (Hreinn), Aulchenko, Y.S. (Yurii), Nelis, M. (Mari), Aben, K.K.H. (Katja), Heijer, M. (Martin) den, Soranzo, N. (Nicole), Valdes, A.M. (Ana Maria), Steves, C.J. (Claire), Uitterlinden, A.G. (André), Hofman, A. (Albert), Tönjes, A. (Anke), Kovacs, P. (Peter), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Vogelzangs, N. (Nicole), Döring, A. (Angela), Dahmen, N. (N.), Nitz, B. (Barbara), Ripatti, S. (Samuli), Perola, M. (Markus), Kettunen, J. (Johannes), Hartikainen, A.L., Pouta, A. (Anneli), Laitinen, J. (Jaana), Isohanni, M.K. (Matti), Huei-Yi, S. (Shen), Allen, M. (Maxine), Krestyaninova, M. (Maria), Hall, A. (Anne), Thompson, J.R. (John), Oskarsson, H. (Hogni), Tyrfingsson, T. (Thorarinn), Kiemeney, L.A.L.M. (Bart), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Stumvoll, M. (Michael), Spector, T.D. (Timothy), Wichmann, H.E. (Heinz Erich), Metspalu, A. (Andres), Samani, N.J. (Nilesh), Penninx, B.W.J.H. (Brenda), Oostra, B.A. (Ben), Boomsma, D.I. (Dorret), Tiemeier, H.W. (Henning), Duijn, C.M. (Cornelia) van, Kaprio, J. (Jaakko), Gulcher, J.R. (Jeffrey), Kim, Y. (Yunjung), Dackor, J. (Jennifer), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Ardissino, D. (Diego), Bernardinelli, L. (Luisa), Mannucci, P.M. (Pier), Mauri, F. (Francesco), Merlini, P.A. (Piera), Absher, D. (Devin), Assimes, T.L. (Themistocles), Fortmann, S.P. (Stephen), Iribarren, C. (Carlos), Knowles, J.W. (Joshua), Quertermous, T. (Thomas), Ferrucci, L. (Luigi), Tanaka, T. (Toshiko), Bis, J.C. (Joshua), Haritunians, T. (Talin), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Thacker, E.L. (Evan), Almgren, P. (Peter), Groop, L. (Leif), Ladenvall, C. (Claes), Boehnke, M. (Michael), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Stringham, H.M. (Heather), Tuomilehto, J. (Jaakko), Benjamin, E.J. (Emelia), Hwang, S.J., Levy, D. (Daniel), Preis, S.R., Vasan, R.S. (Ramachandran Srini), Duan, J. (Jubao), Gejman, P.V. (Pablo), Levinson, D.F. (Douglas), Sanders, A.R. (Alan), Shi, J. (Jianxin), Lips, E.H. (Esther), McKay, J.D. (James), Agudo, A. (Antonio), Barzan, L. (Luigi), Bencko, V. (Vladimir), Benhamou, S. (Simone), Castellsagué, X. (Xavier), Canova, C. (Cristina), Conway, D.I. (David), Fabianova, E. (Eleonora), Foretova, L. (Lenka), Janout, V. (Vladimir), Healy, C.M. (Claire), Holcátová, I. (Ivana), Kjaerheim, K. (Kristina), Lagiou, P., Lissowska, J. (Jolanta), Lowry, R. (Ray), MacFarlane, T.V. (Tatiana), Mates, D. (Dana), Richiardi, L. (Lorenzo), Rudnai, P. (Peter), Szeszenia-Dabrowska, N. (Neonilia), Zaridze, D., Znaor, A. (Ariana), Lathrop, M. (Mark), Brennan, P. (Paul), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Guralnik, J.M. (Jack), Milaneschi, Y. (Yuri), Perry, J.R.B. (John), Altshuler, D. (David), Elosua, R. (Roberto), Kathiresan, S. (Sekar), Lucas, G. (Gavin), Melander, O. (Olle), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Voight, B.F. (Benjamin), Smith, A.V. (Davey), Geus, E.J.C. (Eco) de, Chanock, S.J. (Stephen), Gu, F. (Fangyi), Hankinson, S.E. (Susan), Hunter, D. (David), Chasman, D.I. (Daniel), Everett, B.M. (Brendan), Paré, G. (Guillaume), Ridker, P.M. (Paul), Li, M.D. (Ming), Maes, H.H. (Hermine), Audrain-Mcgovern, J. (Janet), Posthuma, D. (Danielle), Thornton, L.M. (Laura), Lerman, C. (Caryn), Rose, J.E. (Jed), Ioannidis, J.P.A. (John), Kraft, P. (Peter), Lin, D.Y. (Dan), Liu, J. (Jason), Muglia, P. (Pierandrea), Waterworth, D. (Dawn), Pillai, A.D. (Ajay), Middleton, L. (Lefkos), Berrettini, W. (Wade), Knouff, C.W. (Christopher), Yuan, X. (Xin), Waeber, G. (Gérard), Vollenweider, P. (Peter), Preisig, M. (Martin), Wareham, N.J. (Nick), Zhao, J.H. (Jing Hua), Loos, R.J.F. (Ruth), Barroso, I.E. (Inês), Khaw, K-T. (Kay-Tee), Grundy, S.M. (Scott), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), McPherson, R. (Ruth), Vincent, J. (John), Strauss, J.S. (John S), Kennedy, J. (James), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Day, R.N. (Richard), Matthews, K. (Keith), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lucae, S. (Susanne), Ising, M. (Marcus), Brueckl, T. (Tanja), Horstmann, S. (Sonja), Heinrich, J. (Joachim), Lamina, C. (Claudia), Polasek, O. (Ozren), Zgaga, L. (Lina), Huffman, J.E. (Jennifer), Campbell, S. (Susan), Kooner, J.S. (Jaspal), Chambers, J.C. (John), Burnett, M.S., Devaney, J. (Joseph), Pichard, A.D., Kent, K.M. (Kenneth), Satler, L.F., Lindsay, J.M. (Joseph), Waksman, R. (Ron), Epstein, S.E. (Stephen), Wilson, J.F. (James), Wild, S.H. (Sarah), Campbell, H. (Harry), Vitart, V. (Veronique), Reilly, M.P. (Muredach), Li, M. (Mingyao), Qu, L. (Liming), Wilensky, A. (Asaf), Matthai, W. (William), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Franke, A. (Andre), Wittig, M. (Michael), Schäfer, A. (Arne), Uda, M. (Manuela), Terracciano, A., Xiao, X. (Xiangjun), Busonero, F., Scheet, P. (Paul), Schlessinger, D., Clair, D.S., Rujescu, D. (Dan), Abecasis, G.R. (Gonçalo), Grabe, H.J. (Hans Jörgen), Teumer, A. (Alexander), Völzke, H. (Henry), Petersmann, A. (Astrid), John, U. (Ulrich), Rudan, I. (Igor), Hayward, C. (Caroline), Wright, A.F. (Alan), Kolcic, I. (Ivana), Wright, B.J. (Benjamin), Balmforth, A.J. (Anthony), Anderson, C. (Carl), Ahmed, T. (Tariq), Mathew, J. (Joseph), Parkes, M. (Miles), Satsangi, J. (Jack), Caulfield, M. (Mark), Munroe, P. (Patricia), Farrall, M. (Martin), Dominiczak, A. (Anna), Worthington, H. (Helen), Thomson, W. (Wendy), Eyre, D.S. (Dylan Samuel), Barton, A. (Anne), Mooser, V. (Vincent), Francks, C. (Clyde), Thorgeirsson, T.E. (Thorgeir), Gudbjartsson, D.F. (Daniel), Sulem, P. (Patrick), Besenbacher, S. (Søren), Styrkarsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Walters, G.B. (Bragi), Furberg, H. (Helena), Sullivan, P. (Patrick), Marchini, J. (Jonathan), McCarthy, M.I. (M.), Steinthorsdottir, V. (Valgerdur), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Surakka, I. (Ida), Vink, J.M. (Jacqueline), Amin, N. (Najaf), Geller, F. (Frank), Rafnar, T. (Thorunn), Esko, T. (Tõnu), Walter, S. (Stefan), Gieger, C. (Christian), Rawal, R. (Rajesh), Mangino, M. (Massimo), Prokopenko, I. (Inga), Mägi, R. (Reedik), Keskitalo, K. (Kaisu), Gudjonsdottir, I.H. (Iris), Gretarsdottir, S. (Solveig), Stefansson, H. (Hreinn), Aulchenko, Y.S. (Yurii), Nelis, M. (Mari), Aben, K.K.H. (Katja), Heijer, M. (Martin) den, Soranzo, N. (Nicole), Valdes, A.M. (Ana Maria), Steves, C.J. (Claire), Uitterlinden, A.G. (André), Hofman, A. (Albert), Tönjes, A. (Anke), Kovacs, P. (Peter), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Vogelzangs, N. (Nicole), Döring, A. (Angela), Dahmen, N. (N.), Nitz, B. (Barbara), Ripatti, S. (Samuli), Perola, M. (Markus), Kettunen, J. (Johannes), Hartikainen, A.L., Pouta, A. (Anneli), Laitinen, J. (Jaana), Isohanni, M.K. (Matti), Huei-Yi, S. (Shen), Allen, M. (Maxine), Krestyaninova, M. (Maria), Hall, A. (Anne), Thompson, J.R. (John), Oskarsson, H. (Hogni), Tyrfingsson, T. (Thorarinn), Kiemeney, L.A.L.M. (Bart), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Stumvoll, M. (Michael), Spector, T.D. (Timothy), Wichmann, H.E. (Heinz Erich), Metspalu, A. (Andres), Samani, N.J. (Nilesh), Penninx, B.W.J.H. (Brenda), Oostra, B.A. (Ben), Boomsma, D.I. (Dorret), Tiemeier, H.W. (Henning), Duijn, C.M. (Cornelia) van, Kaprio, J. (Jaakko), Gulcher, J.R. (Jeffrey), Kim, Y. (Yunjung), Dackor, J. (Jennifer), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Ardissino, D. (Diego), Bernardinelli, L. (Luisa), Mannucci, P.M. (Pier), Mauri, F. (Francesco), Merlini, P.A. (Piera), Absher, D. (Devin), Assimes, T.L. (Themistocles), Fortmann, S.P. (Stephen), Iribarren, C. (Carlos), Knowles, J.W. (Joshua), Quertermous, T. (Thomas), Ferrucci, L. (Luigi), Tanaka, T. (Toshiko), Bis, J.C. (Joshua), Haritunians, T. (Talin), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Thacker, E.L. (Evan), Almgren, P. (Peter), Groop, L. (Leif), Ladenvall, C. (Claes), Boehnke, M. (Michael), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Stringham, H.M. (Heather), Tuomilehto, J. (Jaakko), Benjamin, E.J. (Emelia), Hwang, S.J., Levy, D. (Daniel), Preis, S.R., Vasan, R.S. (Ramachandran Srini), Duan, J. (Jubao), Gejman, P.V. (Pablo), Levinson, D.F. (Douglas), Sanders, A.R. (Alan), Shi, J. (Jianxin), Lips, E.H. (Esther), McKay, J.D. (James), Agudo, A. (Antonio), Barzan, L. (Luigi), Bencko, V. (Vladimir), Benhamou, S. (Simone), Castellsagué, X. (Xavier), Canova, C. (Cristina), Conway, D.I. (David), Fabianova, E. (Eleonora), Foretova, L. (Lenka), Janout, V. (Vladimir), Healy, C.M. (Claire), Holcátová, I. (Ivana), Kjaerheim, K. (Kristina), Lagiou, P., Lissowska, J. (Jolanta), Lowry, R. (Ray), MacFarlane, T.V. (Tatiana), Mates, D. (Dana), Richiardi, L. (Lorenzo), Rudnai, P. (Peter), Szeszenia-Dabrowska, N. (Neonilia), Zaridze, D., Znaor, A. (Ariana), Lathrop, M. (Mark), Brennan, P. (Paul), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Guralnik, J.M. (Jack), Milaneschi, Y. (Yuri), Perry, J.R.B. (John), Altshuler, D. (David), Elosua, R. (Roberto), Kathiresan, S. (Sekar), Lucas, G. (Gavin), Melander, O. (Olle), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Voight, B.F. (Benjamin), Smith, A.V. (Davey), Geus, E.J.C. (Eco) de, Chanock, S.J. (Stephen), Gu, F. (Fangyi), Hankinson, S.E. (Susan), Hunter, D. (David), Chasman, D.I. (Daniel), Everett, B.M. (Brendan), Paré, G. (Guillaume), Ridker, P.M. (Paul), Li, M.D. (Ming), Maes, H.H. (Hermine), Audrain-Mcgovern, J. (Janet), Posthuma, D. (Danielle), Thornton, L.M. (Laura), Lerman, C. (Caryn), Rose, J.E. (Jed), Ioannidis, J.P.A. (John), Kraft, P. (Peter), Lin, D.Y. (Dan), Liu, J. (Jason), Muglia, P. (Pierandrea), Waterworth, D. (Dawn), Pillai, A.D. (Ajay), Middleton, L. (Lefkos), Berrettini, W. (Wade), Knouff, C.W. (Christopher), Yuan, X. (Xin), Waeber, G. (Gérard), Vollenweider, P. (Peter), Preisig, M. (Martin), Wareham, N.J. (Nick), Zhao, J.H. (Jing Hua), Loos, R.J.F. (Ruth), Barroso, I.E. (Inês), Khaw, K-T. (Kay-Tee), Grundy, S.M. (Scott), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), McPherson, R. (Ruth), Vincent, J. (John), Strauss, J.S. (John S), Kennedy, J. (James), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Day, R.N. (Richard), Matthews, K. (Keith), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lucae, S. (Susanne), Ising, M. (Marcus), Brueckl, T. (Tanja), Horstmann, S. (Sonja), Heinrich, J. (Joachim), Lamina, C. (Claudia), Polasek, O. (Ozren), Zgaga, L. (Lina), Huffman, J.E. (Jennifer), Campbell, S. (Susan), Kooner, J.S. (Jaspal), Chambers, J.C. (John), Burnett, M.S., Devaney, J. (Joseph), Pichard, A.D., Kent, K.M. (Kenneth), Satler, L.F., Lindsay, J.M. (Joseph), Waksman, R. (Ron), Epstein, S.E. (Stephen), Wilson, J.F. (James), Wild, S.H. (Sarah), Campbell, H. (Harry), Vitart, V. (Veronique), Reilly, M.P. (Muredach), Li, M. (Mingyao), Qu, L. (Liming), Wilensky, A. (Asaf), Matthai, W. (William), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Franke, A. (Andre), Wittig, M. (Michael), Schäfer, A. (Arne), Uda, M. (Manuela), Terracciano, A., Xiao, X. (Xiangjun), Busonero, F., Scheet, P. (Paul), Schlessinger, D., Clair, D.S., Rujescu, D. (Dan), Abecasis, G.R. (Gonçalo), Grabe, H.J. (Hans Jörgen), Teumer, A. (Alexander), Völzke, H. (Henry), Petersmann, A. (Astrid), John, U. (Ulrich), Rudan, I. (Igor), Hayward, C. (Caroline), Wright, A.F. (Alan), Kolcic, I. (Ivana), Wright, B.J. (Benjamin), Balmforth, A.J. (Anthony), Anderson, C. (Carl), Ahmed, T. (Tariq), Mathew, J. (Joseph), Parkes, M. (Miles), Satsangi, J. (Jack), Caulfield, M. (Mark), Munroe, P. (Patricia), Farrall, M. (Martin), Dominiczak, A. (Anna), Worthington, H. (Helen), Thomson, W. (Wendy), Eyre, D.S. (Dylan Samuel), Barton, A. (Anne), Mooser, V. (Vincent), and Francks, C. (Clyde)

Abstract

Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10-7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10-5) and CPD (P=9.3 × 10-5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

Published
2013
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34. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., Kathiresan, S., DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., and Kathiresan, S.

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Published
2012

35. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

Author

GIANT Consortium, MAGIC Consortium, GLGC Consortium, Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, AU., Wheeler, E., Glazer, NL., Bouatia-Naji, N., Gloyn, AL., Lindgren, CM., Mägi, R., Morris, AP., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., Henneman, P., Grallert, H., Dehghan, A., Hottenga, JJ., Franklin, CS., Navarro, P., Song, K., Goel, A., Perry, JR., Egan, JM., Lajunen, T., Grarup, N., Sparsø, T., Doney, A., Voight, BF., Stringham, HM., Li, M., Kanoni, S., Shrader, P., Cavalcanti-Proença, C., Kumari, M., Qi, L., Timpson, NJ., Gieger, C., Zabena, C., Rocheleau, G., Ingelsson, E., An, P., O'Connell, J., Luan£££Jian'an£££ J., Elliott, A., McCarroll, SA., Payne, F., Roccasecca, RM., Pattou, F., Sethupathy, P., Ardlie, K., Ariyurek, Y., Balkau, B., Barter, P., Beilby, JP., Ben-Shlomo, Y., Benediktsson, R., Bennett, AJ., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, LL., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, SJ., Charpentier, G., Chen, YD., Chines, P., Clarke, R., Coin, LJ., Cooper, MN., Cornelis, M., Crawford, G., Crisponi, L., Day, IN., de Geus EJ., Delplanque, J., Dina, C., Erdos, MR., Fedson, AC., Fischer-Rosinsky, A., Forouhi, NG., Fox, CS., Frants, R., Franzosi, MG., Galan, P., Goodarzi, MO., Graessler, J., Groves, CJ., Grundy, S., Gwilliam, R., Gyllensten, U., Hadjadj, S., Hallmans, G., Hammond, N., Han, X., Hartikainen, AL., Hassanali, N., Hayward, C., Heath, SC., Hercberg, S., Herder, C., Hicks, AA., Hillman, DR., Hingorani, AD., Hofman, A., Hui, J., Hung, J., Isomaa, B., Johnson, PR., Jørgensen, T., Jula, A., Kaakinen, M., Kaprio, J., Kesaniemi, YA., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, KO., Lathrop, GM., Lawlor, DA., Le Bacquer, O., Lecoeur, C., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, AK., Martínez-Larrad£££María Teresa£££ MT., McAteer, JB., McCulloch, LJ., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, BD., Morken, MA., Mukherjee, S., Naitza, S., Narisu, N., Neville, MJ., Oostra, BA., Orrù, M., Pakyz, R., Palmer, CN., Paolisso, G., Pattaro, C., Pearson, D., Peden, JF., Pedersen, NL., Perola, M., Pfeiffer, AF., Pichler, I., Polasek, O., Posthuma, D., Potter, SC., Pouta, A., Province, MA., Psaty, BM., Rathmann, W., Rayner, NW., Rice, K., Ripatti, S., Rivadeneira, F., Roden, M., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, AA., Scheet, P., Scott, LJ., Seedorf, U., Sharp, SJ., Shields, B., Sigurðsson, G., Sijbrands, EJ., Silveira, A., Simpson, L., Singleton, A., Smith, NL., Sovio, U., Swift, A., Syddall, H., Syvänen, AC., Tanaka, T., Thorand, B., Tichet, J., Tönjes, A., Tuomi, T., Uitterlinden, AG., van Dijk KW., van Hoek, M., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, PJ., Walley, A., Walters, GB., Ward, KL., Watkins, H., Weedon, MN., Wild, SH., Willemsen, G., Witteman, JC., Yarnell, JW., Zeggini, E., Zelenika, D., Zethelius, B., Zhai, G., Zhao, JH., Zillikens, MC., Borecki, IB., Loos, RJ., Meneton, P., Magnusson, PK., Nathan, DM., Williams, GH., Hattersley, AT., Silander, K., Salomaa, V., Smith, GD., Bornstein, SR., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, AR., Cooper, C., Dedoussis, GV., Serrano-Ríos, M., Morris, AD., Lind, L., Palmer, LJ., Hu, FB., Franks, PW., Ebrahim, S., Marmot, M., Kao, WH., Pankow, JS., Sampson, MJ., Kuusisto, J., Laakso, M., Hansen, T., Pedersen, O., Pramstaller, PP., Wichmann, HE., Illig, T., Rudan, I., Wright, AF., Stumvoll, M., Campbell, H., Wilson, JF., Hamsten, A., Bergman, RN., Buchanan, TA., Collins, FS., Mohlke, KL., Tuomilehto, J., Valle, TT., Altshuler, D., Rotter, JI., Siscovick, DS., Penninx, BW., Boomsma, ID., Deloukas, P., Spector, TD., Frayling, TM., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn CM., Aulchenko, YS., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, MR., Waterworth, DM., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, RG., Wareham, NJ., Sladek, R., Froguel, P., Watanabe, RM., Meigs, JB., Groop, L., Boehnke, M., McCarthy, MI., Florez, JC., Barroso£££Inês£££ I., Fox, C.S., Liu, Y., White, C.C., Feitosa, M., Smith, A.V., Heard-Costa, N., Lohman, K., Johnson, A.D., Foster, M.C., Greenawalt, D.M., Griffin, P., Ding, J., Newman, A.B., Tylavsky, F., Miljkovic, I., Kritchevsky, S.B., Launer, L., Garcia, M., Eiriksdottir, G., Carr, J.J., Gudnason, V., Harris, T.B., Cupples, L.A., Borecki, I.B., GIANT Consortium, MAGIC Consortium, GLGC Consortium, Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, AU., Wheeler, E., Glazer, NL., Bouatia-Naji, N., Gloyn, AL., Lindgren, CM., Mägi, R., Morris, AP., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., Henneman, P., Grallert, H., Dehghan, A., Hottenga, JJ., Franklin, CS., Navarro, P., Song, K., Goel, A., Perry, JR., Egan, JM., Lajunen, T., Grarup, N., Sparsø, T., Doney, A., Voight, BF., Stringham, HM., Li, M., Kanoni, S., Shrader, P., Cavalcanti-Proença, C., Kumari, M., Qi, L., Timpson, NJ., Gieger, C., Zabena, C., Rocheleau, G., Ingelsson, E., An, P., O'Connell, J., Luan£££Jian'an£££ J., Elliott, A., McCarroll, SA., Payne, F., Roccasecca, RM., Pattou, F., Sethupathy, P., Ardlie, K., Ariyurek, Y., Balkau, B., Barter, P., Beilby, JP., Ben-Shlomo, Y., Benediktsson, R., Bennett, AJ., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, LL., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, SJ., Charpentier, G., Chen, YD., Chines, P., Clarke, R., Coin, LJ., Cooper, MN., Cornelis, M., Crawford, G., Crisponi, L., Day, IN., de Geus EJ., Delplanque, J., Dina, C., Erdos, MR., Fedson, AC., Fischer-Rosinsky, A., Forouhi, NG., Fox, CS., Frants, R., Franzosi, MG., Galan, P., Goodarzi, MO., Graessler, J., Groves, CJ., Grundy, S., Gwilliam, R., Gyllensten, U., Hadjadj, S., Hallmans, G., Hammond, N., Han, X., Hartikainen, AL., Hassanali, N., Hayward, C., Heath, SC., Hercberg, S., Herder, C., Hicks, AA., Hillman, DR., Hingorani, AD., Hofman, A., Hui, J., Hung, J., Isomaa, B., Johnson, PR., Jørgensen, T., Jula, A., Kaakinen, M., Kaprio, J., Kesaniemi, YA., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, KO., Lathrop, GM., Lawlor, DA., Le Bacquer, O., Lecoeur, C., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, AK., Martínez-Larrad£££María Teresa£££ MT., McAteer, JB., McCulloch, LJ., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, BD., Morken, MA., Mukherjee, S., Naitza, S., Narisu, N., Neville, MJ., Oostra, BA., Orrù, M., Pakyz, R., Palmer, CN., Paolisso, G., Pattaro, C., Pearson, D., Peden, JF., Pedersen, NL., Perola, M., Pfeiffer, AF., Pichler, I., Polasek, O., Posthuma, D., Potter, SC., Pouta, A., Province, MA., Psaty, BM., Rathmann, W., Rayner, NW., Rice, K., Ripatti, S., Rivadeneira, F., Roden, M., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, AA., Scheet, P., Scott, LJ., Seedorf, U., Sharp, SJ., Shields, B., Sigurðsson, G., Sijbrands, EJ., Silveira, A., Simpson, L., Singleton, A., Smith, NL., Sovio, U., Swift, A., Syddall, H., Syvänen, AC., Tanaka, T., Thorand, B., Tichet, J., Tönjes, A., Tuomi, T., Uitterlinden, AG., van Dijk KW., van Hoek, M., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, PJ., Walley, A., Walters, GB., Ward, KL., Watkins, H., Weedon, MN., Wild, SH., Willemsen, G., Witteman, JC., Yarnell, JW., Zeggini, E., Zelenika, D., Zethelius, B., Zhai, G., Zhao, JH., Zillikens, MC., Borecki, IB., Loos, RJ., Meneton, P., Magnusson, PK., Nathan, DM., Williams, GH., Hattersley, AT., Silander, K., Salomaa, V., Smith, GD., Bornstein, SR., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, AR., Cooper, C., Dedoussis, GV., Serrano-Ríos, M., Morris, AD., Lind, L., Palmer, LJ., Hu, FB., Franks, PW., Ebrahim, S., Marmot, M., Kao, WH., Pankow, JS., Sampson, MJ., Kuusisto, J., Laakso, M., Hansen, T., Pedersen, O., Pramstaller, PP., Wichmann, HE., Illig, T., Rudan, I., Wright, AF., Stumvoll, M., Campbell, H., Wilson, JF., Hamsten, A., Bergman, RN., Buchanan, TA., Collins, FS., Mohlke, KL., Tuomilehto, J., Valle, TT., Altshuler, D., Rotter, JI., Siscovick, DS., Penninx, BW., Boomsma, ID., Deloukas, P., Spector, TD., Frayling, TM., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn CM., Aulchenko, YS., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, MR., Waterworth, DM., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, RG., Wareham, NJ., Sladek, R., Froguel, P., Watanabe, RM., Meigs, JB., Groop, L., Boehnke, M., McCarthy, MI., Florez, JC., Barroso£££Inês£££ I., Fox, C.S., Liu, Y., White, C.C., Feitosa, M., Smith, A.V., Heard-Costa, N., Lohman, K., Johnson, A.D., Foster, M.C., Greenawalt, D.M., Griffin, P., Ding, J., Newman, A.B., Tylavsky, F., Miljkovic, I., Kritchevsky, S.B., Launer, L., Garcia, M., Eiriksdottir, G., Carr, J.J., Gudnason, V., Harris, T.B., Cupples, L.A., and Borecki, I.B.

Abstract

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in

Published
2012

36. Genetic variants influencing circulating lipid levels and risk of coronary artery disease

Author

Waterworth, D. (Dawn), Ricketts, S.L. (Sally), Song, K. (Kijoung), Chen, L. (Leslie), Zhao, J.H. (Jing Hua), Ripatti, S. (Samuli), Aulchenko, Y.S. (Yurii), Zhang, W. (Weihua), Yuan, X. (Xin), Lim, N. (Noha), Luan, J., Ashford, S. (Sofie), Wheeler, E. (Eleanor), Young, E.H. (Elizabeth), Hadley, D. (David), Thompson, J.R. (John), Braund, P.S. (Peter), Johnson, T. (Toby), Struchalin, M.V. (Maksim), Surakka, I. (Ida), Luben, R.N. (Robert), Khaw, K-T. (Kay-Tee), Rodwell, S.A. (Sheila), Loos, R.J.F. (Ruth), Boekholdt, S.M. (Matthijs), Inouye, M. (Michael), Deloukas, P. (Panagiotis), Elliott, P. (Paul), Schlessinger, D., Sanna, S. (Serena), Scuteri, A. (Angelo), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Roberts, R. (Robert), Stewart, A. (Alison), Kesaniemi, Y.A. (Antero), Mahley, R. (Robert), Grundy, S.M. (Scott), McArdle, W.L. (Wendy), Cardon, L. (Lon), Waeber, G. (Gérard), Vollenweider, P. (Peter), Chambers, J.C. (John), Boehnke, M. (Michael), Abecasis, G.R. (Gonçalo), Salomaa, V. (Veikko), Järvelin, M.R., Ruokonen, A. (Aimo), Barroso, I.E. (Inês), Epstein, S.E. (Stephen), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), Witteman, J.C.M. (Jacqueline), Hall, A.S. (Alistair), Samani, N.J. (Nilesh), Strachan, D.P. (David), Barter, P. (Phil), Tikka-Kleemola, P. (Päivi), Kooner, J.S. (Jaspal), Peltonen, L. (Leena Johanna), Wareham, N.J. (Nick), McPherson, R. (Ruth), Mooser, V. (Vincent), Sandhu, M.S. (Manjinder), Waterworth, D. (Dawn), Ricketts, S.L. (Sally), Song, K. (Kijoung), Chen, L. (Leslie), Zhao, J.H. (Jing Hua), Ripatti, S. (Samuli), Aulchenko, Y.S. (Yurii), Zhang, W. (Weihua), Yuan, X. (Xin), Lim, N. (Noha), Luan, J., Ashford, S. (Sofie), Wheeler, E. (Eleanor), Young, E.H. (Elizabeth), Hadley, D. (David), Thompson, J.R. (John), Braund, P.S. (Peter), Johnson, T. (Toby), Struchalin, M.V. (Maksim), Surakka, I. (Ida), Luben, R.N. (Robert), Khaw, K-T. (Kay-Tee), Rodwell, S.A. (Sheila), Loos, R.J.F. (Ruth), Boekholdt, S.M. (Matthijs), Inouye, M. (Michael), Deloukas, P. (Panagiotis), Elliott, P. (Paul), Schlessinger, D., Sanna, S. (Serena), Scuteri, A. (Angelo), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Roberts, R. (Robert), Stewart, A. (Alison), Kesaniemi, Y.A. (Antero), Mahley, R. (Robert), Grundy, S.M. (Scott), McArdle, W.L. (Wendy), Cardon, L. (Lon), Waeber, G. (Gérard), Vollenweider, P. (Peter), Chambers, J.C. (John), Boehnke, M. (Michael), Abecasis, G.R. (Gonçalo), Salomaa, V. (Veikko), Järvelin, M.R., Ruokonen, A. (Aimo), Barroso, I.E. (Inês), Epstein, S.E. (Stephen), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), Witteman, J.C.M. (Jacqueline), Hall, A.S. (Alistair), Samani, N.J. (Nilesh), Strachan, D.P. (David), Barter, P. (Phil), Tikka-Kleemola, P. (Päivi), Kooner, J.S. (Jaspal), Peltonen, L. (Leena Johanna), Wareham, N.J. (Nick), McPherson, R. (Ruth), Mooser, V. (Vincent), and Sandhu, M.S. (Manjinder)

Abstract

OBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS

Published
2010
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37. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Dupuis, J. (Josée), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Soranzo, N. (Nicole), Jackson, A.U. (Anne), Wheeler, E. (Eleanor), Glazer, N.L. (Nicole), Bouatia-Naji, N. (Nabila), Gloyn, A.L. (Anna), Lindgren, C.M. (Cecilia), Mägi, R. (Reedik), Morris, A.P. (Andrew), Randall, J.C. (Joshua), Johnson, T. (Toby), Elliott, P. (Paul), Rybin, D. (Denis), Thorleifsson, G. (Gudmar), Steinthorsdottir, V. (Valgerdur), Henneman, P. (Peter), Grallert, H. (Harald), Dehghan, A. (Abbas), JanHottenga, J. (Jouke), Franklin, C.S. (Christopher), Navarro, P. (Pau), Song, K. (Kijoung), Goel, A. (Anuj), Perry, J.R.B. (John), Egan, J.M. (Josephine), Lajunen, T. (Taina), Grarup, N. (Niels), Sparsø, T. (Thomas), Doney, A.S.F. (Alex), Voight, B.F. (Benjamin), Stringham, H.M. (Heather), Li, M. (Man), Kanoni, S. (Stavroula), Shrader, P. (Peter), Cavalcanti-Proença, C. (Christine), Kumari, M. (Meena), Qi, L. (Lu), Timpson, N.J. (Nicholas), Gieger, C. (Christian), Zabena, C. (Carina), Rocheleau, G. (Ghislain), Ingelsson, E. (Erik), An, P. (Ping), O´Connell, J.R., Luan, J., McCarroll, S.A. (Steven), Payne, F. (Felicity), Roccasecca, R.M., Pattou, F. (François), Sethupathy, P. (Praveen), Ardlie, K.G. (Kristin), Ariyurek, Y. (Yavuz), Balkau, B. (Beverley), Barter, P. (Phil), Beilby, J.P. (John), Ben-Shlomo, Y., Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Bergmann, S.M. (Sven), Bochud, M. (Murielle), Boerwinkle, E.A. (Eric), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borch-Johnsen, K., Böttcher, Y. (Yvonne), Brunner, E. (Eric), Bumpstead, S. (Suzannah), Charpentier, G. (Guillaume), IdaChen, Y. (Yii) der, Chines, P.S. (Peter), Clarke, R., McOin, L.J. (Lachlan), Cooper, M.N. (Matthew), Cornelis, M. (Marilyn), Crawford, G. (Gabe), Crisponi, L. (Laura), Day, I.N.M. (Ian), Geus, E.J.C. (Eco) de, Delplanque, J. (Jerome), Dina, C. (Christian), Erdos, M.R. (Michael), Fedson, A.C. (Annette), Fischer-Rosinsky, A. (Antje), Forouhi, N.G. (Nita), Fox, C.S. (Caroline), Frants, R.R. (Rune), GraziaFranzosi, M. (Maria), Galan, P. (Pilar), Goodarzi, M. (Mark), Graessler, J. (Jürgen), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Gwilliam, R. (Rhian), Gyllensten, U. (Ulf), Hadjadj, S. (Samy), Hallmans, G. (Göran), Hammond, N. (Naomi), Han, X. (Xijing), Hartikainen, A.-L. (Anna-Liisa), Hassanali, N. (Neelam), Hayward, C. (Caroline), Heath, S.C. (Simon), Hercberg, S. (Serge), Herder, C. (Christian), Hicks, A.A. (Andrew), Hillman, D.R. (David), Hingorani, A. (Aroon), Hofman, A. (Albert), Hui, J. (Jennie), Hung, J. (Judy), Isomaa, B. (Bo), Jørgensen, T. (Torben), Jula, A. (Antti), Kaakinen, M. (Marika), Kaprio, J. (Jaakko), AnteroKesaniemi, Y., Kivimaki, M. (Mika), Knight, B. (Beatrice), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyvik, K.O. (Kirsten Ohm), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Bacquer, O.L. (Olivier), Lecoeur, C. (Cécile), Lyssenko, V. (Valeriya), Mahley, R. (Robert), Mangino, M. (Massimo), Manning, A.K. (Alisa), TeresaMartínez-Larrad, M. (María), McAteer, J.B. (Jarred), McCulloch, L.J. (Laura), McPherson, R. (Ruth), Meisinger, C. (Christa), Melzer, D. (David), Meyre, D. (David), Mitchell, B.D. (Braxton), Morken, M.A. (Mario), Mukherjee, S. (Sutapa), Naitza, S. (Silvia), Narisu, N. (Narisu), Neville, M.J. (Matthew), Oostra, B.A. (Ben), Orrù, M. (Marco), Pakyz, R. (Ruth), Palmer, C.N.A. (Colin), Paolisso, G. (Giuseppe), Pattaro, C. (Cristian), Pearson, D. (Daniel), Peden, J. (John), Pedersen, N.L. (Nancy), Perola, M. (Markus), Pfeiffer, A.F.H. (Andreas), Pichler, I. (Irene), Polasek, O. (Ozren), Posthuma, D. (Danielle), Potter, S.C. (Simon), Pouta, A. (Anneli), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Rice, K. (Kenneth), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Roden, M. (Michael), Rolandsson, O. (Olov), Sandbaek, A. (Annelli), Sandhu, M.S. (Manjinder), Sanna, S. (Serena), Sayer, A.A., Scheet, P. (Paul), Scott, L.J. (Laura), Seedorf, U. (Udo), Sharp, S.J. (Stephen), Shields, B.M. (Beverley), Sigursson, G. (Gunnar), Sijbrands, E.J.G. (Eric), Silveira, A. (Angela), Simpson, L. (Laila), Singleton, A. (Andrew), Smith, N.L. (Nicholas), Sovio, U. (Ulla), Swift, A.J. (Amy), Syddall, H. (Holly), Syvänen, A.-C. (Ann-Christine), Tanaka, T. (Toshiko), Thorand, B. (Barbara), Tichet, J. (Jean), Tönjes, A. (Anke), Tuomi, T. (Tiinamaija), Uitterlinden, A.G. (André), Willems van Dijk, J.A.P. (Ko), Hoek, M. (Mandy) van, Varma, D. (Dhiraj), Visvikis-Siest, S. (Sophie), Vitart, V. (Veronique), Vogelzangs, N. (Nicole), Waeber, G. (Gérard), Wagner, P.J. (Peter), Walley, A. (Andrew), BragiWalters, G., Ward, K.L. (Kim), Watkins, H. (Hugh), Weedon, M.N. (Michael), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), GYarnell, J.W. (John), Zeggini, E. (Eleftheria), Zelenika, D. (Diana), Zethelius, B. (Björn), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Borecki, I.B. (Ingrid), Loos, R.J.F. (Ruth), Meneton, P. (Pierre), Magnusson, P.K. (Patrik), Nathan, D.M. (David), Williams, G.H. (Gordon), Hattersley, A.T. (Andrew), Silander, K. (Kaisa), Salomaa, V. (Veikko), Bornstein, S.R. (Stefan), Schwarz, P. (Peter), Spranger, J. (Jürgen), Karpe, F. (Fredrik), Shuldiner, A.R. (Alan), Dedoussis, G.V. (George), Serrano-Ríos, M. (Manuel), Lind, L. (Lars), Palmer, C. (Cameron), Hu, F.B. (Frank), Franks, P.W. (Paul), Ebrahim, S. (Shanil), Marmot, M. (Michael), Kao, W.-H.L. (Linda), Pankow, J.S. (James), Sampson, M.J. (Michael), Kuusisto, J. (Johanna), Laakso, M. (Markku), Hansen, T. (Torben), Pramstaller, P.P. (Peter Paul), Wichmann, H.E. (Erich), Illig, T. (Thomas), Rudan, I. (Igor), Wright, A.F. (Alan), Stumvoll, M. (Michael), Campbell, H. (Harry), Wilson, J.F. (James), Bergman, R.N. (Richard), Buchanan, T.A. (Thomas), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Valle, T.T. (Timo), Altshuler, D. (David), Rotter, J.I. (Jerome), Siscovick, D.S. (David), Penninx, B.W.J.H. (Brenda), Boomsma, D.I. (Dorret), Deloukas, P. (Panagiotis), Spector, T.D. (Timothy), Frayling, T.M. (Timothy), Ferrucci, L. (Luigi), Kong, A. (Augustine), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Cao, A. (Antonio), Scuteri, A. (Angelo), Schlessinger, D. (David), Uda, M. (Manuela), Ruokonen, A. (Aimo), Jarvelin, M.-R. (Marjo-Riitta), Waterworth, D. (Dawn), Vollenweider, P. (Peter), Peltonen, L. (Leena Johanna), Mooser, V. (Vincent), Abecasis, G.R. (Gonçalo), Wareham, N.J. (Nick), Sladek, R. (Rob), Froguel, P. (Philippe), Meigs, J.B. (James), Groop, L. (Leif), Watanabe, R.M. (Richard), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Florez, J.C. (Jose), Barroso, I.E. (Inês), Dupuis, J. (Josée), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Soranzo, N. (Nicole), Jackson, A.U. (Anne), Wheeler, E. (Eleanor), Glazer, N.L. (Nicole), Bouatia-Naji, N. (Nabila), Gloyn, A.L. (Anna), Lindgren, C.M. (Cecilia), Mägi, R. (Reedik), Morris, A.P. (Andrew), Randall, J.C. (Joshua), Johnson, T. (Toby), Elliott, P. (Paul), Rybin, D. (Denis), Thorleifsson, G. (Gudmar), Steinthorsdottir, V. (Valgerdur), Henneman, P. (Peter), Grallert, H. (Harald), Dehghan, A. (Abbas), JanHottenga, J. (Jouke), Franklin, C.S. (Christopher), Navarro, P. (Pau), Song, K. (Kijoung), Goel, A. (Anuj), Perry, J.R.B. (John), Egan, J.M. (Josephine), Lajunen, T. (Taina), Grarup, N. (Niels), Sparsø, T. (Thomas), Doney, A.S.F. (Alex), Voight, B.F. (Benjamin), Stringham, H.M. (Heather), Li, M. (Man), Kanoni, S. (Stavroula), Shrader, P. (Peter), Cavalcanti-Proença, C. (Christine), Kumari, M. (Meena), Qi, L. (Lu), Timpson, N.J. (Nicholas), Gieger, C. (Christian), Zabena, C. (Carina), Rocheleau, G. (Ghislain), Ingelsson, E. (Erik), An, P. (Ping), O´Connell, J.R., Luan, J., McCarroll, S.A. (Steven), Payne, F. (Felicity), Roccasecca, R.M., Pattou, F. (François), Sethupathy, P. (Praveen), Ardlie, K.G. (Kristin), Ariyurek, Y. (Yavuz), Balkau, B. (Beverley), Barter, P. (Phil), Beilby, J.P. (John), Ben-Shlomo, Y., Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Bergmann, S.M. (Sven), Bochud, M. (Murielle), Boerwinkle, E.A. (Eric), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borch-Johnsen, K., Böttcher, Y. (Yvonne), Brunner, E. (Eric), Bumpstead, S. (Suzannah), Charpentier, G. (Guillaume), IdaChen, Y. (Yii) der, Chines, P.S. (Peter), Clarke, R., McOin, L.J. (Lachlan), Cooper, M.N. (Matthew), Cornelis, M. (Marilyn), Crawford, G. (Gabe), Crisponi, L. (Laura), Day, I.N.M. (Ian), Geus, E.J.C. (Eco) de, Delplanque, J. (Jerome), Dina, C. (Christian), Erdos, M.R. (Michael), Fedson, A.C. (Annette), Fischer-Rosinsky, A. (Antje), Forouhi, N.G. (Nita), Fox, C.S. (Caroline), Frants, R.R. (Rune), GraziaFranzosi, M. (Maria), Galan, P. (Pilar), Goodarzi, M. (Mark), Graessler, J. (Jürgen), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Gwilliam, R. (Rhian), Gyllensten, U. (Ulf), Hadjadj, S. (Samy), Hallmans, G. (Göran), Hammond, N. (Naomi), Han, X. (Xijing), Hartikainen, A.-L. (Anna-Liisa), Hassanali, N. (Neelam), Hayward, C. (Caroline), Heath, S.C. (Simon), Hercberg, S. (Serge), Herder, C. (Christian), Hicks, A.A. (Andrew), Hillman, D.R. (David), Hingorani, A. (Aroon), Hofman, A. (Albert), Hui, J. (Jennie), Hung, J. (Judy), Isomaa, B. (Bo), Jørgensen, T. (Torben), Jula, A. (Antti), Kaakinen, M. (Marika), Kaprio, J. (Jaakko), AnteroKesaniemi, Y., Kivimaki, M. (Mika), Knight, B. (Beatrice), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyvik, K.O. (Kirsten Ohm), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Bacquer, O.L. (Olivier), Lecoeur, C. (Cécile), Lyssenko, V. (Valeriya), Mahley, R. (Robert), Mangino, M. (Massimo), Manning, A.K. (Alisa), TeresaMartínez-Larrad, M. (María), McAteer, J.B. (Jarred), McCulloch, L.J. (Laura), McPherson, R. (Ruth), Meisinger, C. (Christa), Melzer, D. (David), Meyre, D. (David), Mitchell, B.D. (Braxton), Morken, M.A. (Mario), Mukherjee, S. (Sutapa), Naitza, S. (Silvia), Narisu, N. (Narisu), Neville, M.J. (Matthew), Oostra, B.A. (Ben), Orrù, M. (Marco), Pakyz, R. (Ruth), Palmer, C.N.A. (Colin), Paolisso, G. (Giuseppe), Pattaro, C. (Cristian), Pearson, D. (Daniel), Peden, J. (John), Pedersen, N.L. (Nancy), Perola, M. (Markus), Pfeiffer, A.F.H. (Andreas), Pichler, I. (Irene), Polasek, O. (Ozren), Posthuma, D. (Danielle), Potter, S.C. (Simon), Pouta, A. (Anneli), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Rice, K. (Kenneth), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Roden, M. (Michael), Rolandsson, O. (Olov), Sandbaek, A. (Annelli), Sandhu, M.S. (Manjinder), Sanna, S. (Serena), Sayer, A.A., Scheet, P. (Paul), Scott, L.J. (Laura), Seedorf, U. (Udo), Sharp, S.J. (Stephen), Shields, B.M. (Beverley), Sigursson, G. (Gunnar), Sijbrands, E.J.G. (Eric), Silveira, A. (Angela), Simpson, L. (Laila), Singleton, A. (Andrew), Smith, N.L. (Nicholas), Sovio, U. (Ulla), Swift, A.J. (Amy), Syddall, H. (Holly), Syvänen, A.-C. (Ann-Christine), Tanaka, T. (Toshiko), Thorand, B. (Barbara), Tichet, J. (Jean), Tönjes, A. (Anke), Tuomi, T. (Tiinamaija), Uitterlinden, A.G. (André), Willems van Dijk, J.A.P. (Ko), Hoek, M. (Mandy) van, Varma, D. (Dhiraj), Visvikis-Siest, S. (Sophie), Vitart, V. (Veronique), Vogelzangs, N. (Nicole), Waeber, G. (Gérard), Wagner, P.J. (Peter), Walley, A. (Andrew), BragiWalters, G., Ward, K.L. (Kim), Watkins, H. (Hugh), Weedon, M.N. (Michael), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), GYarnell, J.W. (John), Zeggini, E. (Eleftheria), Zelenika, D. (Diana), Zethelius, B. (Björn), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Borecki, I.B. (Ingrid), Loos, R.J.F. (Ruth), Meneton, P. (Pierre), Magnusson, P.K. (Patrik), Nathan, D.M. (David), Williams, G.H. (Gordon), Hattersley, A.T. (Andrew), Silander, K. (Kaisa), Salomaa, V. (Veikko), Bornstein, S.R. (Stefan), Schwarz, P. (Peter), Spranger, J. (Jürgen), Karpe, F. (Fredrik), Shuldiner, A.R. (Alan), Dedoussis, G.V. (George), Serrano-Ríos, M. (Manuel), Lind, L. (Lars), Palmer, C. (Cameron), Hu, F.B. (Frank), Franks, P.W. (Paul), Ebrahim, S. (Shanil), Marmot, M. (Michael), Kao, W.-H.L. (Linda), Pankow, J.S. (James), Sampson, M.J. (Michael), Kuusisto, J. (Johanna), Laakso, M. (Markku), Hansen, T. (Torben), Pramstaller, P.P. (Peter Paul), Wichmann, H.E. (Erich), Illig, T. (Thomas), Rudan, I. (Igor), Wright, A.F. (Alan), Stumvoll, M. (Michael), Campbell, H. (Harry), Wilson, J.F. (James), Bergman, R.N. (Richard), Buchanan, T.A. (Thomas), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Valle, T.T. (Timo), Altshuler, D. (David), Rotter, J.I. (Jerome), Siscovick, D.S. (David), Penninx, B.W.J.H. (Brenda), Boomsma, D.I. (Dorret), Deloukas, P. (Panagiotis), Spector, T.D. (Timothy), Frayling, T.M. (Timothy), Ferrucci, L. (Luigi), Kong, A. (Augustine), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Cao, A. (Antonio), Scuteri, A. (Angelo), Schlessinger, D. (David), Uda, M. (Manuela), Ruokonen, A. (Aimo), Jarvelin, M.-R. (Marjo-Riitta), Waterworth, D. (Dawn), Vollenweider, P. (Peter), Peltonen, L. (Leena Johanna), Mooser, V. (Vincent), Abecasis, G.R. (Gonçalo), Wareham, N.J. (Nick), Sladek, R. (Rob), Froguel, P. (Philippe), Meigs, J.B. (James), Groop, L. (Leif), Watanabe, R.M. (Richard), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Florez, J.C. (Jose), and Barroso, I.E. (Inês)

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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38. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels

Author

Richards, J.B. (Brent), Waterworth, D. (Dawn), O'Rahilly, S. (Stephen), Hivert, M.-F. (Marie-France), Loos, R.J.F. (Ruth), Perry, J.R.B. (John), Tanaka, T. (Toshiko), Timpson, N.J. (Nicholas), Semple, R.K. (Robert), Soranzo, N. (Nicole), Song, K. (Kijoung), Rocha, N. (Nuno), Grundberg, E. (Elin), Dupuis, J. (Josée), Florez, J.C. (Jose), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Sladek, R. (Rob), Aulchenko, Y.S. (Yurii), Evans, D.M. (David), Waeber, G. (Gérard), Burnett, M.S., Sattar, N. (Naveed), Devaney, J. (Joseph), Willenborg, C. (Christina), Hingorani, A. (Aroon), Witteman, J.C.M. (Jacqueline), Vollenweider, P. (Peter), Glaser, B. (Beate), Hengstenberg, C. (Christian), Ferrucci, L. (Luigi), Melzer, D. (David), Stark, K. (Klaus), Deanfield, J. (John), Winogradow, J. (Janina), Grassl, M. (Martina), Hall, A.S. (Alistair), Egan, J.M. (Josephine), Thompson, J.R. (John), Ricketts, S.L. (Sally), König, I.R. (Inke), Reinhard, W. (Wibke), Grundy, S.M. (Scott), Wichmann, H.E. (Heinz Erich), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), Epstein, S.E. (Stephen), Stewart, A.F.R. (Alexandre), Tikka-Kleemola, P. (Päivi), Schunkert, H. (Heribert), Burling, K.A. (Keith), Erdmann, J. (Jeanette), Deloukas, P. (Panagiotis), Pastinen, T. (Tomi), Samani, N.J. (Nilesh), McPherson, R. (Ruth), Smith, A.V. (Davey), Frayling, T.M. (Timothy), Wareham, N.J. (Nick), Meigs, J.B. (James), Mooser, V. (Vincent), Spector, T.D. (Timothy), Richards, J.B. (Brent), Waterworth, D. (Dawn), O'Rahilly, S. (Stephen), Hivert, M.-F. (Marie-France), Loos, R.J.F. (Ruth), Perry, J.R.B. (John), Tanaka, T. (Toshiko), Timpson, N.J. (Nicholas), Semple, R.K. (Robert), Soranzo, N. (Nicole), Song, K. (Kijoung), Rocha, N. (Nuno), Grundberg, E. (Elin), Dupuis, J. (Josée), Florez, J.C. (Jose), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Sladek, R. (Rob), Aulchenko, Y.S. (Yurii), Evans, D.M. (David), Waeber, G. (Gérard), Burnett, M.S., Sattar, N. (Naveed), Devaney, J. (Joseph), Willenborg, C. (Christina), Hingorani, A. (Aroon), Witteman, J.C.M. (Jacqueline), Vollenweider, P. (Peter), Glaser, B. (Beate), Hengstenberg, C. (Christian), Ferrucci, L. (Luigi), Melzer, D. (David), Stark, K. (Klaus), Deanfield, J. (John), Winogradow, J. (Janina), Grassl, M. (Martina), Hall, A.S. (Alistair), Egan, J.M. (Josephine), Thompson, J.R. (John), Ricketts, S.L. (Sally), König, I.R. (Inke), Reinhard, W. (Wibke), Grundy, S.M. (Scott), Wichmann, H.E. (Heinz Erich), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), Epstein, S.E. (Stephen), Stewart, A.F.R. (Alexandre), Tikka-Kleemola, P. (Päivi), Schunkert, H. (Heribert), Burling, K.A. (Keith), Erdmann, J. (Jeanette), Deloukas, P. (Panagiotis), Pastinen, T. (Tomi), Samani, N.J. (Nilesh), McPherson, R. (Ruth), Smith, A.V. (Davey), Frayling, T.M. (Timothy), Wareham, N.J. (Nick), Meigs, J.B. (James), Mooser, V. (Vincent), and Spector, T.D. (Timothy)

Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10-19for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10-3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal

Published
2009
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39. A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

Author

Richards, JB, Waterworth, D, O'Rahilly, S, Hivert, MF, Loos, RJF, Perry, JRB, Tanaka, T, Timpson, NJ, Semple, RK, Soranzo, N, Song, K, Rocha, N, Grundberg, E, Dupuis, J, Florez, JC, Langenberg, C, Prokopenko, I, Saxena, R, Sladek, R, Aulchenko, Yuriy, Evans, D, Waeber, G, Erdmann, J, Burnett, MS, Sattar, N, Devaney, J, Willenborg, C, Hingorani, A, Witteman, JCM, Vollenweider, P, Glaser, B, Hengstenberg, C, Ferrucci, L, Melzer, D, Stark, K, Deanfield, J, Winogradow, J, Grassl, M, Hall, AS, Egan, JM, Thompson, JR, Ricketts, SL, Konig, IR, Reinhard, W, Grundy, S, Wichmann, HE, Barter, P, Mahley, R, Kesaniemi, YA, Rader, DJ, Reilly, MP, Epstein, SE, Stewart, AFR, Duijn, Cornelia, Schunkert, H, Burling, K, Deloukas, P, Pastinen, T, Samani, NJ, McPherson, R, Smith, GD, Frayling, TM, Wareham, NJ, Meigs, JB, Mooser, V, Spector, TD, Richards, JB, Waterworth, D, O'Rahilly, S, Hivert, MF, Loos, RJF, Perry, JRB, Tanaka, T, Timpson, NJ, Semple, RK, Soranzo, N, Song, K, Rocha, N, Grundberg, E, Dupuis, J, Florez, JC, Langenberg, C, Prokopenko, I, Saxena, R, Sladek, R, Aulchenko, Yuriy, Evans, D, Waeber, G, Erdmann, J, Burnett, MS, Sattar, N, Devaney, J, Willenborg, C, Hingorani, A, Witteman, JCM, Vollenweider, P, Glaser, B, Hengstenberg, C, Ferrucci, L, Melzer, D, Stark, K, Deanfield, J, Winogradow, J, Grassl, M, Hall, AS, Egan, JM, Thompson, JR, Ricketts, SL, Konig, IR, Reinhard, W, Grundy, S, Wichmann, HE, Barter, P, Mahley, R, Kesaniemi, YA, Rader, DJ, Reilly, MP, Epstein, SE, Stewart, AFR, Duijn, Cornelia, Schunkert, H, Burling, K, Deloukas, P, Pastinen, T, Samani, NJ, McPherson, R, Smith, GD, Frayling, TM, Wareham, NJ, Meigs, JB, Mooser, V, and Spector, TD

Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms ( SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P <= 5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P <= 0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5610 26, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Published
2009

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