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1. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Author

Kilpeläinen, Tuomas O, Carli, Jayne F Martin, Skowronski, Alicja A, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F, Hedman, Åsa K, Drong, Alexander W, Hayes, James E, Zhao, Jinghua, Pers, Tune H, Schick, Ursula, Grarup, Niels, Kutalik, Zoltán, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikäinen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renström, Frida, Willems, Sara M, Mahajan, Anubha, Rose, Lynda M, Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E, Pérusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S, Ju Sung, Yun, Ramos, Yolande F, Amin, Najaf, Amuzu, Antoinette, Barroso, Inês, Bellis, Claire, Blangero, John, Buckley, Brendan M, Böhringer, Stefan, I Chen, Yii-Der, de Craen, Anton JN, Crosslin, David R, Dale, Caroline E, Dastani, Zari, Day, Felix R, Deelen, Joris, Delgado, Graciela E, Demirkan, Ayse, Finucane, Francis M, Ford, Ian, Garcia, Melissa E, Gieger, Christian, Gustafsson, Stefan, Hallmans, Göran, Hankinson, Susan E, Havulinna, Aki S, Herder, Christian, Hernandez, Dena, Hicks, Andrew A, Hunter, David J, Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S, Jørgensen, Marit E, Jørgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A, Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P, Myers, Richard H, Männistö, Satu, Nalls, Mike A, Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D, Rankinen, Tuomo, Rasmussen-Torvik, Laura J, Rathmann, Wolfgang, Rice, Treva K, Brent Richards, J, Ridker, Paul M, Sattar, Naveed, and Savage, David B

Subjects
Adipose Tissue, Animals, Mice, Leptin, RNA, Messenger, Tissue Culture Techniques, Gene Expression Regulation, Male, Genome-Wide Association Study, Gene Knockdown Techniques, RNA, Messenger
Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P

Published
2016

3. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Author

Burnett, Lisa C., LeDuc, Charles A., Sulsona, Carlos R., Paull, Daniel, Rausch, Richard, Eddiry, Sanaa, Carli, Jayne F. Martin, Morabito, Michael V., Skowronski, Alicja A., Hubner, Gabriela, Zimmer, Matthew, Wang, Liheng, Day, Robert, Levy, Brynn, Fennoy, Ilene, Dubern, Beatrice, Poitou, Christine, Clement, Karine, Butler, Merlin G., Rosenbaum, Michael, Salles, Jean Pierre, Tauber, Maithe, Driscoll, Daniel J., Egli, Dieter, and Leibel, Rudolph L.

Subjects
Neurons -- Analysis, Gene expression -- Analysis, Prader-Willi syndrome -- Risk factors, Health care industry
Abstract

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcskl expression were reduced in hypothalami of fasted Snord116 paternal knockout ([Snord116.sup.p/m+]) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that [Snord116.sup.p/m+] mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency., Introduction Prader-Willi syndrome (PWS) is the most common syndromic obesity, affecting 1 in 25,000 live births (1, 2). PWS results from a loss of paternally expressed genes at 15q11.2-q13 (Figure [...]

Published
2017
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4. Testbeam studies of barrel and end-cap modules for the ATLAS ITk strip detector before and after irradiation

Author

Ruehr, F., Affolder, A., Ai, X., Arling, J. H., Atlay, B., Basso, M. J., Becot, C., Bruers, B., Buchanan, E., Carli, Jayne F Martin, Ciungu, B., Cunningham, W., David, C., Cornell, S. Diez, Dreyer, E., Escobar Ibanez, C., Gallop, B., Argos, C. Garcia, Greenall, A., Gregor, I. M., Gubbels, C., Guescini, F., Hauser, M., Keller, J., Kisliuk, D., Klein, C. T., Koffas, T., Kovanda, O., Kroll, J., Liberatore, M., Liu, J., Liu, Y., Loenker, J., Meng, H., Milovanovic, M., Minano Moya, M., Moos, F., Ng, S. Y., Phillips, P., Privara, R., Queitsch-Maitland, M., Rabhi, N., Rachac, M., Rehnisch, L., Rodriguez, A. Rodriguez, Rossi, E., Sawyer, C., Song, W., Sperlich, D., Sykora, M., Thomas, J., Wiglesworth, C., Wiik-Fuchs, L., Wonsak, S., Zahradnik, Zhu, H., Ruehr, F., Affolder, A., Ai, X., Arling, J. H., Atlay, B., Basso, M. J., Becot, C., Bruers, B., Buchanan, E., Carli, Jayne F Martin, Ciungu, B., Cunningham, W., David, C., Cornell, S. Diez, Dreyer, E., Escobar Ibanez, C., Gallop, B., Argos, C. Garcia, Greenall, A., Gregor, I. M., Gubbels, C., Guescini, F., Hauser, M., Keller, J., Kisliuk, D., Klein, C. T., Koffas, T., Kovanda, O., Kroll, J., Liberatore, M., Liu, J., Liu, Y., Loenker, J., Meng, H., Milovanovic, M., Minano Moya, M., Moos, F., Ng, S. Y., Phillips, P., Privara, R., Queitsch-Maitland, M., Rabhi, N., Rachac, M., Rehnisch, L., Rodriguez, A. Rodriguez, Rossi, E., Sawyer, C., Song, W., Sperlich, D., Sykora, M., Thomas, J., Wiglesworth, C., Wiik-Fuchs, L., Wonsak, S., Zahradnik, and Zhu, H.

Abstract

In order to cope with the occupancy and radiation doses expected at the High-Luminosity LHC, the ATLAS experiment will replace its Inner Detector with an all-silicon Inner Tracker (ITk), consisting of pixel and strip subsystems.In the last two years, several prototype ITk strip modules have been tested using beams of high energy electrons produced at the DESY-II testbeam facility. Tracking was provided by EUDET telescopes. The modules tested are built from two sensor types: the rectangular ATLAS17LS, which will be used in the outer layers of the central barrel region of the detector, and the annular ATLAS12EC, which will be used in the innermost ring (R0) of the forward region. Additionally, a structure with two RO modules positioned back-to-back has been measured, demonstrating space point reconstruction using the stereo angle of the strips. Finally, one barrel and one RO module have been measured after irradiation to 40% beyond the expected end-of-lifetime fluence. The data obtained allow for thorough tests of the module performance, including charge collection, noise occupancy, detection efficiency, and tracking performance. The results give confidence that the ITk strip detector will meet the requirements of the ATLAS experiment.

Published
2020

5. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author

Admin, Ada, primary, Yaghootkar, Hanieh, primary, Zhang, Yiying, primary, Spracklen, Cassandra N, primary, Karaderi, Tugce, primary, Huang, Lam Opal, primary, Bradfield, Jonathan, primary, Schurmann, Claudia, primary, Fine, Rebecca S, primary, Preuss, Michael H, primary, Kutalik, Zoltan, primary, Wittemans, Laura BL, primary, Lu, Yingchang, primary, Metz, Sophia, primary, Willems, Sara M, primary, Li-Gao, Ruifang, primary, Grarup, Niels, primary, Wang, Shuai, primary, Molnos, Sophie, primary, Sandoval-Zárate, América A, primary, Nalls, Mike A, primary, Lange, Leslie A, primary, Haesser, Jeffrey, primary, Guo, Xiuqing, primary, Lyytikäinen, Leo-Pekka, primary, Feitosa, Mary F, primary, Sitlani, Colleen M, primary, Venturini, Cristina, primary, Mahajan, Anubha, primary, Kacprowski, Tim, primary, Wang, Carol A, primary, Chasman, Daniel I, primary, Amin, Najaf, primary, Broer, Linda, primary, Robertson, Neil, primary, Young, Kristin L, primary, Allison, Matthew, primary, Blüher, Matthias, primary, Borja, Judith B, primary, Bork-Jensen, Jette, primary, Carrasquilla, Germán D, primary, Christofidou, Paraskevi, primary, Demirkan, Ayse, primary, Doege, Claudia A, primary, Garcia, Melissa E, primary, Graff, Mariaelisa, primary, Guo, Kaiying, primary, Hakonarson, Hakon, primary, Hong, Jaeyoung, primary, Chen, Yii-Der Ida, primary, Jackson, Rebecca, primary, Jakupović, Hermina, primary, Jousilahti, Pekka, primary, Justice, Anne E, primary, Kähönen, Mika, primary, Kizer, Jorge R, primary, Kriebe, Jennifer, primary, LeDuc, Charles A, primary, Li, Jin, primary, Lind, Lars, primary, Luan, Jian’an, primary, Mackey, David, primary, Mangino, Massimo, primary, Männistö, Satu, primary, Carli, Jayne F Martin, primary, Medina-Gomez, Carolina, primary, Mook-Kanamori, Dennis O, primary, Morris, Andrew P, primary, Mutsert, Renée de, primary, Nauck, Matthias, primary, Nedeljkovic, Ivana, primary, Pennell, Craig E, primary, Pradhan, Arund D, primary, Psaty, Bruce M, primary, Raitakari, Olli T, primary, Scott, Robert A, primary, Skaaby, Tea, primary, Strauch, Konstantin, primary, Taylor, Kent D, primary, Teumer, Alexander, primary, Uitterlinden, Andre G, primary, Wu, Ying, primary, Yao, Jie, primary, Walker, Mark, primary, North, Kari E, primary, Kovacs, Peter, primary, Ikram, M. Arfan, primary, Duijn, Cornelia M van, primary, Ridker, Paul M, primary, Lye, Stephen, primary, Homuth, Georg, primary, Ingelsson, Erik, primary, Spector, Tim D, primary, McKnight, Barbara, primary, Province, Michael A, primary, Lehtimäki, Terho, primary, Adair, Linda S, primary, Rotter, Jerome I, primary, Reiner, Alexander P, primary, Wilson, James G, primary, Harris, Tamara B, primary, Ripatti, Samuli, primary, Grallert, Harald, primary, Meigs, James B, primary, Salomaa, Veikko, primary, Hansen, Torben, primary, Dijk, Ko Willems van, primary, Wareham, Nicholas J, primary, Grant, Struan FA, primary, Langenberg, Claudia, primary, Frayling, Timothy M, primary, Lindgren, Cecilia M, primary, Mohlke, Karen L, primary, Leibel, Rudolph L, primary, Loos, Ruth JF, primary, and Kilpeläinen, Tuomas O, primary

Published
2020
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8. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Author

Burnett, Lisa C., primary, LeDuc, Charles A., additional, Sulsona, Carlos R., additional, Paull, Daniel, additional, Rausch, Richard, additional, Eddiry, Sanaa, additional, Carli, Jayne F. Martin, additional, Morabito, Michael V., additional, Skowronski, Alicja A., additional, Hubner, Gabriela, additional, Zimmer, Matthew, additional, Wang, Liheng, additional, Day, Robert, additional, Levy, Brynn, additional, Fennoy, Ilene, additional, Dubern, Beatrice, additional, Poitou, Christine, additional, Clement, Karine, additional, Butler, Merlin G., additional, Rosenbaum, Michael, additional, Salles, Jean Pierre, additional, Tauber, Maithe, additional, Driscoll, Daniel J., additional, Egli, Dieter, additional, and Leibel, Rudolph L., additional

Published
2016
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9. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renström, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Söderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., Loos, Ruth J. F., Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renström, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Söderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., and Loos, Ruth J. F.

Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P < 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P < 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Published
2016
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10. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

University of Helsinki, Helsinki Collegium for Advanced Studies, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Clinicum, Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renstrom, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Soderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., Loos, Ruth J. F., University of Helsinki, Helsinki Collegium for Advanced Studies, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Clinicum, Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renstrom, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Soderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., and Loos, Ruth J. F.

Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Published
2016

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