학술논문
Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index
Original Article
Original Article
Document Type
Report
Author
Hinney, A; Kesselmeier, M; Jall, S; Volckmar, A-L; Föcker, M; Antel, J; Perica, Vesna Boraska; Franklin, Christopher S; Floyd, James A B; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; iezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger A H; Kas, Martien J H; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori-Helkamaa, Anu; Van Furth, Eric F; Slof-Op't Landt, Margarita C T; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O'Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver S P; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kove, Carolien; Hendriks, Judith; Koeleman, Bobby P C; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramí, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L; Levitan, Robert D; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Hellard, Stephanie Le; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen W; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham R S; Barrett, Jeff C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M; Anderson, Carl A; Barrett, Jeffrey C; McGinnis, Ralph; Sambrook, Jennifer; Stephens, Jonathan; Ouwehand, Willem H; McArdle, Wendy L; Ring, Susan M; Strachan, David P; Alexander, Graeme; Conlon, Peter J; Dominiczak, Anna; Duncanson, Audrey; Hill, Adrian; Langford, Cordelia; Lord, Graham; Maxwell, Alexander P; Morgan, Linda; Sandford, Richard N; Sheerin, Neil; Vannberg, Frederik O; Blackburn, Hannah; Chen, Wei-Min; Edkins, Sarah; Gillman, Mathew; Gray, Emma; Hunt, Sarah E; Nengut-Gumuscu, Suna; Potter, Simon; Rich, Stephen S; Simpkin, Douglas; Whittaker, Pamela; Heid, I M; Winkler, T W; de Bakker, P; Bültmann, U; Geleijnse, M; Harst, P V; Koppelman, G; Rosmalen, J G; van Rossum, L; Smidt, H; Swertz, M A; Stolk, R P; Alizadeh, B; de Boer, R; Boezen, H M; Bruinenberg, M; Franke, L; van der Harst, P; Hillege, H; van der Klauw, M; Navis, G; Ormel, J; Postma, D; Rosmalen, J; Slaets, J; Snieder, H; Stolk, R; Wolffenbuttel, B; Wijmenga, C; Berg, J; Blackwood, D; Campbell, H; Cavanagh, J; Connell, J; Connor, M; Cunningham-Burley, S; Deary, I; Dominiczak, A; Ellis, P; FitzPatrick, B; Ford, I; Gertz, R; Grau, A; Haddow, G; Jackson, C; Kerr, S; Lindsay, R; McGilchrist, M; McIntyre, D; Morris, A; Morton, R; Muir, W; Murray, G; Palmer, C; Pell, J; Philp, A; Porteous, D; Porteous, M; Procter, R; Ralston, S; Reid, D; Sinnott, R; Smith, B; Clair, D S; Sullivan, F; Sweetland, M; Ure, J; Watt, G; Wolf, R; Wright, A; Berndt, S I; Gustafsson, S; Mägi, R; Ganna, A; Wheeler, E; Feitosa, M F; Justice, A E; Monda, K L; Croteau- Chonka, D C; Day, F R; Esko, T; Fall, T; Ferreira, T; Gentilini, D; Jackson, A U; Luan, J; Randall, J C; Vedantam, S; Willer, C J; Wood, A R; Workalemahu, T; Hu, Y J; Lee, S H; Liang, L; Lin, D Y; Min, J L; Neale, B M; Thorleifsson, G; Yang, J; Albrecht, E; Amin, N; Bragg-Gresham, J L; Cadby, G; den Heijer, M; Eklund, N; Fischer, K; Goel, A; Hottenga, J J; Huffman, J E; Jarick, I; Johansson, A; Johnson, T; Kanoni, S; Kleber, M E; König, I R; Kristiansson, K; Kutalik, Z; Lamina, C; Lecoeur, C; Li, G; Mangino, M; McArdle, W L; Medina-Gomez, C; Müller-Nurasyid, M; Ngwa, J S; Nolte, I M; Paternoster, L; Pechlivanis, S; Perola, M; Peters, M J; Preuss, M; Rose, L M; Shi, J; Shungin, D; Smith, A V; Strawbridge, R J; Surakka, I; Teumer, A; Trip, M D; Tyrer, J; Van Vliet- Ostaptchouk, J V; Vandenput, L; Waite, L L; Zhao, J H; Absher, D; Asselbergs, F W; Atalay, M; Attwood, A P; Balmforth, A J; Basart, H; Beilby, J; Bonnycastle, L L; Brambilla, P; Chasman, D I; Chines, P S; Collins, F S; Connell, J M; Cookson, W; de Faire, U; de Vegt, F; Dei, M; Dimitriou, M; Edkins, S; Estrada, K; Evans, D M; Farrall, M; Ferrario, M M; Ferrières, J; Frau, F; Gejman, P V; Grallert, H; Grönberg, H; Gudnason, V; Hall, A S; Hall, P; Hartikainen, A L; Hayward, C; Heard-Costa, N L; Heath, A C; Hebebrand, J; Homuth, G; Hu, F B; Hunt, S E; Hyppönen, E; Iribarren, C; Jacobs, K B; Jansson, J O; Jula, A; Kähönen, M; Kathiresan, S; Kee, F; Khaw, K T; Kivimaki, M; Koenig, W; Kraja, A T; Kumari, M; Kuulasmaa, K; Kuusisto, J; Laitinen, J H; Lakka, T A; Langenberg, C; Launer, L J; Lind, L; Lindström, J; Liu, J; Liuzzi, A; Lokki, M L; Lorentzon, M; Madden, P A; Magnusson, P K; Manunta, P; Marek, D; März, W; Mateo Leach, I; McKnight, B; Medland, S E; Mihailov, E; Milani, L; Montgomery, G W; Mooser, V; Mühleisen, T W; Munroe, P B; Musk, A W; Narisu, N; Nicholson, G; Nohr, E A; Ong, K K; Oostra, B A; Palmer, C N; Palotie, A; Peden, J F; Pedersen, N; Peters, A; Polasek, O; Pouta, A; Pramstaller, P P; Prokopenko, I; Pütter, C; Radhakrishnan, A; Raitakari, O; Rendon, A; Rivadeneira, F; Rudan, I; Saaristo, T E; Sambrook, J G; Sanders, A R; Sanna, S; Saramies, J; Schipf, S; Schreiber, S; Schunkert, H; Shin, S Y; Signorini, S; Sinisalo, J; Skrobek, B; Soranzo, N; Stancakova, A; Stark, K; Stephens, J C; Stirrups, K; Stumvoll, M; Swift, A J; Theodoraki, E V; Thorand, B; Tregouet, D A; Tremoli, E; Van der Klauw, M M; van Meurs, J B; Vermeulen, S H; Viikari, J; Virtamo, J; Vitart, V; Waeber, G; Wang, Z; Widen, E; Wild, S H; Willemsen, G; Winkelmann, B R; Witteman, J C; Wolffenbuttel, B H; Wong, A; Wright, A F; Zillikens, M; Amouyel, P; Boehm, B O; Boerwinkle, E; Boomsma, D I; Caulfield, M J; Chanock, S J; Cupples, L; Cusi, D; Dedoussis, G V; Erdmann, J; Eriksson, J G; Franks, P W; Froguel, P; Gieger, C; Gyllensten, U; Hamsten, A; Harris, T B; Hengstenberg, C; Hicks, A A; Hingorani, A; Hofman, A; Hovingh, K G; Hveem, K; Illig, T; Jarvelin, M R; Jöckel, K H; Keinanen-Kiukaanniemi, S M; Kiemeney, L A; Kuh, D; Laakso, M; Lehtimäki, T; Levinson, D F; Martin, N G; Metspalu, A; Morris, A D; Nieminen, M S; Njølstad, I; Ohlsson, C; Oldehinkel, A J; Ouwehand, W H; Palmer, L J; Penninx, B; Power, C; Province, M A; Psaty, B M; Qi, L; Rauramaa, R; Ridker, P M; Ripatti, S; Salomaa, V; Samani, N J; Sørensen, T I; Spector, T D; Stefansson, K; Tönjes, A; Tuomilehto, J; Uitterlinden, A G; Uusitupa, M; Vollenweider, P; Wallaschofski, H; Wareham, N J; Watkins, H; Wichmann, H-; Wilson, J F; Abecasis, G R; Assimes, T L; Barroso, I; Boehnke, M; Borecki, I B; Deloukas, P; Fox, C S; Frayling, T; Groop, L C; Haritunian, T; Hunter, D; Kaplan, R C; Karpe, F; Moffatt, M; Mohlke, K L; O'Connell, J R; Pawitan, Y; Schadt, E E; Schlessinger, D; Steinthorsdottir, V; Strachan, D P; Thorsteinsdottir, U; van Duijn, C M; Visscher, P M; Di Blasio, A M; Hirschhorn, J N; Lindgren, C M; Morris, A P; Meyre, D; Scherag, A; McCarthy, M I; Speliotes, E K; North, K E; Loos, R J; Grant, S F A; Adair, L S; Ang, W; van Beijsterveldt, T; Bergen, N; Benke, K; Berry, D J; Bradfield, J P; Charoen, P; Coin, L; Cooper, C; Cousminer, D L; Das, S; Davis, O S; Elliott, P; Estivill, X; Feenstra, B; Flexeder, C; Freathy, R M; Gaillard, R; Geller, F; Gillman, M; Grant, S F; Groen-Blokhuis, M; Goh, L K; Guxens, M; Hakonarson, H; Hattersley, A T; Haworth, C M; Hadley, D; Heinrich, J; Hocher, B; Holloway, J W; Holst, C; Horikoshi, M; Huikari, V; Hypponen, E; Iñiguez, C; Jaddoe, V W; Kaakinen, M; Kilpeläinen, T O; Kirin, M; Kowgier, M; Lakka, H M; Lange, L A; Lawlor, D A; Lewin, A; Lindgren, C; Lindi, V; Maggi, R; Marsh, J; Melbye, M; Middeldorp, C; Millwood, I; Mook-Kanamori, D O; Murray, J C; Nivard, M; Ntalla, I; Oken, E; O'Reilly, P F; Panoutsopoulou, K; Pararajasingham, J; Pearson, E R; Pennell, C E; Price, T S; Raitakari, O T; Rodriguez, A; Salem, R M; Saw, S M; Sebert, S; Siitonen, N; Simell, O; Sovio, U; Pourcain, B S; Sunyer, J; Taal, H R; Teo, Y Y; Thiering, E; Tiesler, C; Timpson, N J; Valcárcel, B; Warrington, N M; White, S; Widén, E; Yaghootkar, H; Zeggini, E; Elks, C E; Perry, J R; Sulem, P; Franceschini, N; He, C; Lunetta, K L; Visser, J A; Byrne, E M; Gudbjartsson, D F; Koller, D L; Lin, P; Marongiu, M; McArdle, P F; Stolk, L; van Wingerden, S H; Corre, T; Ingelsson, E; Smith, E N; Ulivi, S; Warrington, M; Zgaga, L; Alavere, H; Aspelund, T; Bandinelli, S; Berenson, G S; Bergmann, S; Blackburn, H; Buring, J E; Busonero, F; Chen, W; Cornelis, M C; Couper, D; Coviello, A D; d'Adamo, P; de Geus, E J; Döring, A; Davey Smith, G; Easton, D F; Eiriksdottir, G; Emilsson, V; Eriksson, J; Ferrucci, L; Folsom, A R; Foroud, T; Garcia, M; Gasparini, P; Hankinson, S E; Ferreli, L; Hernandez, D G; Järvelin, M R; Johnson, A D; Karasik, D; Kiel, D P; Kolcic, I; Kraft, P; Laven, J S; Li, S; Levy, D; Murray, S S; Nalls, M A; Navarro, P; Nelis, M; Ness, A R; Northstone, K; Peacock, M; Paré, G; Parker, A N; Pedersen, N L; Peltonen, L; Pharoah, P; Plump, A S; Porcu, E; Rafnar, T; Rice, J P; Ring, S M; Sala, C; Schork, N J; Scuteri, A; Segrè, A V; Shuldiner, A R; Srinivasan, S R; Tammesoo, M L; Tikkanen, E; Toniolo, D; Tsui, K; Tryggvadottir, L; Uda, M; van Dam, R M; Waterworth, D M; Weedon, M N; Wichmann, H E; Young, L; Zhai, G; Zhuang, W V; Bierut, L J; Boyd, H A; Crisponi, L; Demerath, E W; Econs, M J; Hunter, D J; Streeten, E A; Murabito, J M; Murray, A; Guo, Y; Bergen, A W; Kaye, W; Berrettini, W; Brandt, Harry; Crawford, Steve; Crow, Scott; Fichter, Manfred M; Halmi, Katherine A; Johnson, Craig; Via, Maria La; Mitchell, James; Strober, Michael; Rotondo, Alessandro; Woodside, D Blake; Keel, Pamela; Lilenfeld, Lisa; Plotnicov, Kathy; Bergen, Andrew W; Berrettini, Wade; Kaye, Walter; Magistretti, Pierre; Herpertz-Dahlmann, B; de Zwaan, M; Herzog, W; Ehrlich, S; Zipfel, S; Egberts, K M; Adan, R; Brandys, M; van Elburg, A; Boraska Perica, V; Franklin, C S; Tschöp, M H; Bulik, C M; Collier, D; Müller, T D
Source
Molecular Psychiatry. February 2017, Vol. 22 Issue 2, 192
Subject
Language
English
ISSN
1359-4184
Abstract
Author(s): A Hinney [1]; M Kesselmeier [2]; S Jall [3, 4]; A-L Volckmar [1]; M Föcker [1]; J Antel [1]; GCAN; Vesna Boraska Perica; Christopher S Franklin; James A B [...]
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values [less than] 5 x 10[sup.-5], Bonferroni-corrected P [less than] 0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; P[sub.overall]: 2.47 x 10[sup.-06]/P[sub.females]: 3.45 x 10[sup.-07]/P[sub.males]: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation. Molecular Psychiatry (2017) 22, 192-201; doi: 10.1038/mp.2016.71 published online 17 May 2016
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values [less than] 5 x 10[sup.-5], Bonferroni-corrected P [less than] 0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; P[sub.overall]: 2.47 x 10[sup.-06]/P[sub.females]: 3.45 x 10[sup.-07]/P[sub.males]: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation. Molecular Psychiatry (2017) 22, 192-201; doi: 10.1038/mp.2016.71 published online 17 May 2016