TY - JOUR
T1 - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index
AU - Children's Hospital of Philadelphia/Price Foundation
AU - GCAN
AU - WTCCC3
AU - GIANT
AU - EGG
AU - Price Foundation Collaborative Group
AU - Hinney, Anke
AU - Kesselmeier, M.
AU - Jall, S.
AU - Volckmar, A. L.
AU - Föcker, M.
AU - Antel, J.
AU - Heid, I. M.
AU - Winkler, T. W.
AU - Grant, S. F.A.
AU - Guo, Yiran
AU - Bergen, A. W.
AU - Kaye, Walter
AU - Berrettini, W.
AU - Hakonarson, Hakon
AU - Herpertz-Dahlmann, Beate
AU - De Zwaan, Martina
AU - Herzog, Wolfgang
AU - Ehrlich, Stefan
AU - Zipfel, Stephan
AU - Egberts, K. M.
AU - Adan, Roger A.H.
AU - Brandys, Marek K.
AU - Van Elburg, A.
AU - Boraska Perica, V.
AU - Müller, T. D.
AU - Tschöp, M. H.
AU - Zeggini, Eleftheria
AU - Bulik, Cynthia M.
AU - Collier, David A.
AU - Scherag, André
AU - Hebebrand, Johannes
AU - Perica, Vesna Boraska
AU - Floyd, James A.B.
AU - Thornton, Laura M.
AU - Huckins, Laura M.
AU - Southam, Lorraine
AU - Rayner, N. William
AU - Tachmazidou, Ioanna
AU - Klump, Kelly L.
AU - Treasure, Janet
AU - Lewis, Cathryn M.
AU - Schmidt, Ulrike
AU - Tozzi, Federica
AU - Iezebrink, Kirsty
AU - Gorwood, Philip
AU - Kas, Martien J.H.
AU - Favaro, Angela
AU - Santonastaso, Paolo
AU - Fernández-Aranda, Fernando
AU - Gratacos, Monica
AU - Rybakowski, Filip
AU - Dmitrzak-Weglarz, Monika
AU - Kaprio, Jaakko
AU - Keski-Rahkonen, Anna
AU - Raevuori-Helkamaa, Anu
AU - Van Furth, Eric F.
AU - Slof-Op’t Landt, Margarita C.T.
AU - Hudson, James I.
AU - Reichborn-Kjennerud, Ted
AU - Knudsen, Gun Peggy S.
AU - Monteleone, Palmiero
AU - Kaplan, Allan S.
AU - Karwautz, Andreas
AU - Li, Dong
AU - Komaki, Gen
AU - Ando, Tetsuya
AU - Inoko, Hidetoshi
AU - Esko, Tõnu
AU - Fischer, Krista
AU - Männik, Katrin
AU - Metspalu, Andres
AU - Baker, Jessica H.
AU - Cone, Roger D.
AU - Dackor, Jennifer
AU - DeSocio, Janiece E.
AU - Hilliard, Christopher E.
AU - O’Toole, Julie K.
AU - Pantel, Jacques
AU - Szatkiewicz, Jin P.
AU - Taico, Chrysecolla
AU - Zerwas, Stephanie
AU - Trace, Sara E.
AU - Davis, Oliver S.P.
AU - Helder, Sietske
AU - Bühren, Katharina
AU - Burghardt, Roland
AU - Imgart, Hartmut
AU - Scherag, Susann
AU - Boni, Claudette
AU - Ramoz, Nicolas
AU - Versini, Audrey
AU - Danner, Unna N.
AU - de Kove, Carolien
AU - Hendriks, Judith
AU - Koeleman, Bobby P.C.
AU - Ophoff, Roel A.
AU - Strengman, Eric
AU - Bruson, Alice
AU - Clementi, Maurizio
AU - Degortes, Daniela
AU - Forzan, Monica
AU - Tenconi, Elena
AU - Docampo, Elisa
AU - Jiménez-Murcia, Geòrgia Escaramí Susana
AU - Lissowska, Jolanta
AU - Rajewski, Andrzej
AU - Szeszenia-Dabrowska, Neonila
AU - Slopien, Agnieszka
AU - Hauser, Joanna
AU - Karhunen, Leila
AU - Meulenbelt, Ingrid
AU - Slagboom, P. Eline
AU - Tortorella, Alfonso
AU - Maj, Mario
AU - Dedoussis, George
AU - Dedoussis, G. V.
AU - Dikeos, Dimitris
AU - Gonidakis, Fragiskos
AU - Tziouvas, Konstantinos
AU - Tsitsika, Artemis
AU - Papezova, Hana
AU - Slachtova, Lenka
AU - Martaskova, Debora
AU - Kennedy, James L.
AU - Levitan, Robert D.
AU - Yilmaz, Zeynep
AU - Huemer, Julia
AU - Koubek, Doris
AU - Merl, Elisabeth
AU - Wagner, Gudrun
AU - Lichtenstein, Paul
AU - Breen, Gerome
AU - Cohen-Woods, Sarah
AU - Farmer, Anne
AU - McGuffin, Peter
AU - Cichon, Sven
AU - Giegling, Ina
AU - Herms, Stefan
AU - Rujescu, Dan
AU - Schreiber, Stefan
AU - Wichmann, H. Erich
AU - Christian, Dina
AU - Sladek, Rob
AU - Gambaro, Giovanni
AU - Soranzo, Nicole
AU - Julia, Antonio
AU - Marsal, Sara
AU - Rabionet, Raquel
AU - Gaborieau, Valerie
AU - Dick, Danielle M.
AU - Palotie, Aarno
AU - Ripatti, Samuli
AU - Widén, Elisabeth
AU - Andreassen, Ole A.
AU - Espeseth, Thomas
AU - Lundervold, Astri
AU - Reinvang, Ivar
AU - Steen, Vidar M.
AU - Le Hellard, Stephanie
AU - Mattingsdal, Morten
AU - Ntalla, Ioanna
AU - Bencko, Vladimir
AU - Foretova, Lenka
AU - Janout, Vladimir
AU - Navratilova, Marie
AU - Gallinger, Steven
AU - Pinto, Dalila
AU - Scherer, Stephen W.
AU - Aschauer, Harald
AU - Carlberg, Laura
AU - Schosser, Alexandra
AU - Alfredsson, Lars
AU - Ding, Bo
AU - Klareskog, Lars
AU - Padyukov, Leonid
AU - Finan, Chris
AU - Kalsi, Gursharan
AU - Roberts, Marion
AU - Logan, Darren W.
AU - Peltonen, Leena
AU - Ritchie, Graham R.S.
AU - Barrett, Jeffrey C.
AU - Estivill, Xavier
AU - Sullivan, Patrick F.
AU - Anderson, Carl A.
AU - McGinnis, Ralph
AU - Sambrook, Jennifer
AU - Stephens, Jonathan
AU - Ouwehand, Willem H.
AU - McArdle, Wendy L.
AU - McArdle, P. F.
AU - Ring, Susan M.
AU - Strachan, David P.
AU - Alexander, Graeme
AU - Conlon, Peter J.
AU - Dominiczak, Anna
AU - Duncanson, Audrey
AU - Heath, A. C.
AU - Rice, J. P.
AU - Bierut, L. J.
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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 <5 × 10-5, Bonferroni-corrected P<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; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 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.
AB - 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 <5 × 10-5, Bonferroni-corrected P<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; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 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.
UR - http://www.scopus.com/inward/record.url?scp=84968552358&partnerID=8YFLogxK
U2 - 10.1038/mp.2016.71
DO - 10.1038/mp.2016.71
M3 - Article
C2 - 27184124
AN - SCOPUS:84968552358
SN - 1359-4184
VL - 22
SP - 192
EP - 201
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 2
ER -