Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

L. M. Huckins, K. Hatzikotoulas, L. Southam, L. M. Thornton, J. Steinberg, F. Aguilera-Mckay, J. Treasure, U. Schmidt, C. Gunasinghe, A. Romero, C. Curtis, D. Rhodes, J. Moens, G. Kalsi, D. Dempster, R. Leung, A. Keohane, R. Burghardt, S. Ehrlich, J. HebebrandA. Hinney, A. Ludolph, E. Walton, P. Deloukas, A. Hofman, A. Palotie, P. Palta, F. J.A. van Rooij, K. Stirrups, R. Adan, C. Boni, R. Cone, G. Dedoussis, E. van Furth, F. Gonidakis, P. Gorwood, J. Hudson, J. Kaprio, M. Kas, A. Keski-Rahonen, K. Kiezebrink, G. P. Knudsen, M. C.T. Slof-Op ’T Landt, M. Maj, A. M. Monteleone, P. Monteleone, A. H. Raevuori, T. Reichborn-Kjennerud, F. Tozzi, A. Tsitsika, A. Elburg, D. A. Collier, P. F. Sullivan, G. Breen, C. M. Bulik, E. Zeggini, R. A.H. Adan, L. Alfredsson, T. Ando, O. A. Andreassen, H. Aschauer, J. H. Baker, J. C. Barrett, V. Bencko, A. W. Bergen, W. H. Berrettini, A. Birgegård, C. Boni, V. Boraska Perica, H. Brandt, C. M. Bulik, L. Carlberg, M. Cassina, S. Cichon, M. Clementi, S. Cohen-Woods, J. Coleman, R. D. Cone, P. Courtet, S. Crawford, S. Crow, J. Crowley, U. N. Danner, O. S.P. Davis, M. Zwaan, G. Dedoussis, D. Degortes, J. E. Desocio, D. M. Dick, D. Dikeos, C. Dina, B. Ding, M. Dmitrzak-Weglarz, E. Docampo, L. Duncan, K. Egberts, S. Ehrlich, G. Escaramís, T. Esko, T. Espeseth, X. Estivill, A. Favaro, F. Fernández-Aranda, M. M. Fichter, C. Finan, K. Fischer, J. A.B. Floyd, L. Foretova, M. Forzan, C. S. Franklin, S. Gallinger, G. Gambaro, H. A. Gaspar, I. Giegling, F. Gonidakis, P. Gorwood, M. Gratacos, S. Guillaume, Y. Guo, H. Hakonarson, K. A. Halmi, K. Hatzikotoulas, J. Hauser, J. Hebebrand, S. Helder, S. Herms, B. Herpertz-Dahlmann, W. Herzog, C. E. Hilliard, A. Hinney, C. Hübel, L. M. Huckins, J. I. Hudson, J. Huemer, H. Inoko, V. Janout, S. Jiménez-Murcia, C. Johnson, A. Julià, A. Juréus, G. Kalsi, D. Kaminska, A. S. Kaplan, J. Kaprio, L. Karhunen, A. Karwautz, M. J.H. Kas, W. Kaye, J. L. Kennedy, A. Keski-Rahkonen, K. Kiezebrink, L. Klareskog, K. L. Klump, G. P.S. Knudsen, B. P.C. Koeleman, D. Koubek, MC C.L. Via, M. Landén, S. Le Hellard, R. D. Levitan, D. Li, P. Lichtenstein, L. Lilenfeld, J. Lissowska, A. Lundervold, P. Magistretti, M. Maj, K. Mannik, S. Marsal, N. Martin, M. Mattingsdal, S. McDevitt, P. McGuffin, E. Merl, A. Metspalu, I. Meulenbelt, N. Micali, J. Mitchell, K. Mitchell, P. Monteleone, A. M. Monteleone, P. Mortensen, M. A. Munn-Chernoff, M. Navratilova, I. Nilsson, C. Norring, I. Ntalla, R. A. Ophoff, J. K. O'toole, A. Palotie, J. Pantel, H. Papezova, D. Pinto, R. Rabionet, A. Raevuori, A. Rajewski, N. Ramoz, N. W. Rayner, T. Reichborn-Kjennerud, S. Ripatti, M. Roberts, A. Rotondo, D. Rujescu, F. Rybakowski, P. Santonastaso, A. Scherag, S. W. Scherer, U. Schmidt, N. J. Schork, A. Schosser, L. Slachtova, R. Sladek, P. E. Slagboom, M. C.T. Slof-Op 'T Landt, A. Slopien, N. Soranzo, L. Southam, V. M. Steen, E. Strengman, M. Strober, P. F. Sullivan, J. P. Szatkiewicz, N. Szeszenia-Dabrowska, I. Tachmazidou, E. Tenconi, L. M. Thornton, A. Tortorella, F. Tozzi, J. Treasure, A. Tsitsika, K. Tziouvas, A. A. Elburg, E. F. Furth, G. Wagner, E. Walton, H. Watson, H. E. Wichmann, E. Widen, D. B. Woodside, J. Yanovski, S. Yao, Z. Yilmaz, E. Zeggini, S. Zerwas, S. Zipfel

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16 Scopus citations

Abstract

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6), and rs7700147, an intergenic variant (P=2.93 × 10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Original languageEnglish (US)
Pages (from-to)1169-1180
Number of pages12
JournalMolecular psychiatry
Volume23
Issue number5
DOIs
StatePublished - May 1 2018

Bibliographical note

Funding Information:
Abbreviations: AN, anorexia nervosa; QC, quality control. aIn all, 3000 UK controls were randomly selected from the 9828 samples, genotyped as part of the UK household longitudinal survey. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www. understandingsociety.ac.uk/.

Funding Information:
GB has received grant funding and consultancy fees from Eli Lilly. DD is speaker, consultant or on advisory boards of various pharmaceutical companies, including AstraZeneca, Boehringer, Bristol Myers Squibb, Eli Lilly, 28 Genesis Pharma, GlaxoSmithKline, Janssen, Lundbeck, Organon, Sanofi, UniPharma and Wyeth, and he has unrestricted grants from Lilly and AstraZeneca as director of the Sleep Research Unit of Eginition Hospital (National and Kapodistrian University of Athens, Greece). AK is on the Shire Canada BED Advisory Board. JK is a member of SAB of AssurexHealth Inc (unpaid). ML has received lecture honoraria from Lundbeck, AstraZeneca and Biophausia Sweden, and served as scientific consultant for EPID Research Oy. There exists no other equity ownership, profit-sharing agreements, royalties, or patents. PS is scientific advisor to Pfizer, Inc. JT received an honorarium for speaking at a diabetic conference for Lilly and royalties from a published book. The remaining authors declare no conflicts of interest.

Funding Information:
Klarman Family Foundation: This study was supported by a grant from the Klarman Family Foundation.

Funding Information:
Wellcome Trust Case Control Consortium: This work was funded by a grant from the WTCCC3 WT088827/Z/09 entitled ‘A genomewide association study of anorexia nervosa’.

Funding Information:
Acknowledgements for specific authors: Eleftheria Zeggini is supported by the Wellcome Trust (098051). Lorraine Southam is supported by the Wellcome Trust (098051). Laura Huckins acknowledges Wellcome Trust (098051) and the MRC (MR/ J500355/1). Cynthia Bulik acknowledges funding from the Swedish Research Council (VR Dnr: 538–2013–8864). Esther Walton is supported by the German Research Foundation (Wa 3635/1–1). Zeynep Yilmaz is funded by NIH K01MH109782. Allan Kaplan, Robert Levitan and James Kennedy acknowledge support from Ontario Mental Health Foundation for the collection of samples. Jaakko Kaprio is suppoted by the Academy of Finland (263278).

Funding Information:
This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.' We gratefully acknowledge capital equipment funding from the Maudsley Charity (Grant Ref. 980) and Guy’s and St Thomas’s Charity (Grant Ref. STR130505).

Funding Information:
TEENAGE (TEENs of Attica: Genes and Environment): This work was funded by the Wellcome Trust (098051) and has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program ‘Education and Lifelong Learning’ of the National Strategic Reference Framework (NSRF)— Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund. We thank all study participants and their families as well as all volunteers for their contribution in this study. We thank the following staff from the Sample Management and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, QC and genotyping: Dave Jones, Doug Simpkin, Emma Gray, Hannah Blackburn and Sarah Edkins.

Funding Information:
UKHLS (The UK Household Longitudinal Study): The UK Household Longitudinal Study (UKHLS) is led by the Institute for Social and Economic Research at the University of Essex and is funded by the Economic and Social Research Council. The survey was conducted by NatCen, and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www. understandingsociety.ac.uk/.

Funding Information:
CommonMind Consortium: CommonMind Consortium Data were used in this manuscript. These data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F Hoffman-La Roche and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: Pamela Sklar, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici, Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite, Mette Peters (Sage Bionetworks), Thomas Lehner and Barbara Lipska (NIMH)’.

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