Common Genetic Variation and Age of Onset of Anorexia Nervosa

  • Hunna J. Watson
  • , Laura M. Thornton
  • , Zeynep Yilmaz
  • , Jessica H. Baker
  • , Jonathan R.I. Coleman
  • , Roger A.H. Adan
  • , Lars Alfredsson
  • , Ole A. Andreassen
  • , Helga Ask
  • , Wade H. Berrettini
  • , Michael Boehnke
  • , Ilka Boehm
  • , Claudette Boni
  • , Katharina Buehren
  • , Josef Bulant
  • , Roland Burghardt
  • , Xiao Chang
  • , Sven Cichon
  • , Roger D. Cone
  • , Philippe Courtet
    • Scott Crow, James J. Crowley, Unna N. Danner, Martina de Zwaan, George Dedoussis, Janiece E. DeSocio, Danielle M. Dick, Dimitris Dikeos, Christian Dina, Srdjan Djurovic, Monika Dmitrzak-Weglarz, Elisa Docampo-Martinez, Philibert Duriez, Karin Egberts, Stefan Ehrlich, Johan G. Eriksson, Geòrgia Escaramís, Tõnu Esko, Xavier Estivill, Anne Farmer, Fernando Fernández-Aranda, Manfred M. Fichter, Manuel Föcker, Lenka Foretova, Andreas J. Forstner, Oleksandr Frei, Steven Gallinger, Ina Giegling, Johanna Giuranna, Fragiskos Gonidakis, Philip Gorwood, Mònica Gratacòs, Sébastien Guillaume, Yiran Guo, Hakon Hakonarson, Joanna Hauser, Alexandra Havdahl, Johannes Hebebrand, Sietske G. Helder, Stefan Herms, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, Christopher Hübel, James I. Hudson, Hartmut Imgart, Stephanie Jamain, Vladimir Janout, Susana Jiménez-Murcia, Ian R. Jones, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Martien J.H. Kas, Pamela K. Keel, James L. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Lars Klareskog, Kelly L. Klump, Gun Peggy S. Knudsen, Maria C. La Via, Stephanie Le Hellard, Marion Leboyer, Dong Li, Lisa Lilenfeld, Bochao Lin, Jolanta Lissowska, Jurjen Luykx, Pierre Magistretti, Mario Maj, Sara Marsal, Christian R. Marshall, Morten Mattingsdal, Ingrid Meulenbelt, Nadia Micali, Karen S. Mitchell, Alessio Maria Monteleone, Palmiero Monteleone, Richard Myers, Marie Navratilova, Ionna Ntalla, Julie K. O'Toole, Roel A. Ophoff, Leonid Padyukov, Jacques Pantel, Hana Papežová, Dalila Pinto, Anu Raevuori, Nicolas Ramoz, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Stephan Ripke, Franziska Ritschel, Marion Roberts, Alessandro Rotondo, Dan Rujescu, Filip Rybakowski, André Scherag, Stephen W. Scherer, Ulrike Schmidt, Laura J. Scott, Jochen Seitz, Yasmina Silén, Lenka Šlachtová, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Sandro Sorbi, Beata Świątkowska, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Esther Walton, Elisabeth Widen, Stephanie Zerwas, Stephan Zipfel, Andrew W. Bergen, Joseph M. Boden, Harry Brandt, Steven Crawford, Katherine A. Halmi, L. John Horwood, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, James E. Mitchell, Catherine M. Olsen, John F. Pearson, Nancy L. Pedersen, Michael Strober, Thomas Werge, David C. Whiteman, D. Blake Woodside, Scott Gordon, Sarah Maguire, Janne T. Larsen, Richard Parker, Liselotte V. Petersen, Jennifer Jordan, Martin Kennedy, Tracey D. Wade, Andreas Birgegård, Paul Lichtenstein, Mikael Landén, Nicholas G. Martin, Preben Bo Mortensen, Gerome Breen, Cynthia M. Bulik*
*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism–h2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.

Original languageEnglish
Pages (from-to)368-378
Number of pages11
JournalBiological Psychiatry Global Open Science
Volume2
Issue number4
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Funding

The PGC is supported by funding from the National Institute of Mental Health (Grant Nos. U01MH109528 and U01MH109514). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (Grant No. NWO 480-05-003, principal investigator: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. This content is the responsibility of the authors and does not represent the views of the funding bodies. We are deeply thankful to the thousands of individuals who contributed their time and biological samples, and to the many collaborators who helped to collate these samples over the years. We are extremely grateful to members of the Eating Disorders Working Group of the Psychiatric Genomics Consortium for their contributions, efforts, and leadership (see Supplemental Appendix in Supplement 1). We thank the Anorexia Nervosa Genetics Initiative, which is an initiative of the Klarman Family Foundation. We thank the Children's Hospital of Philadelphia, the Price Foundation Collaborative Group, Genetic Consortium for Anorexia Nervosa, and the Wellcome Trust Case Control Consortium-3. We thank the Stockholm Centre for Eating Disorders (SCÄ), the Swedish National Quality Register for Eating Disorders (Riksät), and Lifegene for their support of Anorexia Nervosa Genetics Initiative Sweden. We also thank the QSkin Sun and Health Study for control samples. OAA is a consultant for HealthLytix. CMB is a grant recipient from Shire Pharmaceuticals and served on Shire Scientific Advisory Board; she receives royalties from Pearson. All other authors report no biomedical financial interests or potential conflicts of interest.

FundersFunder number
Anorexia Nervosa Genetics Initiative
Dutch Brain Foundation
QSkin Sun and Health Study
Stockholm Centre for Eating Disorders
Swedish National Quality Register for Eating Disorders
National Institute of Mental HealthU01MH109528, U01MH109514
Klarman Family Foundation
Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia
Wellcome Trust
Vrije Universiteit Amsterdam
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO 480-05-003
Shire

    UN SDGs

    This output contributes to the following UN Sustainable Development Goals (SDGs)

    1. SDG 3 - Good Health and Well-being
      SDG 3 Good Health and Well-being

    Keywords

    • Age of onset
    • Anorexia nervosa
    • Early-onset
    • Genetic risk score
    • Genetics
    • GWAS
    • Menarche
    • Mendelian randomization
    • Puberty

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