Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Hunna J. Watson; Laura M. Thornton; Zeynep Yilmaz; Jessica H. Baker; Jonathan RI. Coleman; Roger AH. 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; 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 JH. 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 CT. 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

doi:10.1016/j.bpsgos.2021.09.001

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Hunna J. Watson, Laura M. Thornton, Zeynep Yilmaz, Jessica H. Baker, Jonathan RI. Coleman, Roger AH. 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 CourtetScott 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, 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 JH. 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 CT. 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)

^*Corresponding author for this work

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

8 Citations (Scopus)

Abstract

Background
Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at 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 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at 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 (SNP-h2) were 0.01-0.04 for age at 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 at onset and early-onset AN estimated from independent GWASs significantly predicted age at 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 at onset and implicate biological pathways regulating menarche and reproduction.

Original language	English
Pages (from-to)	368-378
Number of pages	11
Journal	Biological Psychiatry Global Open Science
Volume	2
Issue number	4
Early online date	20 Sept 2021
DOIs	https://doi.org/10.1016/j.bpsgos.2021.09.001
Publication status	Published - 14 Oct 2022

Bibliographical note

Acknowledgments
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 (Appendix). The Psychiatric Genomics Consortium is supported by funding from the National Institute of Mental Health (U01MH109528, U01MH109514). We are grateful to the Anorexia Nervosa Genetics Initiative (ANGI), which is an initiative of the Klarman Family Foundation. We thank the Children’s Hospital of Philadelphia (CHOP), the Price Foundation Collaborative Group (PFCG), Genetic Consortium for Anorexia Nervosa (GCAN), and the Wellcome Trust Case-Control Consortium-3 (WTCCC3). We would also like to thank the Stockholm Centre for Eating Disorders (SCÄ), the Swedish National Quality Register for Eating Disorders (Riksät), and Lifegene for their support of ANGI Sweden. We thank the QSkin Sun and Health Study for control samples. 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 (NWO 480-05-003 PI: 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.

Data Availability Statement

Supplementary material cited in this article is available online at https://doi.org/10.1016/j.bpsgos.2021.09.001.

Keywords

age at onset
anorexia nervosa
early-onset
genetics
genetic risk score
GWAS
menarche
Mendelian randomization
puberty

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Watson_etal_BPGOS_Common_Genetic_Variation_VoR
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Cite this

Watson, H. J., Thornton, L. M., Yilmaz, Z., Baker, J. H., Coleman, J. RI., Adan, R. AH., Alfredsson, L., Andreassen, O. A., Ask, H., Berrettini, W. H., Boehnke, M., Boehm, I., Boni, C., Buehren, K., Bulant, J., Burghardt, R., Chang, X., Cichon, S., Cone, R. D., ... Bulik, C. M. (2022). Common Genetic Variation And Age at Onset Of Anorexia Nervosa. Biological Psychiatry Global Open Science, 2(4), 368-378. https://doi.org/10.1016/j.bpsgos.2021.09.001

Watson, HJ, Thornton, LM, Yilmaz, Z, Baker, JH, Coleman, JRI, Adan, RAH, Alfredsson, L, Andreassen, OA, Ask, H, Berrettini, WH, Boehnke, M, Boehm, I, Boni, C, Buehren, K, Bulant, J, Burghardt, R, Chang, X, Cichon, S, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, de Zwaan, M, Dedoussis, G, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Djurovic, S, Dmitrzak-Weglarz, M, Docampo-Martinez, E, Duriez, P, Egberts, K, Ehrlich, S, Eriksson, JG, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Fernández-Aranda, F, Fichter, MM, Föcker, M, Foretova, L, Forstner, AJ, Frei, O, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacòs, M, Guillaume, S, Guo, Y, Hakonarson, H, Hauser, J, Havdahl, A, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Hinney, A, Hudson, JI, Imgart, H, Jamain, S, Janout, V, Jiménez-Murcia, S, Jones, IR, Julià, A, Kalsi, G, Kaminská, D, Kaprio, J, Karhunen, L, Kas, MJH, Keel, PK, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Klareskog, L, Klump, KL, Knudsen, GPS, La Via, MC, Le Hellard, S, Leboyer, M, Li, D, Lilenfeld, L, Lin, B, Lissowska, J, Luykx, J, Magistretti, P, Maj, M, Marsal, S, Marshall, CR, Mattingsdal, M, Meulenbelt, I, Micali, N, Mitchell, KS, Monteleone, AM, Monteleone, P, Myers, R, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, RA, Padyukov, L, Pantel, J, Papežová, H, Pinto, D, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ripke, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Scherag, A, Scherer, SW, Schmidt, U, Scott, LJ, Seitz, J, Silén, Y, Šlachtová, L, Slagboom, PE, Slof-Op 't Landt, MCT, Slopien, A, Sorbi, S, Świątkowska, B, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Walton, E, Widen, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, JE, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Gordon, S, Maguire, S, Larsen, JT, Parker, R, Petersen, LV, Jordan, J, Kennedy, M, Wade, TD, Birgegård, A, Lichtenstein, P, Landén, M, Martin, NG, Mortensen, PB, Breen, G & Bulik, CM 2022, 'Common Genetic Variation And Age at Onset Of Anorexia Nervosa', Biological Psychiatry Global Open Science, vol. 2, no. 4, pp. 368-378. https://doi.org/10.1016/j.bpsgos.2021.09.001

@article{e8dd94fe31e14f9ca1f11781df5c3c68,

title = "Common Genetic Variation And Age at Onset Of Anorexia Nervosa",

abstract = "BackgroundGenetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at 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 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at 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 (SNP-h2) were 0.01-0.04 for age at 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 at onset and early-onset AN estimated from independent GWASs significantly predicted age at 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 at onset and implicate biological pathways regulating menarche and reproduction.",

keywords = "age at onset, anorexia nervosa, early-onset, genetics, genetic risk score, GWAS, menarche, Mendelian randomization, puberty",

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

note = "Acknowledgments 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 (Appendix). The Psychiatric Genomics Consortium is supported by funding from the National Institute of Mental Health (U01MH109528, U01MH109514). We are grateful to the Anorexia Nervosa Genetics Initiative (ANGI), which is an initiative of the Klarman Family Foundation. We thank the Children{\textquoteright}s Hospital of Philadelphia (CHOP), the Price Foundation Collaborative Group (PFCG), Genetic Consortium for Anorexia Nervosa (GCAN), and the Wellcome Trust Case-Control Consortium-3 (WTCCC3). We would also like to thank the Stockholm Centre for Eating Disorders (SC{\"A}), the Swedish National Quality Register for Eating Disorders (Riks{\"a}t), and Lifegene for their support of ANGI Sweden. We thank the QSkin Sun and Health Study for control samples. 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 (NWO 480-05-003 PI: 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.",

year = "2022",

month = oct,

day = "14",

doi = "10.1016/j.bpsgos.2021.09.001",

language = "English",

volume = "2",

pages = "368--378",

journal = "Biological Psychiatry Global Open Science",

issn = "2667-1743",

publisher = "Elsevier BV",

number = "4",

}

TY - JOUR

T1 - Common Genetic Variation And Age at Onset Of Anorexia Nervosa

AU - Watson, Hunna J.

AU - Thornton, Laura M.

AU - Yilmaz, Zeynep

AU - Baker, Jessica H.

AU - Coleman, Jonathan RI.

AU - Adan, Roger AH.

AU - Alfredsson, Lars

AU - Andreassen, Ole A.

AU - Ask, Helga

AU - Berrettini, Wade H.

AU - Boehnke, Michael

AU - Boehm, Ilka

AU - Boni, Claudette

AU - Buehren, Katharina

AU - Bulant, Josef

AU - Burghardt, Roland

AU - Chang, Xiao

AU - Cichon, Sven

AU - Cone, Roger D.

AU - Courtet, Philippe

AU - Crow, Scott

AU - Crowley, James J.

AU - Danner, Unna N.

AU - de Zwaan, Martina

AU - Dedoussis, George

AU - DeSocio, Janiece E.

AU - Dick, Danielle M.

AU - Dikeos, Dimitris

AU - Dina, Christian

AU - Djurovic, Srdjan

AU - Dmitrzak-Weglarz, Monika

AU - Docampo-Martinez, Elisa

AU - Duriez, Philibert

AU - Egberts, Karin

AU - Ehrlich, Stefan

AU - Eriksson, Johan G.

AU - Escaramís, Geòrgia

AU - Esko, Tõnu

AU - Estivill, Xavier

AU - Farmer, Anne

AU - Fernández-Aranda, Fernando

AU - Fichter, Manfred M.

AU - Föcker, Manuel

AU - Foretova, Lenka

AU - Forstner, Andreas J.

AU - Frei, Oleksandr

AU - Gallinger, Steven

AU - Giegling, Ina

AU - Giuranna, Johanna

AU - Gonidakis, Fragiskos

AU - Gorwood, Philip

AU - Gratacòs, Mònica

AU - Guillaume, Sébastien

AU - Guo, Yiran

AU - Hakonarson, Hakon

AU - Hauser, Joanna

AU - Havdahl, Alexandra

AU - Hebebrand, Johannes

AU - Helder, Sietske G.

AU - Herms, Stefan

AU - Herpertz-Dahlmann, Beate

AU - Herzog, Wolfgang

AU - Hinney, Anke

AU - Hudson, James I.

AU - Imgart, Hartmut

AU - Jamain, Stephanie

AU - Janout, Vladimir

AU - Jiménez-Murcia, Susana

AU - Jones, Ian R.

AU - Julià, Antonio

AU - Kalsi, Gursharan

AU - Kaminská, Deborah

AU - Kaprio, Jaakko

AU - Karhunen, Leila

AU - Kas, Martien JH.

AU - Keel, Pamela K.

AU - Kennedy, James L.

AU - Keski-Rahkonen, Anna

AU - Kiezebrink, Kirsty

AU - Klareskog, Lars

AU - Klump, Kelly L.

AU - Knudsen, Gun Peggy S.

AU - La Via, Maria C.

AU - Le Hellard, Stephanie

AU - Leboyer, Marion

AU - Li, Dong

AU - Lilenfeld, Lisa

AU - Lin, Bochao

AU - Lissowska, Jolanta

AU - Luykx, Jurjen

AU - Magistretti, Pierre

AU - Maj, Mario

AU - Marsal, Sara

AU - Marshall, Christian R.

AU - Mattingsdal, Morten

AU - Meulenbelt, Ingrid

AU - Micali, Nadia

AU - Mitchell, Karen S.

AU - Monteleone, Alessio Maria

AU - Monteleone, Palmiero

AU - Myers, Richard

AU - Navratilova, Marie

AU - Ntalla, Ionna

AU - O'Toole, Julie K.

AU - Ophoff, Roel A.

AU - Padyukov, Leonid

AU - Pantel, Jacques

AU - Papežová, Hana

AU - Pinto, Dalila

AU - Raevuori, Anu

AU - Ramoz, Nicolas

AU - Reichborn-Kjennerud, Ted

AU - Ricca, Valdo

AU - Ripatti, Samuli

AU - Ripke, Stephan

AU - Ritschel, Franziska

AU - Roberts, Marion

AU - Rotondo, Alessandro

AU - Rujescu, Dan

AU - Rybakowski, Filip

AU - Scherag, André

AU - Scherer, Stephen W.

AU - Schmidt, Ulrike

AU - Scott, Laura J.

AU - Seitz, Jochen

AU - Silén, Yasmina

AU - Šlachtová, Lenka

AU - Slagboom, P. Eline

AU - Slof-Op 't Landt, Margarita CT.

AU - Slopien, Agnieszka

AU - Sorbi, Sandro

AU - Świątkowska, Beata

AU - Tortorella, Alfonso

AU - Tozzi, Federica

AU - Treasure, Janet

AU - Tsitsika, Artemis

AU - Tyszkiewicz-Nwafor, Marta

AU - Tziouvas, Konstantinos

AU - van Elburg, Annemarie A.

AU - van Furth, Eric F.

AU - Walton, Esther

AU - Widen, Elisabeth

AU - Zerwas, Stephanie

AU - Zipfel, Stephan

AU - Bergen, Andrew W.

AU - Boden, Joseph M.

AU - Brandt, Harry

AU - Crawford, Steven

AU - Halmi, Katherine A.

AU - Horwood, L. John

AU - Johnson, Craig

AU - Kaplan, Allan S.

AU - Kaye, Walter H.

AU - Mitchell, James E.

AU - Olsen, Catherine M.

AU - Pearson, John F.

AU - Pedersen, Nancy L.

AU - Strober, Michael

AU - Werge, Thomas

AU - Whiteman, David C.

AU - Woodside, D Blake

AU - Gordon, Scott

AU - Maguire, Sarah

AU - Larsen, Janne T.

AU - Parker, Richard

AU - Petersen, Liselotte V.

AU - Jordan, Jennifer

AU - Kennedy, Martin

AU - Wade, Tracey D.

AU - Birgegård, Andreas

AU - Lichtenstein, Paul

AU - Landén, Mikael

AU - Martin, Nicholas G.

AU - Mortensen, Preben Bo

AU - Breen, Gerome

AU - Bulik, Cynthia M.

N1 - Acknowledgments 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 (Appendix). The Psychiatric Genomics Consortium is supported by funding from the National Institute of Mental Health (U01MH109528, U01MH109514). We are grateful to the Anorexia Nervosa Genetics Initiative (ANGI), which is an initiative of the Klarman Family Foundation. We thank the Children’s Hospital of Philadelphia (CHOP), the Price Foundation Collaborative Group (PFCG), Genetic Consortium for Anorexia Nervosa (GCAN), and the Wellcome Trust Case-Control Consortium-3 (WTCCC3). We would also like to thank the Stockholm Centre for Eating Disorders (SCÄ), the Swedish National Quality Register for Eating Disorders (Riksät), and Lifegene for their support of ANGI Sweden. We thank the QSkin Sun and Health Study for control samples. 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 (NWO 480-05-003 PI: 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.

PY - 2022/10/14

Y1 - 2022/10/14

N2 - BackgroundGenetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at 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 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at 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 (SNP-h2) were 0.01-0.04 for age at 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 at onset and early-onset AN estimated from independent GWASs significantly predicted age at 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 at onset and implicate biological pathways regulating menarche and reproduction.

AB - BackgroundGenetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at 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 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at 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 (SNP-h2) were 0.01-0.04 for age at 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 at onset and early-onset AN estimated from independent GWASs significantly predicted age at 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 at onset and implicate biological pathways regulating menarche and reproduction.

KW - age at onset

KW - anorexia nervosa

KW - early-onset

KW - genetics

KW - genetic risk score

KW - GWAS

KW - menarche

KW - Mendelian randomization

KW - puberty

U2 - 10.1016/j.bpsgos.2021.09.001

DO - 10.1016/j.bpsgos.2021.09.001

M3 - Article

SN - 2667-1743

VL - 2

SP - 368

EP - 378

JO - Biological Psychiatry Global Open Science

JF - Biological Psychiatry Global Open Science

IS - 4

ER -

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

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