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; Dong Li; Pierre Magistretti; Nicholas G. Martin

doi:10.1016/j.bpsgos.2021.09.001

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 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, Dong Li, Pierre Magistretti, Nicholas G. Martin

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

8 Scopus citations

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 language	English (US)
Pages (from-to)	368-378
Number of pages	11
Journal	Biological Psychiatry Global Open Science
Volume	2
Issue number	4
DOIs	https://doi.org/10.1016/j.bpsgos.2021.09.001
State	Published - Oct 2022

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2021 The Authors

Keywords

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

ASJC Scopus subject areas

Phychiatric Mental Health
Clinical Neurology
Psychiatry and Mental health
Biological Psychiatry

UN SDGs

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

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10.1016/j.bpsgos.2021.09.001

Cite this

Watson, H. J., Thornton, L. M., Yilmaz, Z., Baker, J. H., Coleman, J. R. I., Adan, R. A. H., 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., ... Martin, N. G. (2022). Common Genetic Variation and Age of Onset of Anorexia Nervosa. Biological Psychiatry Global Open Science, 2(4), 368-378. https://doi.org/10.1016/j.bpsgos.2021.09.001

@article{f04ad2dc4e264ab39fc3f57be6172427,

title = "Common Genetic Variation and Age of Onset of Anorexia Nervosa",

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.",

keywords = "Age of onset, Anorexia nervosa, Early-onset, Genetic risk score, Genetics, GWAS, Menarche, Mendelian randomization, Puberty",

author = "Watson, {Hunna J.} and Thornton, {Laura M.} and Zeynep Yilmaz and Baker, {Jessica H.} and Coleman, {Jonathan R.I.} and Adan, {Roger A.H.} 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 Dong Li and Pierre Magistretti and Martin, {Nicholas G.}",

note = "Funding Information: 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 (SC{\"A}), the Swedish National Quality Register for Eating Disorders (Riks{\"a}t), 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. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = oct,

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

language = "English (US)",

volume = "2",

pages = "368--378",

journal = "Biological Psychiatry Global Open Science",

issn = "2667-1743",

publisher = "Elsevier BV",

number = "4",

}

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, Li, D, Magistretti, P & Martin, NG 2022, 'Common Genetic Variation and Age of 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

TY - JOUR

T1 - Common Genetic Variation and Age of Onset of Anorexia Nervosa

AU - Watson, Hunna J.

AU - Thornton, Laura M.

AU - Yilmaz, Zeynep

AU - Baker, Jessica H.

AU - Coleman, Jonathan R.I.

AU - Adan, Roger A.H.

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 - Li, Dong

AU - Magistretti, Pierre

AU - Martin, Nicholas G.

N1 - Funding Information: 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. Publisher Copyright: © 2021 The Authors

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Age of onset

KW - Anorexia nervosa

KW - Early-onset

KW - Genetic risk score

KW - Genetics

KW - GWAS

KW - Menarche

KW - Mendelian randomization

KW - Puberty

UR - http://www.scopus.com/inward/record.url?scp=85129769148&partnerID=8YFLogxK

U2 - 10.1016/j.bpsgos.2021.09.001

DO - 10.1016/j.bpsgos.2021.09.001

M3 - Article

C2 - 36324647

AN - SCOPUS:85129769148

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 of Onset of Anorexia Nervosa

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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