. 2018 May;23(5):1169-1180.

doi: 10.1038/mp.2017.88. Epub 2017 Jul 25.

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

L M Huckins^{1

2}, K Hatzikotoulas¹, L Southam¹, L M Thornton³, J Steinberg¹, F Aguilera-McKay¹, J Treasure⁴, U Schmidt⁴, C Gunasinghe^{4

5}, A Romero^{4

5}, C Curtis^{4

5}, D Rhodes^{4

5}, J Moens^{4

5}, G Kalsi^{4

5}, D Dempster^{4

5}, R Leung^{4

5}, A Keohane^{4

5}, R Burghardt⁶, S Ehrlich^{7

8}, J Hebebrand⁹, A Hinney⁹, A Ludolph¹⁰, E Walton^{11

12}, P Deloukas¹, A Hofman¹³, A Palotie^{14

15}, P Palta¹⁵, F J A van Rooij¹³, K Stirrups¹, R Adan¹⁶, C Boni¹⁷, R Cone¹⁸, G Dedoussis¹⁹, E van Furth²⁰, F Gonidakis²¹, P Gorwood¹⁷, J Hudson²², J Kaprio¹⁵, M Kas²³, A Keski-Rahkonen²⁴, K Kiezebrink²⁵, G-P Knudsen²⁶, M C T Slof-Op 't Landt²⁰, M Maj²⁷, A M Monteleone²⁷, P Monteleone²⁸, A H Raevuori²⁴, T Reichborn-Kjennerud²⁹, F Tozzi³⁰, A Tsitsika³¹, A van Elburg³²; Eating Disorder Working Group of the Psychiatric Genomics Consortium; D A Collier³³, P F Sullivan^{34

35}, G Breen³⁶, C M Bulik^{3

35}, E Zeggini¹

Collaborators, Affiliations

Collaborators

Eating Disorder Working Group of the Psychiatric Genomics Consortium:
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 Birgegard, C Boni, V Boraska Perica, H Brandt, G Breen, 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 de 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, M C La 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 Pante, 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 van Elburg, E F van 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

Affiliations

¹ Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
² Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Psychiatry and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵ NIHR BRC SLaM BioResource for Mental Health, SGDP Centre & Centre for Neuroimaging Sciences, Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁶ Klinik für Kinder- und Jugendpsychiatrie, Psychotherapie und Psychosomatik Klinikum Frankfurt, Frankfurt, Germany.
⁷ Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁸ Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁹ Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁰ Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany.
¹¹ Division of Psychological & Social Medicine and Developmental Neurosciences, Technische Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus, Dresden, Germany.
¹² Department of Psychology, Georgia State University, Atlanta, GA, USA.
¹³ Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁴ Center for Human Genome Research at the Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Public Health & Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
¹⁶ Brain Center Rudolf Magnus, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁷ INSERM U984, Centre of Psychiatry and Neuroscience, Paris, France.
¹⁸ Mary Sue Coleman Director, Life Sciences Institute, Professor of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.
²⁰ Rivierduinen Eating Disorders Ursula, Leiden, Zuid-Holland, The Netherlands.
²¹ Eating Disorders Unit, 1st Department of Psychiatry, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
²² Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
²³ Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
²⁴ Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
²⁵ Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
²⁶ Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
²⁷ Department of Psychiatry, University of Naples SUN, Naples, Italy.
²⁸ Department of Medicine and Surgery, Section of Neurosciences, University of Salerno, Salerno, Italy.
²⁹ Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
³⁰ eHealth Lab-Computer Science Department, University of Cyprus, Nicosia, Cyprus.
³¹ Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics - Medical School, University of Athens "P. & A. Kyriakou" Children's Hospital, Athens, Greece.
³² Center for Eating Disorders Rintveld, University of Utrecht, Utrecht, The Netherlands.
³³ Eli Lilly and Company, Erl Wood Manor, Windlesham, UK.
³⁴ Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁵ Department of Medical Epidemiology and Biostatistics, Karolinksa Institutet, Stockholm, Sweden.
³⁶ Social Genetic and Developmental Psychiatry, King's College London, London, UK.

PMID: 29155802
PMCID: PMC5828108
DOI: 10.1038/mp.2017.88

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

L M Huckins et al. Mol Psychiatry. 2018 May.

. 2018 May;23(5):1169-1180.

doi: 10.1038/mp.2017.88. Epub 2017 Jul 25.

Authors

Collaborators

Eating Disorder Working Group of the Psychiatric Genomics Consortium:
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 Birgegard, C Boni, V Boraska Perica, H Brandt, G Breen, 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 de 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, M C La 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 Pante, 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 van Elburg, E F van 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

Affiliations

¹ Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
² Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Psychiatry and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵ NIHR BRC SLaM BioResource for Mental Health, SGDP Centre & Centre for Neuroimaging Sciences, Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁶ Klinik für Kinder- und Jugendpsychiatrie, Psychotherapie und Psychosomatik Klinikum Frankfurt, Frankfurt, Germany.
⁷ Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁸ Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁹ Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁰ Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany.
¹¹ Division of Psychological & Social Medicine and Developmental Neurosciences, Technische Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus, Dresden, Germany.
¹² Department of Psychology, Georgia State University, Atlanta, GA, USA.
¹³ Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁴ Center for Human Genome Research at the Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Public Health & Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
¹⁶ Brain Center Rudolf Magnus, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁷ INSERM U984, Centre of Psychiatry and Neuroscience, Paris, France.
¹⁸ Mary Sue Coleman Director, Life Sciences Institute, Professor of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.
²⁰ Rivierduinen Eating Disorders Ursula, Leiden, Zuid-Holland, The Netherlands.
²¹ Eating Disorders Unit, 1st Department of Psychiatry, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
²² Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
²³ Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
²⁴ Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
²⁵ Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
²⁶ Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
²⁷ Department of Psychiatry, University of Naples SUN, Naples, Italy.
²⁸ Department of Medicine and Surgery, Section of Neurosciences, University of Salerno, Salerno, Italy.
²⁹ Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
³⁰ eHealth Lab-Computer Science Department, University of Cyprus, Nicosia, Cyprus.
³¹ Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics - Medical School, University of Athens "P. & A. Kyriakou" Children's Hospital, Athens, Greece.
³² Center for Eating Disorders Rintveld, University of Utrecht, Utrecht, The Netherlands.
³³ Eli Lilly and Company, Erl Wood Manor, Windlesham, UK.
³⁴ Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁵ Department of Medical Epidemiology and Biostatistics, Karolinksa Institutet, Stockholm, Sweden.
³⁶ Social Genetic and Developmental Psychiatry, King's College London, London, UK.

PMID: 29155802
PMCID: PMC5828108
DOI: 10.1038/mp.2017.88

Erratum in

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.
Huckins LM, Hatzikotoulas K, Southam L, Thornton LM, Steinberg J, Aguilera-McKay F, Treasure J, Schmidt U, Gunasinghe C, Romero A, Curtis C, Rhodes D, Moens J, Kalsi G, Dempster D, Leung R, Keohane A, Burghardt R, Ehrlich S, Hebebrand J, Hinney A, Ludolph A, Walton E, Deloukas P, Hofman A, Palotie A, Palta P, van Rooij FJA, Stirrups K, Adan R, Boni C, Cone R, Dedoussis G, van Furth E, Gonidakis F, Gorwood P, Hudson J, Kaprio J, Kas M, Keski-Rahonen A, Kiezebrink K, Knudsen GP; MCT Slof-Op ’t Landt; Maj M, Monteleone AM, Monteleone P, Raevuori AH, Reichborn-Kjennerud T, Tozzi F, Tsitsika A, van Elburg A; Eating Disorder Working Group of the Psychiatric Genomics Consortium; Collier DA, Sullivan PF, Breen G, Bulik CM, Zeggini E. Huckins LM, et al. Mol Psychiatry. 2018 Sep;23(9):1969. doi: 10.1038/mp.2017.202. Mol Psychiatry. 2018. PMID: 30420737 Free PMC article.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Figure 1**
Geographical distribution of samples across Europe. (a) Distribution of cases across Europe; 375 USA cases are not shown in this diagram. (b) Distribution of controls across Europe; 873 USA controls are not shown in this diagram.

**Figure 2**
Results from discovery-phase meta-analyses. (a) Manhattan plot for meta-analyzed P-values, across all nine populations. (b) QQ plot (λ=0.94).

**Figure 3**
Odds ratios for two notable single-nucleotide polymorphisms (SNPs) across discovery and replication cohorts. (a) rs10791286 and (b) rs7700147.

See this image and copyright information in PMC

References

1. Strober M, Freeman R, Lampert C, Diamond J, Kaye W. Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J Psychiatry 2000; 157: 393–401. - PubMed
1. Strober M, Freeman R, Lampert C, Diamond J, Kaye W. Males with anorexia nervosa: a controlled study of eating disorders in first-degree relatives. Int J Eat Disord 2001; 29: 263–269. - PubMed
1. Lilenfeld LR, Kaye WH, Greeno CG, Merikangas KR, Plotnicov K, Pollice C et al. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity. Arch Gen Psychiatry 1998; 55: 603–610. - PubMed
1. Bulik CM, Slof-Op’t Landt MCT, van Furth EF, Sullivan PF. The genetics of anorexia nervosa. Annu Rev Nutr 2007; 27: 263–275. - PubMed
1. Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL. Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 2006; 63: 305–312. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources