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, 51 (8), 1207-1214

Genome-wide Association Study Identifies Eight Risk Loci and Implicates Metabo-Psychiatric Origins for Anorexia Nervosa

Hunna J Watson  1   2   3 Zeynep Yilmaz  1   4 Laura M Thornton  1 Christopher Hübel  5   6 Jonathan R I Coleman  5   7 Héléna A Gaspar  5   7 Julien Bryois  6 Anke Hinney  8 Virpi M Leppä  6 Manuel Mattheisen  9   10   11   12 Sarah E Medland  13 Stephan Ripke  14   15   16 Shuyang Yao  6 Paola Giusti-Rodríguez  4 Anorexia Nervosa Genetics InitiativeKen B Hanscombe  17 Kirstin L Purves  5 Eating Disorders Working Group of the Psychiatric Genomics ConsortiumRoger A H Adan  18   19   20 Lars Alfredsson  21 Tetsuya Ando  22 Ole A Andreassen  23 Jessica H Baker  1 Wade H Berrettini  24 Ilka Boehm  25 Claudette Boni  26 Vesna Boraska Perica  27   28 Katharina Buehren  29 Roland Burghardt  30 Matteo Cassina  31 Sven Cichon  32 Maurizio Clementi  31 Roger D Cone  33 Philippe Courtet  34 Scott Crow  35 James J Crowley  4   10 Unna N Danner  19 Oliver S P Davis  36   37 Martina de Zwaan  38 George Dedoussis  39 Daniela Degortes  40 Janiece E DeSocio  41 Danielle M Dick  42 Dimitris Dikeos  43 Christian Dina  44 Monika Dmitrzak-Weglarz  45 Elisa Docampo  46   47   48 Laramie E Duncan  49 Karin Egberts  50 Stefan Ehrlich  25 Geòrgia Escaramís  46   47   48 Tõnu Esko  51   52 Xavier Estivill  46   47   48   53 Anne Farmer  5 Angela Favaro  40 Fernando Fernández-Aranda  54   55 Manfred M Fichter  56   57 Krista Fischer  51 Manuel Föcker  8 Lenka Foretova  58 Andreas J Forstner  32   59   60   61   62 Monica Forzan  31 Christopher S Franklin  27 Steven Gallinger  63 Ina Giegling  64 Johanna Giuranna  8 Fragiskos Gonidakis  65 Philip Gorwood  26   66 Monica Gratacos Mayora  46   47   48 Sébastien Guillaume  34 Yiran Guo  67 Hakon Hakonarson  67   68 Konstantinos Hatzikotoulas  27   69 Joanna Hauser  70 Johannes Hebebrand  8 Sietske G Helder  5   71 Stefan Herms  32   60   62 Beate Herpertz-Dahlmann  29 Wolfgang Herzog  72 Laura M Huckins  27   73 James I Hudson  74 Hartmut Imgart  75 Hidetoshi Inoko  76 Vladimir Janout  77 Susana Jiménez-Murcia  54   55 Antonio Julià  78 Gursharan Kalsi  5 Deborah Kaminská  79 Jaakko Kaprio  80   81 Leila Karhunen  82 Andreas Karwautz  83 Martien J H Kas  18   84 James L Kennedy  85   86   87 Anna Keski-Rahkonen  80 Kirsty Kiezebrink  88 Youl-Ri Kim  89 Lars Klareskog  90 Kelly L Klump  91 Gun Peggy S Knudsen  92 Maria C La Via  1 Stephanie Le Hellard  93   94   95 Robert D Levitan  85   86   87 Dong Li  67 Lisa Lilenfeld  96 Bochao Danae Lin  18 Jolanta Lissowska  97 Jurjen Luykx  18 Pierre J Magistretti  98   99 Mario Maj  100 Katrin Mannik  51   101 Sara Marsal  78 Christian R Marshall  102 Morten Mattingsdal  23 Sara McDevitt  103   104 Peter McGuffin  5 Andres Metspalu  51   105 Ingrid Meulenbelt  106 Nadia Micali  107   108   109 Karen Mitchell  110 Alessio Maria Monteleone  100 Palmiero Monteleone  111 Melissa A Munn-Chernoff  1 Benedetta Nacmias  112 Marie Navratilova  58 Ioanna Ntalla  39 Julie K O'Toole  113 Roel A Ophoff  18   114 Leonid Padyukov  90 Aarno Palotie  52   81   115 Jacques Pantel  26 Hana Papezova  79 Dalila Pinto  73 Raquel Rabionet  116   117   118 Anu Raevuori  80 Nicolas Ramoz  26 Ted Reichborn-Kjennerud  92   119 Valdo Ricca  112   120 Samuli Ripatti  52   80   121 Franziska Ritschel  25   122 Marion Roberts  5   123   124 Alessandro Rotondo  125 Dan Rujescu  56   64 Filip Rybakowski  126 Paolo Santonastaso  127 André Scherag  128 Stephen W Scherer  129 Ulrike Schmidt  7   130 Nicholas J Schork  131 Alexandra Schosser  132 Jochen Seitz  29 Lenka Slachtova  133 P Eline Slagboom  106 Margarita C T Slof-Op 't Landt  134   135 Agnieszka Slopien  136 Sandro Sorbi  112   137 Beata Świątkowska  138 Jin P Szatkiewicz  4 Ioanna Tachmazidou  27 Elena Tenconi  40 Alfonso Tortorella  139   140 Federica Tozzi  141 Janet Treasure  7   130 Artemis Tsitsika  142 Marta Tyszkiewicz-Nwafor  136 Konstantinos Tziouvas  143 Annemarie A van Elburg  19   144 Eric F van Furth  134   135 Gudrun Wagner  83 Esther Walton  25 Elisabeth Widen  81 Eleftheria Zeggini  27   69 Stephanie Zerwas  1 Stephan Zipfel  145 Andrew W Bergen  146   147 Joseph M Boden  148 Harry Brandt  149 Steven Crawford  149 Katherine A Halmi  150 L John Horwood  148 Craig Johnson  151 Allan S Kaplan  85   86   87 Walter H Kaye  152 James E Mitchell  153 Catherine M Olsen  13 John F Pearson  154 Nancy L Pedersen  6 Michael Strober  155   156 Thomas Werge  157 David C Whiteman  13 D Blake Woodside  86   87   158   159 Garret D Stuber  1   160 Scott Gordon  13 Jakob Grove  9   161   162   163 Anjali K Henders  164 Anders Juréus  6 Katherine M Kirk  13 Janne T Larsen  161   165   166 Richard Parker  13 Liselotte Petersen  161   165   166 Jennifer Jordan  123   167 Martin Kennedy  168 Grant W Montgomery  13   164   169 Tracey D Wade  170 Andreas Birgegård  10   11 Paul Lichtenstein  6 Claes Norring  10   11 Mikael Landén  6   171 Nicholas G Martin  13 Preben Bo Mortensen  161   165   166 Patrick F Sullivan  1   4   6 Gerome Breen  5   7 Cynthia M Bulik  172   173   174
Affiliations

Genome-wide Association Study Identifies Eight Risk Loci and Implicates Metabo-Psychiatric Origins for Anorexia Nervosa

Hunna J Watson et al. Nat Genet.

Abstract

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Conflict of interest statement

Competing interests

The authors report the following potential competing interests. O.A.A. received a speaker’s honorarium from Lundbeck. G.B. received grant funding and consultancy fees in preclinical genetics from Eli Lilly, consultancy fees from Otsuka and has received honoraria from Illumina. C.M.B. is a grant recipient from Shire Pharmaceuticals and served on Shire Scientific Advisory Board; she receives author royalties from Pearson. D.D. served as a speaker and on advisory boards, and has received consultancy fees for participation in research from various pharmaceutical industry companies including: AstraZeneca, Boehringer, Bristol Myers Squibb, Eli Lilly, Genesis Pharma, GlaxoSmithKline, Janssen, Lundbeck, Organon, Sanofi, UniPharma, and Wyeth; he has received unrestricted grants from Lilly and AstraZeneca as director of the Sleep Research Unit of Eginition Hospital (National and Kapodistrian University of Athens, Greece). J.I.H. has received grant support from Shire and Sunovion, and has received consulting fees from DiaMentis, Shire, and Sunovion. A.S.K. is a member of the Shire Canadian BED Advisory Board and is on the steering committee for the Shire B/educated Educational Symposium: June 15-16, 2018. J.L.K. served as an unpaid member of the scientific advisory board of AssurexHealth Inc. M.L. declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as scientific consultant for EPID Research Oy. No other equity ownership, profit-sharing agreements, royalties, or patent. P.F.S. is on the Lundbeck advisory committee and is a Lundbeck grant recipient; he has served on the scientific advisory board for Pfizer, has received a consultation fee from Element Genomics, and a speaker reimbursement fee from Roche. J.T. has received an honorarium for participation in an EAP meeting and has received royalties from several books from Routledge, Wiley, and Oxford University press. T.W. has acted as a lecturer and scientific advisor to H. Lundbeck A/S. All other authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.. The Manhattan plot for the primary genome-wide association meta-analysis of anorexia nervosa with 33 case-control samples (16,992 cases and 55,525 controls of European descent).
The −log10(P) values for the association tests (two-tailed) are shown on the y-axis and the chromosomes are ordered on the x-axis. Eight genetic loci surpassed genome-wide significance (−log10(P) > 7.3). The lead variant is indicated by a diamond and green circles show the variants in linkage-disequilibrium. The blue and red colors differentiate adjacent chromosomes.
Figure. 2.
Figure. 2.. Bonferroni-significant genetic correlations (SNP-rgs) and standard errors (error bars) between anorexia nervosa and other phenotypes as estimated by LD score regression.
Only traits with significant P values following Bonferroni correction are shown. Correlations with 447 phenotypes were tested (Bonferroni-corrected significance threshold P > 1.11 × 10−4). Complete results are shown in Table S10. PGC = Psychiatric Genomics Consortium, UKB = UK Biobank, HOMA-IR = Homeostatic model assessment - insulin resistance.

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