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-h 2) 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.

1st Department of Psychiatry National and Kapodistrian University of Athens Medical School Eginition Hospital Athens Greece

Adolescent Health Unit 2nd Department of Pediatrics Athens Greece

Altrecht Eating Disorders Rintveld Zeist the Netherlands

Analytic and Translational Genetics Unit Massachusetts General Hospital Boston Massachusetts

Barcelona Institute of Science and Technology Barcelona Spain

BESE Division King Abdullah University of Science and Technology Thuwal Saudi Arabia

Biological Psychiatry Laboratory McLean Hospital Harvard Medical School Boston Massachusetts

Biorealm Research Walnut California

Biostatistics and Computational Biology Unit University of Otago Christchurch New Zealand

Brain Center Rudolf Magnus Department of Translational Neuroscience University Medical Center Utrecht the Netherlands

Brain Sciences Department Stremble Ventures Limassol Cyprus

Cancer Control Group University of Queensland Brisbane Queensland Australia

Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania

Center for Neurobehavioral Genetics University of California at Los Angeles Los Angeles California

Centre for Addiction and Mental Health Toronto Ontario Canada

Centre for Human Genetics University of Marburg Marburg Germany

Centre for Integrated Register Based Research Aarhus University Aarhus Denmark

Centre for Mental Health University Health Network Toronto Ontario Canada

Centre of Excellence for Eating Disorders University Tuebingen Tuebingen Germany

Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública Barcelona Spain

Clinical Research Unit Canterbury District Health Board Christchurch New Zealand

Clinicum Department of Public Health University of Helsinki Helsinki Finland

CMME Hôpital Sainte Anne Paris France

College Behavioral and Emotional Health Institute Commonwealth University Richmond Virginia

College of Education Psychology and Social Work Flinders University Adelaide South Australia Australia

College of Nursing Seattle University Seattle Washington

David Geffen School of Medicine University of California at Los Angeles Los Angeles California

Department of Adolescent Psychiatry Helsinki University Hospital and University of Helsinki Helsinki Finland

Department of Adolescent Psychiatry University of Helsinki Helsinki Finland

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biochemistry and Molecular Biology Institute of Organic Chemistry and Biochemistry Prague Czech Republic

Department of Biomedical Data Science Leiden University Medical Centre Leiden the Netherlands

Department of Biomedicine University of Basel Basel Switzerland

Department of Biometry University of Helsinki Helsinki Finland

Department of Biostatistics University of Michigan Ann Arbor Michigan

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Cancer Epidemiology and Prevention M Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Department of Child and Adolescent Psychiatry Klinikum Frankfurt Oder Frankfurt Germany

Department of Child and Adolescent Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy RWTH Aachen University Aachen Germany

Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy University Hospital Essen University of Duisburg Essen Essen Germany

Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy University Hospital of Würzburg Centre for Mental Health Würzburg Germany

Department of Child and Adolescent Psychiatry University Hospital Münster Münster Germany

Department of Clinical Medicine Laboratory Building Haukeland University Hospital Bergen Norway

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Clinical Psychology Faculty of Social Sciences University Utrecht Utrecht the Netherlands

Department of Clinical Psychology the Chicago School of Professional Psychology Washington DC

Department of Clinical Science K G Jebsen Centre for Psychosis Research Norwegian Centre for Mental Disorders Research University of Bergen Bergen Norway

Department of Clinical Sciences School of Medicine University of Barcelona Barcelona Spain

Department of Emergency Psychiatry and Post Acute Care CHRU Montpellier University of Montpellier Montpellier France

Department of Environmental Epidemiology the Reference Center for Asbestos Exposure and Health Risk Assessment Lódź Poland

Department of General Internal Medicine and Psychosomatics Heidelberg University Hospital Heidelberg University Heidelberg Germany

Department of General Practice and Primary Health Care University of Helsinki and Helsinki University Hospital Helsinki Finland

Department of Genetics and Genome Biology and the Center for Applied Genomics the Hospital for Sick Children Toronto Ontario Canada

Department of Genetics University of North Carolina at Chapel Hill Chapel Hill North Carolina

Department of Health Science University of Florence Florence Italy

Department of Human and Molecular Genetics Commonwealth University Richmond Virginia

Department of Internal Medicine 6 Psychosomatic Medicine and Psychotherapy University Medical Hospital Tuebingen Tuebingen Germany

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Genetics University of Bergen Bergen Norway

Department of Medicine Surgery and Dentistry Scuola Medica Salernitana University of Salerno Salerno Italy

Department of Mental Disorders Norwegian Institute of Public Health Oslo Norway

Department of Neuroscience Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Nutrition and Dietetics Harokopio University Athens Greece

Department of Nutrition University of North Carolina at Chapel Hill Chapel Hill North Carolina

Department of Paediatric Laboratory Medicine the Hospital for Sick Children Toronto Ontario Canada

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pediatrics Gynaecology and Obstetrics University of Geneva Geneva Switzerland

Department of Pediatrics University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania

Department of Psychiatric Genetics Poznan University of Medical Sciences Poznan Poland

Department of Psychiatry 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Psychiatry and Behavioral Science School of Medicine and Health Sciences University of North Dakota Fargo North Dakota

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilians University Munich Germany

Department of Psychiatry Boston University Boston Massachusetts

Department of Psychiatry Center for Neurobiology and Behavior Philadelphia Pennsylvania

Department of Psychiatry Erasmus MC University Medical Center Rotterdam Rotterdam the Netherlands

Department of Psychiatry Faculty of Medicine University of Geneva Geneva Switzerland

Department of Psychiatry Leiden University Medical Centre Leiden the Netherlands

Department of Psychiatry Neurobiology Pharmacology and Biotechnologies University of Pisa Pisa Italy

Department of Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Psychiatry Psychotherapy and Psychosomatics Martin Luther University Halle Wittenberg Halle Germany

Department of Psychiatry University Hospital Bellvitge IDIBELL and CIBEROBN Barcelona Spain

Department of Psychiatry University of California San Diego San Diego California

Department of Psychiatry University of Campania Luigi Vanvitelli Naples Italy

Department of Psychiatry University of Lausanne University Hospital of Lausanne Lausanne Switzerland

Department of Psychiatry University of Minnesota Minneapolis Minnesota

Department of Psychiatry University of North Carolina at Chapel Hill Chapel Hill North Carolina

Department of Psychiatry University of Perugia Perugia Italy

Department of Psychiatry University of Toronto Toronto Ontario Canada

Department of Psychological Medicine Institute of Psychiatry Psychology and Neuroscience Social Genetic and Developmental Psychiatry Centre King's College London London United Kingdom

Department of Psychological Medicine University of Otago Christchurch New Zealand

Department of Psychology Commonwealth University Richmond Virginia

Department of Psychology Florida State University Tallahassee Florida

Department of Psychology Michigan State University Lansing Michigan

Department of Psychosomatic Medicine and Psychotherapy Hannover Medical School Hannover Germany

Department of Public Health Solutions National Institute for Health and Welfare Helsinki Finland

Department of Public Health University of Helsinki Helsinki Finland

Department of Surgery University of Toronto Toronto Ontario Canada

Division of Paediatrics School of Medicine The University of Western Australia Perth Western Australia Australia

Division of Psychiatric Genomics Department of Psychiatry and Genetics and Genomics Sciences Icahn School of Medicine at Mount Sinai New York

Division of Psychological and Social Medicine and Developmental Neurosciences Faculty of Medicine Technische Universität Dresden Dresden Germany

Division of Rheumatology Department of Medicine Karolinska Institutet Karolinska Institutet and Karolinska University Hospital Solna Sweden

Dr Einar Martens Research Group for Biological Psychiatry Center for Medical Genetics and Molecular Medicine Haukeland University Hospital Bergen Norway

Eating Disorders Research and Treatment Center Department of Child and Adolescent Psychiatry Faculty of Medicine Technische Universität Dresden Dresden Germany

Eating Disorders Unit Department of Psychiatry 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Eating Disorders Unit Parklandklinik Bad Wildungen Germany

Eating Recovery Center Denver Colorado

Estonian Genome Center Institute of Genomics University of Tartu Tartu Estonia

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Folkhälsan Research Center Helsinki Finland

Genomics and Disease Bioinformatics and Genomics Programme Centre for Genomic Regulation Barcelona Spain

GHU Paris Psychiatrie et Neurosciences CMME Paris France

Groningen Institute for Evolutionary Life Sciences University of Groningen Groningen the Netherlands

HudsonAlpha Institute for Biotechnology Huntsville Alabama

INSERM 1124 Université de Paris Paris France

INSERM 1266 Institute of Psychiatry and Neuroscience of Paris Paris France

Inserm U955 Institut Mondor de recherches Biomédicales Laboratoire Neuro Psychiatrie Translationnelle and Fédération Hospitalo Universitaire de Précision Médecine en Addictologie et Psychiatrie University Paris Est Créteil Créteil France

InsideOut Institute for Eating Disorders The Charles Perkins Centre the University of Sydney Sydney New South Wales Australia

Institute for Molecular Medicine Finland Helsinki Institute of Life Science Helsinki Finland

Institute for Molecular Medicine Finland Helsinki Institute of Life Science University of Helsinki Helsinki Finland

Institute of Applied Health Sciences School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen United Kingdom

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Medical Science University of Toronto Toronto Ontario Canada

Institute of Medical Statistics Computer and Data Sciences Jena University Hospital Friedrich Schiller University Jena Jena Germany

Institute of Neuroscience and Medicine Research Center Jülich Jülich Germany

Institute of Neuroscience and Physiology Gothenburg University Gothenburg Sweden

Institute of Psychiatry Psychology and Neuroscience Social Genetic and Developmental Psychiatry Centre King's College London London United Kingdom

Institute of Public Health and Clinical Nutrition Department of Clinical Nutrition University of Eastern Finland Kuopio Finland

IRCSS Fondazione Don Carlo Gnocchi Florence Italy

Kartini Clinic Portland Oregon

L'institut du thorax INSERM CNRS UNIV Nantes Nantes France

Life Sciences Institute and Department of Molecular and Integrative Physiology University of Michigan Ann Arbor Michigan

Lundbeck Foundation Initiative for Integrative Psychiatric Research Aarhus Denmark

McLaughlin Centre University of Toronto Toronto Ontario Canada

National Centre for Mental Health MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Cardiff United Kingdom

National Centre for Register based Research Aarhus BSS Aarhus Denmark

National Institute for Health Research Biomedical Research Centre King's College London and South London and Maudsley National Health Service Foundation Trust London United Kingdom

New York Presbyterian Hospital Westchester Division Weill Cornell Medical College of Cornell University White Plains New York

Nic Waals Institute Lovisenberg Diaconal Hospitaland Oslo Norway

NORMENT Centre Department of Clinical Science University of Oslo Oslo Norway

NORMENT Centre Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

NORMENT Centre Institute of Clinical Medicine University of Oslo Oslo Norway

Oregon Research Institute Eugene Oregon

Pathology and Biomedical Science University of Otago Christchurch New Zealand

Pediatric Intensive Care Unit P and A Kyriakou Children's Hospital University of Athens Athens Greece

Program for Eating Disorders University Health Network Toronto Ontario Canada

Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge Massachusetts

QIMR Berghofer Medical Research Institute University of Queensland Brisbane Queensland Australia

Rheumatology Research Group Vall d'Hebron Research Institute Barcelona Spain

Rivierduinen Eating Disorders Ursula Leiden the Netherlands

Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Schön Klinik Roseneck Affiliated With the Medical Faculty of the University of Munich Prien Germany

School of Psychology Curtin University Perth Western Australia Australia

Semel Institute for Neuroscience and Human Behavior University of California at Los Angeles Los Angeles California

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts

Sydney Local Health District NSW Health St Leonards New South Wales Australia

The Center for Eating Disorders at Sheppard Pratt Baltimore Maryland

Universitat Pompeu Fabra Barcelona Spain

Women's Health Sciences Division National Center for PTSD Boston Massachusetts

Zorg op Orde Delft the Netherlands

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Genome-wide association studies of binge eating behaviour and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes