OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

3rd Faculty of Medicine Charles University Prague Prague Czech Republic

AMEOS Clinical Center Hildesheim Hildesheim Germany

AMEOS Clinical Center Osnabrück Osnabrück Germany

Asklepios Specialized Hospital Göttingen Germany

ASKLEPIOS Specialized Hospital Tiefenbrunn Rosdorf Germany

Assistance Publique Hôpitaux de Paris Hôpital Albert Chenevier Henri Mondor Pôle de Psychiatrie Créteil France

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Bipolar Disorders Program Institute of Neurosciences Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Spain

Bipolar Zentrum Wiener Neustadt Austria

Black Dog Institute Prince of Wales Hospital Sydney NSW Australia

CH Ch Perrens Bordeaux France

Clinic for Psychiatry and Psychotherapy Clinical Center Werra Meißner Eschwege Germany

Departament Biologia Evolutiva Ecologia i Ciències Ambientals Facultat de Biologia Institut de Biomedicina de la Universitat de Barcelona CIBERSAM Universitat de Barcelona Barcelona Spain

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Molecular Medicine and Surgery Karolinska Institutet and The Centre for Psychiatric Research Stockholm Sweden

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Pharmacy VA San Diego Healthcare System San Diego CA USA

Department of Psychiatry 2 Ulm University Bezirkskrankenhaus Günzburg Günzburg Germany

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD USA

Department of Psychiatry and Psychotherapy Agaplesion Diakonieklinikum Rotenburg Germany

Department of Psychiatry and Psychotherapy Bezirkskrankenhaus Augsburg Augsburg Germany

Department of Psychiatry and Psychotherapy Carl Gustav Carus University Hospital Technische Universität Dresden Dresden Germany

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilians University Munich Munich Germany

Department of Psychiatry and Psychotherapy Neurophysiology and Interventional Neuropsychiatry University of Tübingen Tübingen Germany

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany

Department of Psychiatry Campania University L Vanvitelli Naples Italy

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Karolinska Institutet Stockholm Sweden

Department of Psychiatry Klinikum Bremen Ost Bremen Germany

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry Psychotherapy and Psychosomatics Clinical Center Wilhelmshaven Wilhelmshaven Germany

Department of Psychiatry Psychotherapy and Psychosomatics Medical School Brandenburg Neuruppin Germany

Department of Psychiatry Ruhr University Bochum LWL University Hospital Bochum Germany

Department of Psychiatry University of Basel Basel Switzerland

Department of Psychiatry University of California San Diego San Diego CA USA

Department of Psychiatry University of Münster Münster Germany

Department of Psychiatry University of Perugia Perugia Italy

Discipline of Psychiatry Royal Adelaide Hospital Adelaide School of Medical Schooline The University of Adelaide Adelaide SA Australia

Douglas Hospital Verdun QC Canada

Gothenburg University Sahlgrenska Academy Gothenburg Sweden

Hospital Neunkirchen Neunkirchen Germany

Human Genetics Branch Section on Genetic Basis of Mood and Anxiety Disorders National Institutes of Health Bethesda MD USA

Human Genomics Research Group Department of Biomedicine University of Basel Basel Switzerland

INSERM U955 Equipe 15 Psychiatrie Genetique Hopital Henri Mondor Creteil Cedex France

INSERM UMR S 1144 Université Paris Diderot Pôle de Psychiatrie AP HP Groupe Hospitalier Lariboisière F Widal Paris France

Institute of Human Genetics University of Bonn and Department of Genomics Life and Brain Center Bonn Germany

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

Instituto de Salud Carlos 3 Biomedical Network Research Centre on Mental Health Barcelona Spain

International Max Planck Research School for Translational Psychiatry Munich Germany

Intramural Research Program National Institute of Mental Health National Institutes of Health US Dept of Health and Human Services Bethesda MD USA

Karl Jaspers Clinic European Medical School Oldenburg Groningen Oldenburg Germany

Laboratory of Psychiatric Genetics Poznan University of Medical Sciences Poznan Poland

Lindner Center of HOPE Research Institute Mason OH USA

Max Planck Institute of Psychiatry Munich Germany

Mayo Clinic Rochester MN USA

Medical University of Graz Graz Austria

Mental Health Program IMIM CIBERSAM Barcelona Catolonia Spain

Mood Disorders Program McGill University Health Centre Montreal QC Canada

Mood Disorders Unit Department of Psychiatry HUG Geneva University Hospitals Geneva Switzerland

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney NSW Australia

Neurosciences Section Department of Medicine and Surgery University of Salerno Salerno Italy

Private Neuropathic Hospital Dr med Kurt Fontheim Liebenburg Germany

Psychiatric Hospital Lüneburg Lüneburg Germany

Psychiatry University of Iowa Iowa City IA USA

School of Medical Sciences University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales Sydney NSW Australia

Section of Psychiatry Department of Public Health Clinical and Molecular Medicine University of Cagliari Cagliari Italy

Service de Psychiatrie et Psychologie Clinique Centre Psychothérapique de Nancy Université de Lorraine Nancy France

Sigmund Freud University Vienna Austria

Stanley Center for Psychiatric Research Broad Institute Cambridge MA USA

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

Unitat d'Antropologia Universitat de Barcelona CIBERSAM Barcelona Spain

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