BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Analytic and Translational Genetics Unit Massachusetts General Hospital USA; and Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard USA

Cell Biology SUNY Downstate Medical Center College of Medicine USA; and Institute for Genomic Health SUNY Downstate Medical Center College of Medicine USA

Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior University of California Los Angeles USA

Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior University of California Los Angeles USA; and Human Genetics University of California Los Angeles USA

Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior University of California Los Angeles USA; Human Genetics University of California Los Angeles USA; and Psychiatry Erasmus University Medical Center the Netherlands

Dalla Lana School of Public Health Biostatistics Division University of Toronto Canada

Department of Biochemistry and Molecular Biology Indiana University School of Medicine USA

Department of Biomedical Science Section of Neuroscience and Clinical Pharmacology University of Cagliari Italy

Department of Biomedical Science Section of Neuroscience and Clinical Pharmacology University of Cagliari Italy; and Unit of Clinical Pharmacology University Hospital Agency of Cagliari Italy

Department of Biomedicine University of Basel Switzerland; Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Germany; Institute of Medical Genetics and Pathology University Hospital Basel Switzerland; and Institute of Neuroscience and Medicine Research Centre Julich Germany

Department of Child and Adolescent Psychiatry Psychology Erasmus University Medical Centre Sophia Children's Hospital the Netherlands

Department of Clinical Neuroscience Centre for Psychiatry Research Karolinska Institutet Sweden; Department of Psychiatric Research Diakonhjemmet Hospital Norway; and NORMENT Centre Division of Mental Health and Addiction Institute of Clinical Medicine University of Oslo Norway

Department of Clinical Sciences Medical Faculty Umeå University Sweden

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

Department of Medical Genetics Oslo University Hospital Ullevål Norway; and NORMENT Department of Clinical Science University of Bergen Norway

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

Department of Neurology Klinikum rechts der Isar School of Medicine Technical University of Munich Germany

Department of Psychiatric Genetics Poznan University of Medical Sciences Poland

Department of Psychiatry and Behavioral Neuroscience University of Chicago USA; and Department of Human Genetics University of Chicago USA

Department of Psychiatry and Behavioral Sciences Emory University USA

Department of Psychiatry and Behavioral Sciences Howard University Hospital USA

Department of Psychiatry and Behavioral Sciences Johns Hopkins University USA

Department of Psychiatry and Behavioral Sciences SUNY Downstate Health Sciences University USA; and VA NY Harbor Healthcare System USA

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Sweden

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Sweden; and Department of Medical Epidemiology and Biostatistics Karolinska Institutet Sweden

Department of Psychiatry and Psychology Mayo Clinic USA

Department of Psychiatry and Psychology Mayo Clinic USA; and Department of Health Sciences Research Mayo Clinic USA

Department of Psychiatry and Psychotherapeutic Medicine Medical University Graz Austria

Department of Psychiatry and Psychotherapy Charite Universitätsmedizin Germany

Department of Psychiatry and Psychotherapy Philipps University Marburg Germany

Department of Psychiatry and Psychotherapy Philipps University Marburg Germany; and Center for Mind Brain and Behavior Germany

Department of Psychiatry and Psychotherapy University Hospital Munich Germany

Department of Psychiatry and Psychotherapy University Hospital Munich Germany; Max Planck Institute of Psychiatry Germany; and Institute of Psychiatry Psychology and Neuroscience Kings College London UK

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Germany

Department of Psychiatry and Trinity Translational Medicine Institute Trinity College Dublin Ireland

Department of Psychiatry Dalhousie University Canada

Department of Psychiatry Dalhousie University Canada; and Department of Biomedical Science Section of Neuroscience and Clinical Pharmacology University of Cagliari Italy

Department of Psychiatry Geneva University Hospitals Switzerland

Department of Psychiatry Icahn School of Medicine at Mount Sinai USA

Department of Psychiatry Icahn School of Medicine at Mount Sinai USA; and Department of Genetics and Genomics Icahn School of Medicine at Mount Sinai USA

Department of Psychiatry McGill University Canada

Department of Psychiatry McGill University Canada; and Douglas Institute McGill University Canada

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Germany

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Germany; and Department of Psychiatry Psychotherapy and Psychosomatics University Hospital Wurzburg Germany

Department of Psychiatry Rush Medical College USA

Department of Psychiatry Stony Brook University USA

Department of Psychiatry University of California San Diego USA

Department of Psychiatry University of Campania 'Luigi Vanvitelli' Italy

Department of Psychiatry University of Michigan USA

Department of Psychiatry University of Münster Germany; Department of Psychiatry Melbourne Medical School The University of Melbourne Australia; The Florey Institute of Neuroscience and Mental Health The University of Melbourne Australia; and Discipline of Psychiatry Adelaide Medical School The University of Adelaide Australia

Department of Psychiatry University of Perugia Italy

Department of Psychiatry University of Toronto Canada; The Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Canada; and Institute of Medical Science University of Toronto Canada

Department of Psychiatry University of Toronto Canada; The Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Canada; Institute of Medical Science University of Toronto Canada; Laboratory Medicine and Pathobiology University of Toronto Canada; and Harvard T H Chan School of Public Health USA

Department of Psychiatry University of Toronto Toronto Canada; and Centre for Addiction and Mental Health Toronto Canada

Department of Translational Research Max Planck Institute of Psychiatry Germany

Discipline of Psychiatry University of Adelaide Australia; and Bazil Hetzel Institute Australia

Discipline of Psychiatry University of Adelaide Australia; and Northern Adelaide Mental Health Service SA Health Australia

Division of Genetic Medicine Department of Medicine Vanderbilt Genetics Institute Vanderbilt University Medical Center USA; Department of Biomedical Informatics Vanderbilt University Medical Center USA; and Department of Psychiatry and Behavioral Sciences Vanderbilt University Medical Center USA

Division of Mental Health and Addiction Oslo University Hospital Norway; and NORMENT Centre Inst of Clinical Medicine University of Oslo Norway

Division of Psychiatric Genomics Mount Sinai School of Medicine USA

Division of Psychiatry University College London UK

Division of Psychiatry University of Edinburgh UK

Faculty of medicine University of Geneva Switzerland; and Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Germany

Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Spain

Human Genetics Branch Intramural Research Program National Institute of Mental Health USA

Institute for Genomic Health SUNY Downstate Medical Center College of Medicine USA

Institute for Translational Psychiatry Westfälische Wilhelms Universität Münster Germany

Institute for Translational Psychiatry Westfälische Wilhelms Universität Münster Germany; and Institute for Translational Neuroscience University of Münster Germany

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

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Germany; and Centre for Human Genetics University of Marburg Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Germany; and Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy University Hospital Essen University of Duisburg Essen Germany

Institute of Psychiatric Phenomics and Genomics Spain

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Germany

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Germany; and Department of Psychiatry and Psychotherapy University Hospital Munich Germany

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Germany; Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Germany; Department of Psychiatry and Psychotherapy University Medical Center Göttingen Germany; Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine USA; and Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University USA

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Germany; Department of Psychiatry and Psychotherapy University Hospital Munich Germany; and International Max Planck Research School for Translational Psychiatry Germany

International Max Planck Research School for Translational Psychiatry Germany; and Max Planck Institute of Psychiatry Germany

Max Planck Institute of Psychiatry Germany

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics Division of Psychological Medicine and Clinical Neurosciences Cardiff University UK

Mental Health Department University Regional Hospital Biomedicine Institute Spain

Montreal Neurological Institute Canada and Department of Neurology McGill University Canada

Mood Disorders Centre of Ottawa Canada; and Department of Psychiatry University of Toronto Canada

National Institute of Mental Health Czech Republic

National Institute of Mental Health Czech Republic; and Department of Psychiatry Dalhousie University Canada

Neuroscience Janssen Research and Development USA

Neuroscience Research Australia Australia; and School of Medical Sciences University of New South Wales Australia

NORMENT Centre Division of Mental Health and Addiction Institute of Clinical Medicine and Diakonhjemmet Hospital University of Oslo Norway; and Division of Mental Health and Addiction Oslo University Hospital Norway

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

NORMENT Centre Inst of Clinical Medicine University of Oslo Norway; and Division of Mental Health and Addiction Oslo University Hosptial Norway

NORMENT Division of Mental Health and Addiction Oslo University Hospital Norway

Nova Scotia Health Authority Canada

Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry and Center for Genomic Medicine Massachusetts General Hospital USA; and Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard USA

Psychiatric Clinic Alexander University Hospital Bulgaria

Psychiatry and the Behavioral Sciences University of Southern California USA

Psychiatry Indiana University School of Medicine USA

Psychiatry UMC Utrecht Brain Center the Netherlands

Psychiatry University of California San Francisco USA

Psychiatry University of Pennsylvania USA

Psychological Medicine University of Worcester UK

Research Institute Lindner Center of HOPE USA

School of Psychiatry University of New South Wales Australia

Translational Genomics USC USA

Unit of Clinical Pharmacology University Hospital Agency of Cagliari Italy

Unit of Psychiatry Department of Medical Sciences and Public Health University of Cagliari Italy and Department of Pharmacology Dalhousie University Canada

Universite de Paris France; INSERM UMRS 1144 France; and DMU Neurosciences GHU Lariboisière Fernand Widal Departement de Psychiatrie APHP France

Universite Paris Est Creteil France; and INSERM U 955 Neuropsychiatrie Translationnelle France

University of Iowa Hospitals and Clinics USA

Zobrazit více v PubMed

Cloutier M, Greene M, Guerin A, Touya M, Wu E. The economic burden of bipolar I disorder in the United States in 2015. J Affect Disord 2018; 226: 45–51. PubMed

Berk M, Dodd S, Callaly P, Berk L, Fitzgerald P, de Castella AR, et al. History of illness prior to a diagnosis of bipolar disorder or schizoaffective disorder. J Affect Disord 2007. Nov; 103: 181–6. PubMed

Dagani J, Signorini G, Nielssen O, Bani M, Pastore A, Girolamo Gd, et al. Meta-analysis of the Interval between the Onset and Management of Bipolar Disorder. Can J Psychiatry 2017; 62: 247–58. PubMed PMC

Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, et al. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study. Lancet 2016; 387: 156–67. PubMed PMC

Bergen SE, O'Dushlaine CT, Lee PH, Fanous AH, Ruderfer DM, Ripke S, et al. Genetic modifiers and subtypes in schizophrenia: Investigations of age at onset, severity, sex and family history. Schizophr Res 2014; 154: 48–53. PubMed PMC

Naj AC, Jun G, Reitz C, Kunkle BW, Perry W, Park YS, et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: A genome-wide association study. JAMA Neurol 2014; 71: 1394–404. PubMed PMC

Rhebergen D, Lamers F, Spijker J, De Graaf R, Beekman ATF, Penninx BWJH. Course trajectories of unipolar depressive disorders identified by latent class growth analysis. Psychol Med 2012; 42: 1383–96. PubMed

Howes OD, Lim S, Theologos G, Yung AR, Goodwin GM, McGuire P. A comprehensive review and model of putative prodromal features of bipolar affective disorder. Psychol Med 2011; 41: 1567–77. PubMed PMC

Wijnands JMA, Kingwell E, Zhu F, Zhao Y, Högg T, Stadnyk K, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol 2017. Jun 1; 16: 445–51. PubMed

Smoller JW, Finn CT. Family, twin, and adoption studies of bipolar disorder. Am J Med Genet Part C Semin Med Genet 2003. Nov 15; 123C: 48–58. PubMed

Rice J, Reich T, Andreasen NC, Endicott J, Van Eerdewegh M, Fishman R, et al. The familial transmission of bipolar illness. Arch Gen Psychiatry 1987; 44: 441–7. PubMed

Hafeman DM, Merranko J, Goldstein TR, Axelson D, Goldstein BI, Monk K, et al. Assessment of a person-level risk calculator to predict new-onset bipolar spectrum disorder in youth at familial risk. JAMA Psychiatry 2017. Aug 1; 74: 841. PubMed PMC

Ruderfer DM, Ripke S, McQuillin A, Boocock J, Stahl EA, Pavlides JMW, et al. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell 2018; 1737: 1705–1715.e16. PubMed PMC

Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet 2019; 51: 793–803. PubMed PMC

Coleman JRI, Gaspar HA, Bryois J, Byrne EM, Forstner AJ, Holmans PA, et al. The genetics of the mood disorder spectrum: genome-wide association analyses of more than 185,000 cases and 439,000 controls. Biol Psychiatry 2020; 88(2): 169–184. PubMed PMC

Kalman JL, Papiol S, Forstner AJ, Heilbronner U, Degenhardt F, Strohmaier J, et al. Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study. Bipolar Disord 2019. Jun 28; 21: 68–75. PubMed PMC

Aas M, Bellivier F, Bettella F, Henry C, Gard S, Kahn JP, et al. Childhood maltreatment and polygenic risk in bipolar disorders. Bipolar Disord 2020; 22: 174–81. PubMed

Belmonte Mahon P, Pirooznia M, Goes FS, Seifuddin F, Steele J, Lee PH, et al. Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2011. Apr; 156B: 370–8. PubMed PMC

Jamain S, Cichon S, Etain B, Mühleisen TW, Georgi A, Zidane N, et al. Common and rare variant analysis in early-onset bipolar disorder vulnerability. PLoS One 2014; 9: e104326. PubMed PMC

Kassem L, Lopez V, Hedeker D, Steele J, Zandi P, Bipolar Disorder Consortium NGI, et al. Familiality of polarity at illness onset in bipolar affective disorder. Am J Psychiatry 2006. Oct; 163: 1754–9. PubMed

Schulze TG, Alda M, Adli M, Akula N, Ardau R, Bui ET, et al. The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology 2010; 62: 72–8. PubMed PMC

Van Bergen AH, Verkooijen S, Vreeker A, Abramovic L, Hillegers MH, Spijker AT, et al. The characteristics of psychotic features in bipolar disorder. Psychol Med 2019. Sep 10; 49: 2036–48. PubMed

Budde M, Anderson-Schmidt H, Gade K, Reich-Erkelenz D, Adorjan K, Kalman JL, et al. A longitudinal approach to biological psychiatric research: the PsyCourse study. Am J Med Genet B Neuropsychiatr Genet 2019; 180: 89–102. PubMed PMC

Kircher T, Wöhr M, Nenadic I, Schwarting R, Schratt G, Alferink J, et al. Neurobiology of the major psychoses: a translational perspective on brain structure and function—the FOR2107 consortium. Eur Arch Psychiatry Clin Neurosci 2019; 269: 949–62. PubMed

Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M, DelBello MP, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry 2004. May 1; 55: 875–81. PubMed

Etain B, Lajnef M, Bellivier F, Mathieu F, Raust A, Cochet B, et al. Clinical expression of bipolar disorder type I as a function of age and polarity at onset: Convergent findings in samples from France and the United States. J Clin Psychiatry 2012; 73(4): e561–6. PubMed

Andlauer TFM, Buck D, Antony G, Bayas A, Bechmann L, Berthele A, et al. Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Sci Adv 2016. Jun 17; 2: e1501678. PubMed PMC

Mullins N, Forstner AJ, O'Connell KS, Coombes B, Coleman JRI, Qiao Z, et al. Genome-wide association study of over 40,000 bipolar disorder cases provides novel biological insights. medRxiv [Preprint]. 2020; Available from: https://www.medrxiv.org/content/10.1101/2020.09.17.20187054v1. PubMed PMC

Vreeker A, Boks MPM, Abramovic L, Verkooijen S, Van Bergen AH, Hillegers MHJ, et al. High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls. Psychol Med 2016. Mar 1; 46: 807–18. PubMed PMC

Post RM, Luckenbaugh DA, Leverich GS, Altshuler LL, Frye MA, Suppes T, et al. Incidence of childhood-onset bipolar illness in the USA and Europe. Br J Psychiatry 2008. Feb; 192: 150–1. PubMed

Cai N, Revez JA, Adams MJ, Andlauer TFM, Breen G, Byrne EM, et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet 2020; 52: 437–47. PubMed PMC

Manchia M, Maina G, Carpiniello B, Pinna F, Steardo L, D'Ambrosio V, et al. Clinical correlates of age at onset distribution in bipolar disorder: a comparison between diagnostic subgroups. Int J Bipolar Disord 2017. Dec 1; 5: 28. PubMed PMC

Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses