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Bipolar Disord. 2019 Feb;21(1):68-75. doi: 10.1111/bdi.12659. Epub 2018 Jun 28.

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

Kalman JL1,2,3, Papiol S1,2,4, Forstner AJ5,6,7, Heilbronner U1,8, Degenhardt F5, Strohmaier J9, Adli M10, Adorjan K1,2, Akula N11, Alda M12, Anderson-Schmidt H1,8, Andlauer TF13, Anghelescu IG14, Ardau R15, Arias B16, Arolt V17, Aubry JM18, Backlund L19, Bartholdi K1, Bauer M20, Baune BT21, Becker T22, Bellivier F23, Benabarre A24, Bengesser S25, Bhattacharjee AK26, Biernacka JM27, Birner A25, Brichant-Petitjean C23, Budde M1, Cervantes P28, Chillotti C15, Cichon S5,7, Clark SR21, Colom F29, Comes AL1,3, Cruceanu C13,28, Czerski PM30, Dannlowski U17, Dayer A18, Del Zompo M31, DePaulo JR32, Dietrich DE33, Étain B23, Ethofer T34, Falkai P2, Fallgatter A34, Figge C35, Flatau L1, Folkerts H36, Frisen L19, Frye MA27, Fullerton JM37,38, Gade K1,8, Gard S39, Garnham JS12, Goes FS32, Grigoroiu-Serbanescu M40, Gryaznova A1, Hake M1, Hauser J30, Herms S5,7, Hoffmann P5,7, Hou L11, Jäger M22, Jamain S41, Jiménez E24, Juckel G42, Kahn JP43, Kassem L44, Kelsoe J26, Kittel-Schneider S45, Kliwicki S46, Klohn-Sagatholislam F1,2, Koller M47, König B48, Konrad C49, Lackner N25, Laje G11, Landén M50,51, Lang FU22, Lavebratt C39, Leboyer M41,52, Leckband SG53, Maj M54, Manchia M55,56, Martinsson L57, McCarthy MJ26, McElroy SL58, McMahon FJ11, Mitchell PB59,60, Mitjans M61, Mondimore FM32, Monteleone P54,62, Nieratschker V34, Nievergelt CM26, Novák T63,64, Ösby U65, Pfennig A20, Potash JB66, Reich-Erkelenz D1, Reif A45, Reimer J67, Reininghaus E25, Reitt M8, Ripke S10,68, Rouleau GA28, Rybakowski JK46, Schalling M19, Scherk H69, Schmauß M70, Schofield PR37,38, Schubert KO21, Schulte EC1,2, Schulz S67, Senner F1,2, Severino G31, Shekhtman T26, Shilling PD26, Simhandl C71,72, Slaney CM12, Spitzer C73, Squassina A31, Stamm T10,74, Stegmaier S34, Stierl S75, Stopkova P63, Thiel A49, Tighe SK66, Tortorella A76, Turecki G77, Vieta E24, Veeh J45, von Hagen M78, Wigand ME22, Wiltfang J8, Witt S9, Wright A59,60, Zandi PP32, Zimmermann J67, Nöthen M5, Rietschel M9, Schulze TG1.

Author information

1
Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
2
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
3
International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
4
Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
5
Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
6
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
7
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
8
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
9
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
10
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
11
Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Dept of Health & Human Services, Bethesda, MD, USA.
12
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
13
Max Planck Institute of Psychiatry, Munich, Germany.
14
Private Neuropathic Hospital Dr. med. Kurt Fontheim, Liebenburg, Germany.
15
Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
16
Departament Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona (IBUB), CIBERSAM, Universitat de Barcelona, Barcelona, Spain.
17
Department of Psychiatry, University of Münster, Münster, Germany.
18
Mood Disorders Unit, Department of Psychiatry, HUG - Geneva University Hospitals, Geneva, Switzerland.
19
Department of Molecular Medicine and Surgery, Karolinska Institutet and The Centre for Psychiatric Research, Stockholm, Sweden.
20
Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany.
21
Discipline of Psychiatry, Royal Adelaide Hospital, Adelaide School of Medical Schooline, The University of Adelaide, Adelaide, SA, Australia.
22
Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.
23
INSERM UMR-S 1144 - Université Paris Diderot, Pôle de Psychiatrie, AP-HP, Groupe Hospitalier Lariboisière-F. Widal, Paris, France.
24
Bipolar Disorders Program, Institute of Neurosciences, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
25
Medical University of Graz, Graz, Austria.
26
Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
27
Mayo Clinic, Rochester, MN, USA.
28
Mood Disorders Program, McGill University Health Centre, Montreal, QC, Canada.
29
Mental Health Program, IMIM (Hospital del Mar Medical Research Institute), CIBERSAM Barcelona, Catolonia, Spain.
30
Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.
31
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
32
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
33
AMEOS Clinical Center Hildesheim, Hildesheim, Germany.
34
Department of Psychiatry and Psychotherapy, Neurophysiology & Interventional Neuropsychiatry, University of Tübingen, Tübingen, Germany.
35
Karl-Jaspers Clinic, European Medical School Oldenburg-Groningen, Oldenburg, Germany.
36
Department of Psychiatry, Psychotherapy and Psychosomatics, Clinical Center Wilhelmshaven, Wilhelmshaven, Germany.
37
Neuroscience Research Australia, Sydney, NSW, Australia.
38
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
39
CH Ch Perrens, Bordeaux, France.
40
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
41
INSERM U955 Equipe 15 - Psychiatrie Genetique, Hopital Henri Mondor, Creteil, Cedex, France.
42
Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.
43
Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
44
Human Genetics Branch, Section on Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health, Bethesda, MD, USA.
45
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
46
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
47
Asklepios Specialized Hospital, Göttingen, Germany.
48
Hospital Neunkirchen, Neunkirchen, Germany.
49
Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum, Rotenburg, Germany.
50
Gothenburg University, Sahlgrenska Academy, Gothenburg, Sweden.
51
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
52
Assistance Publique-Hôpitaux de Paris, Hôpital Albert Chenevier - Henri Mondor, Pôle de Psychiatrie, Créteil, France.
53
Department of Pharmacy, VA San Diego Healthcare System, San Diego, CA, USA.
54
Department of Psychiatry, Campania University L. Vanvitelli, Naples, Italy.
55
Section of Psychiatry, Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
56
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
57
Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
58
Lindner Center of HOPE, Research Institute, Mason, OH, USA.
59
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
60
Black Dog Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
61
Unitat d'Antropologia (Dp. Biología Animal), Department of Biologia Animal, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM, Barcelona, Spain.
62
Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
63
National Institute of Mental Health, Klecany, Czech Republic.
64
Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
65
Department of Psychiatry, Karolinska Institutet, Stockholm, Sweden.
66
Psychiatry, University of Iowa, Iowa City, IA, USA.
67
Department of Psychiatry, Klinikum Bremen-Ost, Bremen, Germany.
68
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
69
AMEOS Clinical Center Osnabrück, Osnabrück, Germany.
70
Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Augsburg, Augsburg, Germany.
71
Sigmund Freud University, Vienna, Austria.
72
Bipolar Zentrum, Wiener Neustadt, Austria.
73
ASKLEPIOS Specialized Hospital Tiefenbrunn, Rosdorf, Germany.
74
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical School Brandenburg, Neuruppin, Germany.
75
Psychiatric Hospital Lüneburg, Lüneburg, Germany.
76
Department of Psychiatry, University of Perugia, Perugia, Italy.
77
Douglas Hospital, Verdun, QC, Canada.
78
Clinic for Psychiatry and Psychotherapy, Clinical Center Werra-Meißner, Eschwege, Germany.

Abstract

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.

KEYWORDS:

age at onset; bipolar disorder; early onset; polygenic risk score; schizophrenia

PMID:
29956436
DOI:
10.1111/bdi.12659

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