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Multicenter Study
, 21 (1), 68-75

Investigating Polygenic Burden in Age at Disease Onset in Bipolar Disorder: Findings From an International Multicentric Study

Janos L Kalman  1   2   3 Sergi Papiol  1   2   4 Andreas J Forstner  5   6   7 Urs Heilbronner  1   8 Franziska Degenhardt  5 Jana Strohmaier  9 Mazda Adli  10 Kristina Adorjan  1   2 Nirmala Akula  11 Martin Alda  12 Heike Anderson-Schmidt  1   8 Till Fm Andlauer  13 Ion-George Anghelescu  14 Raffaella Ardau  15 Bárbara Arias  16 Volker Arolt  17 Jean-Michel Aubry  18 Lena Backlund  19 Kim Bartholdi  1 Michael Bauer  20 Bernhard T Baune  21 Thomas Becker  22 Frank Bellivier  23 Antonio Benabarre  24 Susanne Bengesser  25 Abesh Kumar Bhattacharjee  26 Joanna M Biernacka  27 Armin Birner  25 Clara Brichant-Petitjean  23 Monika Budde  1 Pablo Cervantes  28 Caterina Chillotti  15 Sven Cichon  5   7 Scott R Clark  21 Francesc Colom  29 Ashley L Comes  1   3 Cristiana Cruceanu  13   28 Piotr M Czerski  30 Udo Dannlowski  17 Alexandre Dayer  18 Maria Del Zompo  31 Jay Raymond DePaulo  32 Detlef E Dietrich  33 Bruno Étain  23 Thomas Ethofer  34 Peter Falkai  2 Andreas Fallgatter  34 Christian Figge  35 Laura Flatau  1 Here Folkerts  36 Louise Frisen  19 Mark A Frye  27 Janice M Fullerton  37   38 Katrin Gade  1   8 Sébastien Gard  39 Julie S Garnham  12 Fernando S Goes  32 Maria Grigoroiu-Serbanescu  40 Anna Gryaznova  1 Maria Hake  1 Joanna Hauser  30 Stefan Herms  5   7 Per Hoffmann  5   7 Liping Hou  11 Markus Jäger  22 Stephane Jamain  41 Esther Jiménez  24 Georg Juckel  42 Jean-Pierre Kahn  43 Layla Kassem  44 John Kelsoe  26 Sarah Kittel-Schneider  45 Sebastian Kliwicki  46 Farah Klohn-Sagatholislam  1   2 Manfred Koller  47 Barbara König  48 Carsten Konrad  49 Nina Lackner  25 Gonzalo Laje  11 Mikael Landén  50   51 Fabian U Lang  22 Catharina Lavebratt  39 Marion Leboyer  41   52 Susan G Leckband  53 Mario Maj  54 Mirko Manchia  55   56 Lina Martinsson  57 Michael J McCarthy  26 Susan L McElroy  58 Francis J McMahon  11 Philip B Mitchell  59   60 Marina Mitjans  61 Francis M Mondimore  32 Palmiero Monteleone  54   62 Vanessa Nieratschker  34 Caroline M Nievergelt  26 Tomas Novák  63   64 Urban Ösby  65 Andrea Pfennig  20 James B Potash  66 Daniela Reich-Erkelenz  1 Andreas Reif  45 Jens Reimer  67 Eva Reininghaus  25 Markus Reitt  8 Stephan Ripke  10   68 Guy A Rouleau  28 Janusz K Rybakowski  46 Martin Schalling  19 Harald Scherk  69 Max Schmauß  70 Peter R Schofield  37   38 K Oliver Schubert  21 Eva C Schulte  1   2 Sybille Schulz  67 Fanny Senner  1   2 Giovanni Severino  31 Tatyana Shekhtman  26 Paul D Shilling  26 Christian Simhandl  71   72 Claire M Slaney  12 Carsten Spitzer  73 Alessio Squassina  31 Thomas Stamm  10   74 Sophia Stegmaier  34 Sebastian Stierl  75 Pavla Stopkova  63 Andreas Thiel  49 Sarah K Tighe  66 Alfonso Tortorella  76 Gustavo Turecki  77 Eduard Vieta  24 Julia Veeh  45 Martin von Hagen  78 Moritz E Wigand  22 Jens Wiltfang  8 Stephanie Witt  9 Adam Wright  59   60 Peter P Zandi  32 Jörg Zimmermann  67 Markus Nöthen  5 Marcella Rietschel  9 Thomas G Schulze  1
Multicenter Study

Investigating Polygenic Burden in Age at Disease Onset in Bipolar Disorder: Findings From an International Multicentric Study

Janos L Kalman et al. Bipolar Disord.


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.

Conflict of interest statement

The authors declare no conflict of interest. The funding agencies had no role in the design of the study; in the collection, analyses, or interpretation of data. Neither were they involved in the writing of the manuscript, or in the decision to publish the results.

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    1. Nöthen MM, Nieratschker V, Cichon S, Rietschel M. New findings in the genetics of major psychoses. Dialogues Clin Neurosci. 2010;12:85‐93. - PMC - PubMed
    1. Zheng J, Erzurumluoglu AM, Elsworth BL, et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics. 2017;33:272‐279. - PMC - PubMed
    1. Lichtenstein P, Yip BH, Björk C, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population‐based study. Lancet. 2009;373:234‐239. - PMC - PubMed
    1. Hou L, Bergen SE, Akula N, et al. Genome‐wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Hum Mol Genet. 2016;25:3383‐3394. - PMC - PubMed
    1. Leboyer M, Bellivier F, Nosten‐Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998;21:102‐105. - PubMed

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