Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study
Authors: Kalman Janos L , Papiol Sergi , Forstner Andreas J , Heilbronner Urs , Degenhardt Franziska , Strohmaier Jana , Adli Mazda , Adorjan Kristina , Akula Nirmala , Alda Martin , Anderson‐Schmidt Heike , Andlauer Till FM , Anghelescu Ion‐George , Ardau Raffaella , Arias Bárbara , Arolt Volker , Aubry Jean‐Michel , Backlund Lena , Bartholdi Kim , Bauer Michael , Baune Bernhard T , Becker Thomas , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Bhattacharjee Abesh Kumar , Biernacka Joanna M , Birner Armin , Brichant‐Petitjean Clara , Budde Monika , Cervantes Pablo , Chillotti Caterina , Cichon Sven , Clark Scott R , Colom Francesc , Comes Ashley L , Cruceanu Cristiana , Czerski Piotr M , Dannlowski Udo , Dayer Alexandre , Del Zompo Maria , DePaulo Jay Raymond , Dietrich Detlef E , Étain Bruno , Ethofer Thomas , Falkai Peter , Fallgatter Andreas , Figge Christian , Flatau Laura , Folkerts Here , Frisen Louise , Frye Mark A , Fullerton Janice M , Gade Katrin , Gard Sébastien , Garnham Julie S , Goes Fernando S , Grigoroiu‐Serbanescu Maria , Gryaznova Anna , Hake Maria , Hauser Joanna , Herms Stefan , Hoffmann Per , Hou Liping , Jäger Markus , Jamain Stephane , Jiménez Esther , Juckel Georg , Kahn Jean‐Pierre , Kassem Layla , Kelsoe John , Kittel‐Schneider Sarah , Kliwicki Sebastian , Klohn‐Sagatholislam Farah , Koller Manfred , König Barbara , Konrad Carsten , Lackner Nina , Laje Gonzalo , Landén Mikael , Lang Fabian U , Lavebratt Catharina , Leboyer Marion , Leckband Susan G , Maj Mario , Manchia Mirko , Martinsson Lina , McCarthy Michael J , McElroy Susan L , McMahon Francis J , Mitchell Philip B , Mitjans Marina , Mondimore Francis M , Monteleone Palmiero , Nieratschker Vanessa , Nievergelt Caroline M , Novák Tomas , Ösby Urban , Pfennig Andrea , Potash James B , Reich‐Erkelenz Daniela , Reif Andreas , Reimer Jens , Reininghaus Eva , Reitt Markus , Ripke Stephan , Rouleau Guy A , Rybakowski Janusz K , Schalling Martin , Scherk Harald , Schmauß Max , Schofield Peter R , Schubert K Oliver , Schulte Eva C , Schulz Sybille , Senner Fanny , Severino Giovanni , Shekhtman Tatyana , Shilling Paul D , Simhandl Christian , Slaney Claire M , Spitzer Carsten , Squassina Alessio , Stamm Thomas , Stegmaier Sophia , Stierl Sebastian , Stopkova Pavla , Thiel Andreas , Tighe Sarah K , Tortorella Alfonso , Turecki Gustavo , Vieta Eduard , Veeh Julia , von Hagen Martin , Wigand Moritz E , Wiltfang Jens , Witt Stephanie , Wright Adam , Zandi Peter P , Zimmermann Jörg , Nöthen Markus , Rietschel Marcella , Schulze Thomas G 
Published: June 2018

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.