Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder
Authors: Amare Azmeraw T. , Oliver Schubert Klaus , Hou Liping , Clark Scott R. , Papiol Sergi , Cearns Micah , Heilbronner Urs , Degenhardt Franziska , Tekola-Ayele Fasil , Hsu Yi-Hsiang , Shekhtman Tatyana , Adli Mazda , Akula Nirmala , Akiyama Kazufumi , Ardau Raffaella , Arias Bárbara , Aubry Jean-Michel , Backlund Lena , Bhattacharjee Abesh Kumar , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Biernacka Joanna M. , Birner Armin , Brichant-Petitjean Clara , Cervantes Pablo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Cruceanu Cristiana , Czerski Piotr M. , Dalkner Nina , Dayer Alexandre , Del Zompo Maria , Raymond DePaulo J. , Étain Bruno , Falkai Peter , Forstner Andreas J. , Frisen Louise , Frye Mark A. , Fullerton Janice M. , Gard Sébastien , Garnham Julie S. , Goes Fernando S. , Grigoroiu-Serbanescu Maria , Grof Paul , Hashimoto Ryota , Hauser Joanna , Herms Stefan , Hoffmann Per , Hofmann Andrea , Jamain Stephane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kuo Po-Hsiu , Kato Tadafumi , Kelsoe John , Kittel-Schneider Sarah , Kliwicki Sebastian , König Barbara , Kusumi Ichiro , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan G. , Tortorella Alfonso , Manchia Mirko , Martinsson Lina , McCarthy Michael J. , McElroy Susan , Colom Francesc , Mitjans Marina , Mondimore Francis M. , Monteleone Palmiero , Nievergelt Caroline M. , Nöthen Markus M. , Novák Tomas , O’Donovan Claire , Ozaki Norio , Ösby Urban , Pfennig Andrea , Potash James B. , Reif Andreas ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Reininghaus Eva , Rouleau Guy A. , Rybakowski Janusz K. , Schalling Martin , Schofield Peter R. , Schweizer Barbara W. , Severino Giovanni , Shilling Paul D. , Shimoda Katzutaka , Simhandl Christian , Slaney Claire M. , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Maj Mario , Turecki Gustavo , Vieta Eduard , Veeh Julia , Witt Stephanie H. , Wright Adam , Zandi Peter P. , Mitchell Philip B. , Bauer Michael , Alda Martin , Rietschel Marcella , McMahon Francis J. , Schulze Thomas G. , Baune Bernhard T. 
Published: October 2018

Background

Lithium is a first-line medication for bipolar disorder (BD), but only ~30% of patients respond optimally to the drug. Since genetic factors are known to mediate lithium treatment response, we hypothesized whether polygenic susceptibility to the spectrum of depression traits is associated with treatment outcomes in patients with BD. In addition, we explored the potential molecular underpinnings of this relationship.

Methods

Weighted polygenic scores (PGSs) were computed for major depressive disorder (MDD) and depressive symptoms (DS) in BD patients from the Consortium on Lithium Genetics (ConLi+Gen; n=2,586) who received lithium treatment. Lithium treatment outcome was assessed using the ALDA scale. Summary statistics from genome-wide association studies (GWAS) in MDD (130,664 cases and 330,470 controls) and DS (n=161,460) were used for PGS weighting. Associations between PGSs of depression traits and lithium treatment response were assessed by binary logistic regression. We also performed a cross-trait meta-GWAS, followed by Ingenuity® Pathway Analysis.

Outcomes

BD patients with a low polygenic load for depressive traits were more likely to respond well to lithium, compared to patients with high polygenic load (MDD: OR =1.64 [95%CI: 1.26-2.15], lowest vs highest PGS quartiles; DS: OR=1.53 [95%CI: 1.18-2.00]). Associations were significant for type 1, but not type 2 BD. Cross-trait GWAS and functional characterization implicated voltage-gated potassium channels, insulin-related pathways, mitogen-activated protein-kinase (MAPK) signaling, and miRNA expression.

Interpretation

Genetic loading to depression traits in BD patients lower their odds of responding optimally to lithium. Our findings support the emerging concept of a lithium-responsive biotype in BD.

Funding

See attached details