Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients.

2021

Schubert, Klaus Oliver

Thalamuthu, Anbupalam

Amare, Azmeraw T

Frank, Joseph

Streit, Fabian

Adl, Mazda

Akula, Nirmala

Akiyama, Kazufumi

Ardau, Raffaella

Arias, Bárbara

Aubry, Jean-Michel

Heilbronner, Urs

Kahn, Jean-Pierre

Herms, Stefan

Hoffmann, Per

Hou, Liping

Hsu, Yi-Hsiang

Jamain, Stephane

Jiménez, Esther

Kassem, Layla

Kuo, Po-Hsiu

Laje, Gonzalo

Kato, Tadafumi

Kelsoe, John

Kittel-Schneider, Sarah

Ferensztajn-Rochowiak, Ewa

König, Barbara

Kusumi, Ichiro

Martinsson, Lina

Landén, Mikael

Lavebratt, Catharina

Leboyer, Marion

Leckband, Susan G

Maj, Mario

Manchia, Mirko

McCarthy, Michael J

McElroy, Susan

Novák, Tomas

Colom, Francesc

Mitjans, Marina

Mondimore, Francis M

Monteleone, Palmiero

Nievergelt, Caroline M

Nöthen, Markus M

Potash, James B

O'Donovan, Claire

Ozaki, Norio

Ösby, Urban

Papiol, Sergi

Pfennig, Andrea

Pisanu, Claudia

Reif, Andreas

Reininghaus, Eva

Shekhtman, Tatyana

Rouleau, Guy A

Rybakowski, Janusz K

Schalling, Martin

Schofield, Peter R

Schweizer, Barbara W

Severino, Giovanni

Stopkova, Pavla

Shilling, Paul D

Shimoda, Katzutaka

Simhandl, Christian

Slaney, Claire M

Squassina, Alessio

Stamm, Thomas

Tekola-Ayele, Fasil

Tortorella, Alfonso

Alda, Martin

Turecki, Gustavo

Veeh, Julia

Vieta, Eduard

Witt, Stephanie H

Roberts, Gloria

Zandi, Peter P

Backlund, Lena

Bauer, Michael

McMahon, Francis J

Mitchell, Philip B

Schulze, Thomas G

Rietschel, Marcella

Baune, Bernhard T

Bhattacharjee, Abesh Kumar

Bellivier, Frank

Cervantes, Pablo

Benabarre, Antonio

Bengesser, Susanne

Biernacka, Joanna M

Birner, Armin

Marie-Claire, Cynthia

Cearns, Micah

Chen, Hsi-Chung

Chillotti, Caterina

Cichon, Sven

Clark, Scott R

Cruceanu, Cristiana

Czerski, Piotr M

Dalkner, Nina

Dayer, Alexandre

Degenhardt, Franziska

Frye, Mark A

Del Zompo, Maria

DePaulo, J Raymond

Étain, Bruno

Falkai, Peter

Forstner, Andreas J

Frisen, Louise

Fullerton, Janice M

Gard, Sébastien

Garnham, Julie S

Goes, Fernando S

Grigoroiu-Serbanescu, Maria

Grof, Paul

Hashimoto, Ryota

Hauser, Joanna

Journal Article

0000-0002-7940-0335

0000-0003-4867-9465

0000-0003-1080-4339

0000-0001-9350-4440

0000-0003-1640-5611

0000-0002-7799-5531

0000-0003-0745-5916

0000-0001-9491-5938

0000-0002-1876-6368

0000-0001-6997-4215

0000-0003-4014-4490

0000-0002-7987-4995

0000-0002-1304-6687

0000-0002-6621-3493

0000-0001-7135-762X

0000-0002-2786-8200

0000-0003-3972-245X

0000-0002-4321-4100

0000-0002-3013-2333

0000-0002-8747-5070

0000-0002-4496-6451

0000-0003-4987-2718

0000-0001-5473-3697

0000-0001-5766-8923

0000-0002-8770-2464

0000-0002-7360-4898

0000-0001-9366-8728

0000-0002-9151-4319

0000-0002-0992-634X

0000-0001-8403-1418

0000-0003-2967-9662

0000-0002-6354-2662

0000-0002-0129-5504

0000-0002-9663-6243

0000-0001-7415-7607

0000-0002-1571-1468

0000-0001-9544-3944

0000-0002-2666-859X

0000-0002-9469-305X

0000-0002-7954-5235

0000-0001-6624-2975

10.1038/s41398-021-01702-2

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

link

Translational Psychiatry 2021; 11(1): 606

Translational psychiatry