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. 2020 Mar 16.
doi: 10.1038/s41380-020-0689-5. Online ahead of print.

Association of Polygenic Score for Major Depression With Response to Lithium in Patients With Bipolar Disorder

Azmeraw T Amare  1   2 Klaus Oliver Schubert  1   3 Liping Hou  4 Scott R Clark  1 Sergi Papiol  5   6 Micah Cearns  1 Urs Heilbronner  5   7 Franziska Degenhardt  8 Fasil Tekola-Ayele  9 Yi-Hsiang Hsu  10   11 Tatyana Shekhtman  12 Mazda Adli  13 Nirmala Akula  4 Kazufumi Akiyama  14 Raffaella Ardau  15 Bárbara Arias  16 Jean-Michel Aubry  17 Lena Backlund  18   19 Abesh Kumar Bhattacharjee  12 Frank Bellivier  20 Antonio Benabarre  21 Susanne Bengesser  22 Joanna M Biernacka  23   24 Armin Birner  22 Clara Brichant-Petitjean  20 Pablo Cervantes  25 Hsi-Chung Chen  26 Caterina Chillotti  15 Sven Cichon  8   27 Cristiana Cruceanu  28 Piotr M Czerski  29 Nina Dalkner  22 Alexandre Dayer  17 Maria Del Zompo  30 J Raymond DePaulo  31 Bruno Étain  20 Stephane Jamain  32 Peter Falkai  6 Andreas J Forstner  8   27   33 Louise Frisen  18   19 Mark A Frye  24 Janice M Fullerton  34   35 Sébastien Gard  36 Julie S Garnham  37 Fernando S Goes  31 Maria Grigoroiu-Serbanescu  38 Paul Grof  39 Ryota Hashimoto  40   41 Joanna Hauser  29 Stefan Herms  8   27 Per Hoffmann  8   27 Andrea Hofmann  8 Esther Jiménez  21 Jean-Pierre Kahn  42 Layla Kassem  4 Po-Hsiu Kuo  43 Tadafumi Kato  44 John R Kelsoe  12 Sarah Kittel-Schneider  45 Sebastian Kliwicki  46 Barbara König  47 Ichiro Kusumi  48 Gonzalo Laje  4 Mikael Landén  49   50 Catharina Lavebratt  18   19 Marion Leboyer  51 Susan G Leckband  52 Alfonso Tortorella  53 Mirko Manchia  54   55 Lina Martinsson  56 Michael J McCarthy  12   57 Susan L McElroy  58 Francesc Colom  59   60 Marina Mitjans  16   60   61 Francis M Mondimore  31 Palmiero Monteleone  62   63 Caroline M Nievergelt  12 Markus M Nöthen  8 Tomas Novák  64 Claire O'Donovan  37 Norio Ozaki  65 Urban Ösby  66 Andrea Pfennig  67 James B Potash  31 Andreas Reif  45 Major Depressive Disorder Working Group of the Psychiatric Genomics ConsortiumEva Reininghaus  22 Guy A Rouleau  68 Janusz K Rybakowski  46 Martin Schalling  18   19 Peter R Schofield  34   35 Barbara W Schweizer  31 Giovanni Severino  30 Paul D Shilling  12 Katzutaka Shimoda  69 Christian Simhandl  70 Claire M Slaney  37 Alessio Squassina  30 Thomas Stamm  13 Pavla Stopkova  64 Mario Maj  63 Gustavo Turecki  28 Eduard Vieta  21 Julia Veeh  45 Stephanie H Witt  71 Adam Wright  72 Peter P Zandi  73 Philip B Mitchell  72 Michael Bauer  67 Martin Alda  37   64 Marcella Rietschel  71 Francis J McMahon  4 Thomas G Schulze  4   5   7   31   71 Bernhard T Baune  74   75   76
Collaborators, Affiliations

Association of Polygenic Score for Major Depression With Response to Lithium in Patients With Bipolar Disorder

Azmeraw T Amare et al. Mol Psychiatry. .

Abstract

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

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