TY - JOUR

T1 - Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

AU - Amare, Azmeraw T.

AU - Schubert, Klaus Oliver

AU - Hou, Liping

AU - Clark, Scott R.

AU - Papiol, Sergi

AU - Cearns, Micah

AU - Heilbronner, Urs

AU - Degenhardt, Franziska

AU - Tekola-Ayele, Fasil

AU - Hsu, Yi Hsiang

AU - Shekhtman, Tatyana

AU - Adli, Mazda

AU - Akula, Nirmala

AU - Akiyama, Kazufumi

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Aubry, Jean Michel

AU - Backlund, Lena

AU - Bhattacharjee, Abesh Kumar

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Biernacka, Joanna M.

AU - Birner, Armin

AU - Brichant-Petitjean, Clara

AU - Cervantes, Pablo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Dayer, Alexandre

AU - Del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Étain, Bruno

AU - Jamain, Stephane

AU - Falkai, Peter

AU - Forstner, Andreas J.

AU - Frisen, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Nordentoft, Merete

AU - Werge, Thomas

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Wray, Naomi R

AU - Ripke, Stephan

AU - Matthiesen, Manuel

AU - Agerbo, Esben

AU - Bækvad-Hansen, Marie

AU - Buttenschøn, Henriette N.

AU - Bybjerg-Grauholm, Jonas

AU - Grove, Jakob

AU - Hansen, Christine Søholm

AU - Hansen, Thomas F

AU - Hougaard, David M

AU - Krogh, Jesper

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Qvist, Per

AU - Thompson, Wesley K

AU - Wang, Yunpeng

AU - Weinsheimer, Shantel M.

AU - Mortensen, Preben Bo

AU - Christensen, Jane Varregaard

AU - Børglum, Anders D.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1038/s41380-020-0689-5

DO - 10.1038/s41380-020-0689-5

M3 - Journal article

C2 - 32203155

AN - SCOPUS:85081737215

VL - 26

SP - 2457

EP - 2470

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -