TY - JOUR
T1 - Association of polygenic score for major depression with response to lithium in patients with bipolar disorder
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
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 - Gard, Sébastien
AU - Mondimore, Francis M.
AU - Potash, James B.
AU - Goes, Fernando S.
AU - MacKinnon, Dean F.
AU - DePaulo, J. Raymond
AU - Schweizer, Barbara W.
AU - Zandi, Peter P.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/6/1
Y1 - 2021/6/1
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.
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U2 - 10.1038/s41380-020-0689-5
DO - 10.1038/s41380-020-0689-5
M3 - Article
C2 - 32203155
AN - SCOPUS:85081737215
SN - 1359-4184
VL - 26
SP - 2457
EP - 2470
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 6
ER -