Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study

Abstract

Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).

Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.

Design, setting, and participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.

Main outcomes and measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.

Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.

Conclusions and relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Trial registration: ClinicalTrials.gov NCT00001174.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure.. Polygenic Score (PGS) for Schizophrenia (SCZ) and Treatment Response to Lithium

A, The association of PGS for SCZ and lithium treatment response defined as a categorical and continuous scale, at different SCZ genome-wide association study (GWAS) P value thresholds. The x-axis refers to the percentage of variance in treatment response to lithium accounted for by the PGSs of SCZ at a particular P value threshold. On the y-axis, plotted from top to bottom, are the GWAS P value thresholds used to group single-nucleotide polymorphisms for PGSs. On the right of each bar are the P values of the association between the PGS for SCZ and lithium treatment response. B, Trends in the odds ratios (ORs) for favorable treatment response to lithium for patients with BPAD in the low SCZ deciles (first to ninth) compared with patients in the highest SCZ PGS decile (10th), estimated at the most significant P value thresholds (P < 5 x 10−2) (n = 2586). The open circles on the line plot indicate that the association is not statistically significant at that particular decile. ALDA indicates Retrospective Criteria of Long-term Treatment Response in Research Subjects With Bipolar Disorder.