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

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.

Pharmacogenomics of Lithium Response in Bipolar Disorder

“…Comparing summary statistics from a GWAS in Major Depression (MD) (135,458 cases and 344,901 controls) to the 2586 BD patient ConLiGen sample, they determined response using the Alda scale. Using a parallel study design with the same BD sample, a later GWAS successfully replicated the association [21].…”

“…Building on findings from the previous study, Amare and colleagues (2020) assessed a connection between depression and lithium response [21]. Comparing summary statistics from a GWAS in Major Depression (MD) (135,458 cases and 344,901 controls) to the 2586 BD patient ConLiGen sample, they determined response using the Alda scale.…”

Review and Consensus on Pharmacogenomic Testing in Psychiatry

“…Three independent GWASs have identified SNPs associated with lithium response, but each study implicates a different locus [36][37][38]. Polygenic risk scores derived from schizophrenia and depression GWAS have been associated with lithium response [39,40], but none of these findings have been replicated. The immunologic genes HLA-A and HLA-B are robustly linked to rare, but potentially fatal, severe cutaneous adverse reactions (SCARs) (e. g., Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) following exposure to carbamazepine, oxcarbazepine, and phenytoin [41].…”

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

“…Genotyped subjects overlapped with clinical data from the Maritimes (n = 129; 40%), Montreal (n = 74; 23%), Ontario (n = 62; 19%), and IGSLi (n = 56; 17%), although in the ConLiGen GWAS 8 , they were all classified as from the Maritimes (Dalhousie University, Canada). It bears repeating that none of the 321 genotyped subjects in the present study came from the relatively genetically distinct Sardinian population whose clinical characteristics were evaluated in Step 1 of our study.…”

“…Responders often have a "classical phenotype" characterized by a completely episodic course with full inter-episode remissions, absence of rapid cycling and psychosis (particularly if mood-incongruent), and family history of fully remitting BD or lithium response in a first degree relative 6,7 . The familial nature of lithium responsive BD has been a particular motivator for the pursuit of strong genomic markers of lithium response, and polygenic scores for major depression and schizophrenia are inversely associated with lithium responsiveness 8,9 . However, predictors based on variation measured by single nucleotide polymorphisms (SNPs) remain elusive 10 .…”