Several lines of evidence suggest that genetic factors underlie variability in response to lithium, although pharmacogenetic studies, particularly in African populations, are limited. This study aimed Show more
Several lines of evidence suggest that genetic factors underlie variability in response to lithium, although pharmacogenetic studies, particularly in African populations, are limited. This study aimed to examine the genetic factors associated with lithium response among Ethiopian patients diagnosed with bipolar disorder (BD). This study was conducted at Amanuel Mental Specialized Hospital (AMSH) in Addis Ababa, Ethiopia, involving 101 patients diagnosed with BD and on lithium therapy for at least six months. Participants were selected from a larger cohort recruited for the Neuropsychiatric Genetics of African Populations - Psychosis, Ethiopia (NeuroGAP-P-E) project. The study investigated the association between lithium response and genetic polymorphisms of 22 genes with 53 SNPs implicated in lithium's mechanisms of action. Clinical response to lithium was assessed using the Alda scale, where those with total Aldaβ>β7 were categorized as good responders (GR) and those with Aldaβ<β7 as insufficient responders (IR). Genotyping was performed using PCR-free whole-genome sequencing. Among the participants, 32.5% were classified as GR, while 67.5% were IR. Significant associations were identified between lithium's response and specific SNPs. Notably, the BDNF rs6265 variant (Val166Met) showed stronger correlation, with the CC genotype being more frequent (pβ=β0.0001) in IR, while the rs2030324 A allele and AA genotype were more frequent in GR (pβ<β0.05). Variants in GSK-3Ξ² (rs334558) and dopamine receptor genes, such as DRD1 (rs4532) and DRD2 (rs1800497) also demonstrated significant associations with treatment outcomes (pβ<β0.05). However, after adjustment for multiple testing using false discovery rate (FDR), only polymorphisms within BDNF and DRD1 remain statistically significant. Multivariable analysis revealed that whilst AKT1_rs10138227 TT (pβ<β0.05) genotypes were positive predictors, BDNF_rs962339 GG, DRD2_rs1800497 AG/GG and GSK-3Ξ²_rs334558 AG were negative predictors of good response. The data collectively show that variants in BDNF, dopamine receptor genes, and the AKT1/GSK3B pathway were linked to lithium's response in BD. AKT1 rs10138227 TT genotypes predicted better response, while BDNF rs962339 GG, DRD2 rs1800497 AG/GG, and GSK-3Ξ² rs334558 AG were associated with poor outcomes. These findings highlight the role of genetic variations in predicting lithium's response. Show less