Implication of the ADCY1 Gene in Lithium Response in Bipolar Disorder by Genome-wide Association Meta-analysis

Abstract Lithium is a first-line treatment option for bipolar disorder (BD). However, the response to treatment is variable, and lithium is associated with significant side-effects. Efforts to examine the influence of genetics in the efficacy of lithium using genome-wide association studies (GWAS) have identified several loci. We report data from 1259 participants with BD recruited at University College London who had been treated with lithium. The data comes from three waves of genotyping on different arrays. The GWAS data from each array was analysed separately and then meta-analysed with two published lithium response GWAS datasets. Post-GWAS analyses were conducted to examine the heritability of lithium response and genetic correlations with other traits. We also attempted to replicate past polygenic risk scores (PRS) results. SNP rs116927879 (A/G) was associated with good lithium response at a genome-wide level of significance (p = 4.509×10⁻ ⁰⁸) with a consistent effect across all cohorts. rs116927879 is located on chromosome 7 and maps to the protein coding gene ADCY1 and two pseudo-genes, GTF2IP13 and SEPT7P2. ADCY1 plays a role in the regulatory processes in the central nervous system, memory, and learning. We estimated the SNP heritability (h²) for good lithium response as 20.3% and 15.6% for subjective and objective response definitions, respectively. We did not observe any genetic correlation or PRS association between the lithium response and schizophrenia or major depression disorder. However, we found weak evidence to suggest that males were more likely to be good responders. Our GWAS identifies a genome wide significant finding, and provides updated heritability estimates for lithium efficacy, which require further examination.