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Prior findings from genome-wide association studies (GWAS) have highlighted different loci for the mechanistic action of lithium. This may, in part, be due to different measures of lithium response and small sample sizes. In addition, past polygenic risk score analyses were only calculated using samples from ConLi+Gen. The aim of the present study is to report a much-enlarged University College London (UCL) sample of participants with bipolar disorder taking lithium and conduct GWAS meta-analyses with other compatible European samples. 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. Then we meta-analysed our GWAS results with the summary statistics from Song et al. and Hou et al. (ConLi+Gen), the two largest sets of GWAS on the European population to date. We conducted sign tests and fitted a one-factor model using Genomic Structural equation modelling (GSEM) to investigate potential response definition heterogeneity. We estimated SNP heritability for a good lithium response, and we conducted exploratory analyses based on the GWAS meta-analysis outputs as follow-up. Finally, schizophrenia and major depressive disorder PRSs were calculated in the samples to replicate past findings. We found no evidence for lithium response definition heterogeneity. SNP rs116927879 (A/G) was associated with a good lithium response at a genome-wide level of significance (p = 4.509 × 10-8), 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. The eQTL and sQTL results suggested that rs116927879 genotypes may influence the expression and splicing of ADCY1 across different brain regions. We estimated the SNP heritability (h2) for a good lithium response as 20.3% and 15.6% for subjective/objective response definitions, respectively. We did not observe any genetic correlation or PRS association between the lithium response and schizophrenia or major depressive disorder. However, we found weak evidence to suggest that males were more likely to be good responders. We identified one SNP, rs116927879, that reached the genome-wide significance level. The genomic interval implicated by this finding included the ADCY1 (Adenylate Cyclase 1) gene and two pseudo-genes, GTF2IP13 and SEPT7P2. While the functions of GTF2IP13 and SEPT7P2 remain poorly understood, ADCY1 plays a role in mediating responses to increased cellular Ca2+/calmodulin levels, which is relevant to regulatory processes in the central nervous system, as well as memory and learning. Sleep disturbances and circadian rhythm dysfunction have been commonly noted among patients with BD. It has been suggested that the circadian modulation of contrast sensitivity is associated with Dopamine D4 Receptors (D4Rs) primarily through the ADCY1 signalling pathway. In addition, the sQTL data suggested that rs116927879 genotypes may influence the splicing of ADCY1 across different brain regions. [ABSTRACT FROM AUTHOR]

Many bipolar disorder (BD) patients are non-responsive to lithium. The mechanisms underlying lithium (non-)responsiveness are largely unknown. By using gene-set enrichment analysis methods, we found that core clock gene-sets are significantly associated with lithium response. Among the top hits was BHLHE41 , a modulator of the molecular clock and homeostatic sleep. Since BHLHE41 and its paralog BHLHE40 are functionally redundant, we assessed chronic lithium response in double-knockout mutant mice (DKO). We demonstrated that DKOs are non-responsive to lithium's effect in various behavioral tasks. Cellular assays and patch clamp recordings revealed lowered excitability and reduced lithium-response in prefrontal cortical layer 2/3 DKO neurons and on hippocampal long-term potentiation. Single-cell RNA sequencing identified that lithium deregulated mitochondrial respiration, cation channel and postsynapse associated gene-sets specifically in upper layer excitatory neurons. Our findings show that lithium acts in a highly cell-specific way on neuronal metabolism and excitability and modulates synaptic plasticity depending on BHLHE40/41.

Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10 -05 ), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)