032_ The LiLi-Study: Lipidomics in Lithium Treatment and Response in PsyCourse
Research Question and Aims
As the most abundant compounds in the central nervous system, lipids are known to play an important yet often times disregarded role in neuronal structure and function. This role includes tasks in the regulation of membrane fluidity and permeability, vesicle formation and transport, neurotransmitter release, cell integrity and plasticity. Dysfunction of these processes has been implicated in the pathogenesis of numerous psychiatric disorders (reviewed in PMID 27054615).
There is mounting evidence that lipid species are altered both in the central nervous system and the periphery of individuals with severe psychiatric disorders such as bipolar disorder (BPD) compared to controls (PMID 30089790, own unpublished observation). While it has been shown that mood-stabilizing treatment with lithium influences plasma metabolome composition in smaller studies (PMID 27114925), no analysis of the effect of lithium treatment on the plasma lipidome in individuals with BPD has been performed although it has been demonstrated that lithium treatment alters lipid species such as free fatty acids in the cerebellum of mice (PMID 23936457). Additionally, clinically as well as in vitro, lithium treatment is associated with weight gain/cellular lipid accumulation (PMID 32134852, PMID 31676444).
Accordingly, herein, we propose to perform the first large-scale assessment of lithium-dependent plasma lipidomic profiles in all PsyCourse participants for whom plasma lipidomic profiles are available (n=310 BPD, n=234 schizophrenia (SCZ), n=266 controls). If the data permit, we also aim to assess whether lipidomic profiles differ in those who responded well vs. those who do not respond well to the treatment with lithium. The overarching aim is to identify lithium- and lithium-response-related alterations in plasma lipid profiles that could inform the underlying and as-of-yet insufficiently understood mechanisms of lithium pharmacology and treatment response.
We postulate that lithium-dependent differences in plasma lipid species and/or profiles exist. Further, lipid species could play a role in lithium response in individuals with BPD.
We will use SCID-assessed DSM-IV diagnoses as well as ALDA scale scores for phenotype definition.
Available lipidomics data have been quality controlled by the collaborating lab.
Association analyses will be performed using R software, correcting for relevant covariates.
SCZ will be used as controls with psychiatric disease, as it is known, that there is a transdiagnostic overlap in plasma lipid profiles of individuals with BPD and other severe psychiatric disorders.
Should a lithium-response profile exist, we would like to assess whether this is linked to the polygenic risk score of lithium response in analogy to studies previously published by the authors (e.g. PMID 26806518, PMID 31712617). PCA will be performed to address potential confounders.
raw medication data sets (v1_med_clin_orig, v1_med_con_orig)
raw medication data sets (v2_med_clin_orig, v2_med_con_orig)
raw medication data sets (v3_med_clin_orig, v3_med_con_orig)
raw medication data sets (v4_med_clin_orig, v4_med_con_orig)
Plasma lipidome data for PsyCourse individuals are already available to the applicant through a collaboration with the Khaitovitch Lab at Skolkovo Institute of Technology, Moscow, Russia.
Raw genotypes to calculate PCAs
Imputed genotypes for the calculation of PRS