2020-05-15
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individuals with severe psychiatric disorders such as bipolar disorder (BPD) compared to controls (PMID 30089790, own unpublished observation).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.
Analytic Plan
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.
Resources needed
v1_age
v1_yob
v1_sex
v1_center
v1_cur_psy_trm
v1_age_1st_out_trm
v1_age_1st_inpat_trm
v1_dur_illness
raw medication data sets (v1_med_clin_orig, v1_med_con_orig)
v1_fam_hist
v1_lith
v1_lith_prd
v1_waist
v1_bmi
v1_weight
v1_height
v1_chol_trig
v1_hyperten
v1_ang_pec
v1_heart_att
v1_stroke
v1_diabetes
v1_scid_dsm_dx
v1_scid_dsm_dx_cat
v1_scid_age_MDE
v1_scid_no_MDE
v1_scid_age_mania
v1_scid_no_mania
v1_scid_age_hypomania
v1_scid_no_hypomania
v1_med_pst_wk
v1_med_pst_sx_mths
v1_ever_smkd
v1_age_smk
v2_age
v2_waist
v2_bmi
v2_weight
v2_lith
v2_lith_prd
raw medication data sets (v2_med_clin_orig, v2_med_con_orig)
v2_smk_strt_stp
v2_med_pst_wk
v2_med_pst_sx_mths
v3_age
v3_waist
v3_bmi
v3_weight
v3_lith
v3_lith_prd
raw medication data sets (v3_med_clin_orig, v3_med_con_orig)
v3_smk_strt_stp
v3_med_pst_wk
v3_med_pst_sx_mths
v4_age
v4_waist
v4_bmi
v4_weight
v4_lith
v4_lith_prd
raw medication data sets (v4_med_clin_orig, v4_med_con_orig)
v4_smk_strt_stp
v4_med_pst_wk
v4_med_pst_sx_mths
v4_alda_A
v4_alda_B1
v4_alda_B2
v4_alda_B3
v4_alda_B4
v4_alda_B5
gwas_id
v1_lip_id
v2_lip_id
v3_lip_id
v4_lip_id
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.
Genetic data:
Raw genotypes to calculate PCAs
Imputed genotypes for the calculation of PRS