2024-02-13

076_ Investigating the association of inflammatory cytokines with psychopathology, and suicidal behavior in the PsyCourse Study: Genomic and proteomic analysis

Research Question and Aims

As psychiatric immunology has evolved and new knowledge about the connection between the brain and immune system has emerged, the interaction between neuro-endocrine-immune regulatory mechanisms and brain disorders has come under intensive study (1). Over 300 cytokines are involved in controlling immunological and inflammatory responses (2). Immune-related genes variations have been associated with the risk of developing psychiatric disorders, their severity, symptoms, and response to treatment (2). Alterations in function of glial cells and type and level of cytokines in the central nervous system could be a result of neuroinflammation, which interacts with the serotonergic, dopaminergic, and glutamatergic systems and has a pathogenic role in mental illnesses by inducing damages such as neurotransmission dysregulating and exitotoxicity (1, 2).
Suicide is a major global health issue, and cause of death that results in almost over 700,000 fatalities annually. Suicidal etiology may involve inflammation, as evidenced by recent findings that all forms of suicidal behaviours are accompanied with immune-inflammatory alterations (3, 4). Since previous research has shown a causal link between inflammatory cytokines and the risk of psychiatric disorders (2), and suicidal behaviour (3-5), in this regard and based on a recently published review paper (2) that compiled the findings from recent literature on the association between variants in cytokine genes and major psychiatric disorders (schizophrenia [SCZ], bipolar disorder [BD], major depressive disorder [MDD]), we decided to investigate the associations of genetic variations as well as circulating serum levels of some of the replicated and well-known inflammatory cytokines and receptors, including IL1 (α, β, Receptor Antagonist[RN]), IL1R1, IL1R2, IL6, IL6R, IL10, IL17A, IL18, TNFα, TGFβ, and IFNγ with severity levels of disorders, and suicidal behaviour in the PsyCourse Study.
The goals of this research are to look for association of SNPs within genes of these inflammatory cytokines (in all samples of the PsyCourse Study) as well as levels of their related serum proteins (in a subsample of the PsyCourse Study) with: i) Diagnosis, ii) Cross-sectional psychopathological features and severity levels (affective versus psychotic), and iii) Suicide attempts and suicidal ideation. Additionally, we will investigate the association between the SNPs and the expression levels of the aforementioned genes in the serum of individuals of the subsample (protein quantitative trait loci [pQTLs]).

Analytic Plan

Genetic analysis will use the whole PsyCourse samples (cases and controls) genotyped applying the GSA. Among the genotypic data, we will extract the SNPs of IL1α, IL1β, IL1RN, IL1R1, IL1R2, IL6, IL6R, IL10, IL17A, IL18, TNFα, TGFβ, and IFNγ genes (±10 kb) from the whole dataset. For proteomics analysis, we will use the data from “Olink inflammation panel” (MulioBio project) as a subset of PsyCourse samples, which includes the quantification of 368 inflammatory proteins in the serum of 176 individuals (96 SCZ; 68 BD; 12 MDD). Using these data and psychopathological and phenotypic data, we look for the association of variants in these genes with different features related to severity as well as suicide attempts and suicidal ideation in a cross-sectional approach. In addition, for pQTLs analysis, we check the effect of all SNPs on circulating levels of these proteins in a subsample of 176 individuals. All the analyses will be adjusted for age, sex, educational status, BMI, population stratification, comorbidities like autoimmune disorders, and other relevant covariates in the context of linear/logistic models.

Resources needed

Demographic and physical data:
v1_sex
v1_age
v1_edu_stat
v1_bmi

Clinical data:
v1_cur_psy_trm
v1_dur_illness
v1_scid_dsm_dx_cat
v1_autoimm

Psychopathological data:
v1_panss_sum_pos
v1_panss_sum_neg
v1_panss_sum_gen
v1_ymrs_sum
v1_idsc_sum
v1_bdi2_sum
v1_asrm_sum
v1_idsc_sum
v1_mss_sum

Suicide data:
v1_age_fst_suic_att
v1_age_sec_suic_att
v1_age_thr_suic_att
v1_scid_evr_suic_ide
v1_scid_suic_ide
v1_scid_suic_thght_mth
v1_scid_suic_note_thgts
v1_suic_attmpt
v1_scid_no_suic_attmpt
v1_prep_suic_attp_ord
v1_suic_note_attmpt

Raw data on medication and drug use
210908_v5.0_psycourse_clin_raw_ill_drg_(visit1).RData
210908_v5.0_psycourse_clin_raw_med_(visit1).RData
210908_v5.0_psycourse_con_raw_ill_drg_(visit1).RData
210908_v5.0_psycourse_con_raw_med_(visit1).RData

Genomics data:
Raw genotypes (GSA chip) and imputed data from PsyCourse patients and healthy controls.

Proteomics data:
Olink inflammatory panel data from MulioBio project (O.MulioBio.PsyCourse_NPX)