Genome-wide study of immune biomarkers in cerebrospinal fluid and serum from patients with bipolar disorder and controls

Abstract

Bipolar disorder is a common, chronic psychiatric disorder. Despite high heritability, there is a paucity of identified genetic risk factors. Immune biomarkers are under more direct genetic influence than bipolar disorder. To explore the genetic associations with immune biomarker levels in cerebrospinal fluid (CSF) and blood serum which previously showed differences in bipolar disorder, we performed a study involving 291 individuals (184 bipolar disorder patients and 107 controls). The biomarkers assayed in both CSF and serum were: chitinase-3-like protein-1 (YKL-40), monocyte chemoattractant protein-1 (MCP-1), soluble cluster of differentiation (sCD14), tissue inhibitor of metalloproteinases-1 and 2 (TIMP-1 and TIMP-2). C-reactive protein (CRP) was only quantified in serum, and interleukin 8 (IL-8) measures were only available in CSF. Genome-wide association studies were conducted using PLINK for each of three genotyping waves and incorporated covariates for population substructure, age, sex, and body mass index (BMI). Results were combined by meta-analysis. Genome-wide significant associations were detected for all biomarkers except TIMP-1 and TIMP-2 in CSF. The strongest association in CSF was found for markers within the CNTNAP5 gene with YKL-40 (rs150248456, P = 2.84 × 10 −10 ). The strongest association in serum was also for YKL-40 but localized to the FANCI gene (rs188263039, P = 5.80 × 10 −26 ). This study revealed numerous biologically plausible genetic associations with immune biomarkers in CSF and blood serum. Importantly, the genetic variants regulating immune biomarker levels in CSF and blood serum differ. These results extend our knowledge of how biomarkers showing alterations in bipolar disorder are genetically regulated.

Single nucleotide polymorphisms in C-reactive protein (CRP) predict response to adjunctive celecoxib treatment of resistant bipolar depression

“…The heritability of CRP expression has been documented in many studies with a variety of pathophysiologies, races and ethnic populations. It has also been reported in psychiatric disorders, notably repression ( Ancelin et al, 2015 ; Su et al, 2009 ; Zhang et al, 2020 ) . If heritability can contribute to CRP blood levels, then the CRP gene and associated SNPs should be considered.…”

Calcium imaging reveals depressive- and manic-phase-specific brain neural activity patterns in a murine model of bipolar disorder: a pilot study

“…For example, Hindley et al [ 100 ] reported that GABAergic system-related genes influence neuronal structure and function in the frontostriatal reward system; we did not examine the striatal region in the present study. Moreover, a recent BPD model revealed the involvement of cerebrospinal fluid proteins in neuronal cell–cell and cell–matrix interactions, particularly in the developing brain, and in pathways of importance for lithium’s mechanism of action [ 101 ]. These findings demonstrate the need for more exploration of the central nervous system processes implicated in BPD, and the relationship between the neurological bases of this disorder and behavioral expression [ 102 ].…”

Surrogate Cerebrospinal Fluid Biomarkers for Assessing the Efficacy of Gene Therapy in Hurler Syndrome

“…Both sCD14 and Ch3L1 are considered to be microglial markers, which coincides with our data that microglial activation has a central role in the physiopathology of MPS ( 29 , 30 ). Ch3L1 (in humans also named YKL-40) can be assumed as an almost universal marker of diseases: for neural pathologies, it has been suggested as a biomarker of multiple sclerosis ( 31 ), traumatic brain injury ( 32 ), Alzheimer's disease ( 33 ), amyotrophic lateral sclerosis ( 34 ), iatrogenic and sporadic Creutzfeldt-Jakob disease ( 35 ), or bipolar disorder ( 36 )—not to mention various pathologies in peripheral organs.…”