Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Abstract

Background: Childhood adversity increases the risk of a range of mental disorders including bipolar disorder, but the underlying mechanisms are still unknown. Previous studies identified DNA methylation levels at the cg27512205 locus on the KIT Ligand (KITLG) gene as a mediator between childhood adversity and stress responsivity. This raises the question whether this locus also plays a role in stress related disorders such as bipolar disorder. Therefore, the current study aims to compare the level of KITLG (cg27512205) methylation between bipolar patients and healthy individuals and its relation to childhood adversity.Methods: KITLG (cg27512205) methylation was measured in 50 bipolar disorder patients and 91 healthy control participants using the HumanMethylation450K BeadChip platform. Childhood adversity in each individual was assessed using the Childhood Trauma Questionnaire. Analyses of the association of KITLG methylation with bipolar disorder, the association of childhood adversity with bipolar disorder as well as the association of KITLG methylation with childhood adversity in bipolar patients and controls were conducted using linear regression with age, gender, childhood adversity, smoking, and cell-type composition estimates as covariates.Results: KITLG (cg27512205) methylation level was significantly lower in bipolar disorder patients (β = −0.351, t = −6.316 p < 0.001). Childhood adversity levels were significantly higher in the bipolar disorder group (β = 4.903, t = 2.99, p = 0.003). In the bipolar disorder patients KITLG methylation was not associated with childhood adversity (β = 0.004, t = 1.039, p = 0.304) in contrast to the healthy controls (β = 0.012, t = 3.15, p = 0.002).Conclusions: KITLG methylation was lower in bipolar disorder despite high levels of childhood adversity, whereas childhood adversity was associated with higher KITLG methylation in healthy controls. In addition to lower methylation at this locus there is an indication that failure to adjust KITLG methylation to high levels of childhood adversity is a risk factor for bipolar disorder.

The role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder

“…These findings, however, corroborate other reports of a limited role of DNAm with non-traumatic stress (Marzi et al 2018). Noteworthy, a recent study reported hypermethylation of KITLG associated with childhood trauma in healthy controls (n = 91) but not in bipolar patients (n = 50) (He et al 2018). Although the mechanistic role of DNAm in the phenotypic expression of early life adversities is well established in the literature, other mechanisms may be responsible in adulthood and in association with subsequent events.…”

<p>The Impact of Childhood Trauma on Developing Bipolar Disorder: Current Understanding and Ensuring Continued Progress</p>

“…The latter result was in the context of a significant association between methylation of this gene and CT exposure in a group of healthy volunteers. 154 These data support the possibility that gene expression may be a mechanistically important avenue to integrate into larger scale longitudinal studies examining the contribution of CT to mental health outcomes.…”

“… 151 Other studies showed that decreased methylation in some CpG sites within the 5-hydroxytryptamine 3a receptor ( 5HT3AR ) gene mediated the association between childhood physical abuse and the number of mood episodes reported in a cohort of individuals with BD, borderline personality and attention-deficit hyperactivity disorders. 152 Others found no changes in DNA methylation in the glucocorticoid receptor 1F gene ( GR-1F ) 153 or in the KIT Ligand ( KITLG ) gene 154 in association with CT exposure in BD. The latter result was in the context of a significant association between methylation of this gene and CT exposure in a group of healthy volunteers.…”

Identification of key genes and signaling pathway in the pathogenesis of Huntington's disease via bioinformatics and next generation sequencing data analysis

“…CHRNA4 [707], RELN (reelin) [708], VEGFC (vascular endothelial growth factor C) [709], FRMPD4 [710], SCN4B [711], SLCO5A1 [712] and GPR39 [713] are involved in the development of epilepsy. RELN (reelin) [714], HTR2C [379], GABRR1 [715], RIT2 [324], DSCAM (DS cell adhesion molecule) [381], TLR2 [716], PCDH15 [331], TSPAN8 [333], LHX5 [717], MBP (myelin basic protein) [718], CUX2 [719], ACAN (aggrecan) [334], SHH (sonic hedgehog signaling molecule) [720], P2RX7 [721], CACNA2D4 [722], CDH13 [392], CSMD1 [723], NTF3 [724], GRIA4 [725], GRIA2 [725], MMP3 [726], GABRB2 [727], HLA-DRB1 [728], VWF (von Willebrand factor) [353], MDGA1 [355], LDB2 [729], NR2E1 [730], BRCA2 [362], ST8SIA2 [731], KITLG (KIT ligand) [732], GRM3 [733] and COMT (catechol-O-methyltransferase) [412] could act as diagnosis and prognosis biomarkers for bipolar disorder. However, further investigations are needed to explore and confirm the potentially significant GO terms and signaling pathways for HD and to achieve a comprehensive understanding of this process.…”