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Bee swarm plot showing normalised gene expression values for FANCI in the married-in control ( MI ) and affected carriers of the linked haplotype (ALH) groups. FANCI expression was measured in lymphoblastoid cell lines using qRT-PCR and was normalised to the geometric mean of ATP5B , RPLP0 and UBC . * p ≤ 0.05

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Background: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an...

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... to be out- lier samples. FANCI expression was, therefore, compared between eight ALH, ten ULH and eight MIC individuals (Additional file 1: Table S1). A significant increase in FANCI expression was observed in the ALH group when compared to the MI group using a linear regression model that covaried for gender (p = 0.0423, fold change = 1.21; Fig. 2). A non-significant increase in expression was ob- served when comparing the LH and MI groups (p = 0.206, fold change ...

... However, Bromberg et al. found no differences in global methylation patterns between leukocytes from BD patients and controls (Bromberg et al., 2008). Several other studies analyzed genome-wide methylation in different post-mortem brain regions Xiao et al., 2014) and blood (Houtepen et al., 2016;Li et al., 2015;Walker et al., 2016) from BD subjects and healthy controls. Eventually, the overall clinical relevance of changes in global methylation to the neurobiology of BD needs further investigation. ...

DNA methylation is a broadly-investigated epigenetic modification that has been considered as a heritable and reversible change. Previous findings have indicated that DNA methylation regulates gene expression in the central nervous system (CNS). Also, disturbance of DNA methylation patterns has been associated with destructive consequences that lead to human brain diseases such as neuropsychiatric disorders (NPDs). In this review, we comprehensively discuss the mechanism and function of DNA methylation and its most recent associations with the pathology of NPDs- including Major depressive disorder (MDD), schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and attention/deficit hyperactivity disorder (ADHD). We also discuss how heterogeneous findings demand further investigations. Finally, based on the recent studies we conclude that DNA methylation status may have implications in clinical diagnostics and therapeutics as a potential epigenetics biomarker of NPDs.

... Several studies have examined genome-wide DNA methylation in the peripheral blood [19][20][21][22][23][24][25][26][27][28] . However, most of these studies were designed for symptomatic depression, did not validate their methylation markers by other methods such as pyrosequencing, or did not assess the accuracy using independent subjects. ...

The heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.

... Progress in understanding the etiology of BD has been hampered by phenotypic and genetic heterogeneity [5]. Epidemiological and molecular genetics data are consistent in suggesting BD as a particularly complex disorder [2], indicating that the interaction between genetic risk and the environment can result in an aberrant genetic and epigenetic profile in BD. ...

... Most of the studies have focused on the frontal cortex (FC) [50][51][52][53], prefrontal cortex (PFC) [27,54,55], and dorsolateral prefrontal cortex (DLPFC) [56], but a few reports on the anterior cingulate cortex (ACC) [50] and cerebellum [57] are also available. In addition, genome-wide methylation differences have been analyzed in peripheral tissues, as well, such as whole blood, plasma or serum, urine, saliva, sperm, skeletal muscle, and peripheral blood cells [5,34,37,, as summarized in Table 1. Several differentially methylated regions (DMRs) have been found in the peripheral tissues and fluids of BD patients. ...

Bipolar disorder (BD) is a severe, chronic, and multifactorial psychiatric disorder thought to result from an interaction between genetic susceptibility factors and environmental triggers. Part of BD's heritability might be accounted for by epigenetic mechanisms, which mainly include DNA methylation, histone modifications, chromatin remodeling, and the actions of noncoding RNAs that can modulate gene expression in response to the environment. Epigenetic modifications, described as hereditary but potentially reversible alterations, have been consistently implicated in the pathogenesis of BD, with several studies suggesting that epigenetic alterations may alter the regulation of gene expression in BD, with a great potential use both for discovering disease biomarkers and for therapeutic interventions. This chapter aims to review evidence of the potential key role of epigenetic alterations in the pathophysiology of BD.

... For instance, genome-wide methylation has been explored in a Scottish multiplex family carrying a genetic risk factor and affected by BD and major depressive disorder (MDD). The comparison of affected carriers with married-in controls and unaffected carriers identified methylation differences in the FANCI gene and neurologically relevant genes like CACNB2 (Walker et al., 2016). ...

... Lastly, miRNAs could also be markers of risk. Individuals at-risk for BD (defined as relatives of individuals with BD) had higher expression levels of miR-15b, miR-132 and miR-652 in whole-blood samples for instance (Walker et al., 2016). ...

Introduction: Bipolar disorder (BD) is a chronic, disabling disease characterised by alternate mood episodes, switching through depressive and manic/hypomanic phases. Mood stabilizers, in particular lithium salts, constitute the cornerstone of the treatment in the acute phase as well as for the prevention of recurrences. The pathophysiology of BD and the mechanisms of action of mood stabilizers remain largely unknown but several pieces of evidence point to gene x environment interactions. Epigenetics, defined as the regulation of gene expression without genetic changes, could be the molecular substrate of these interactions. In this literature review, we summarize the main epigenetic findings associated with BD and response to mood stabilizers. Methods: We searched PubMed, and Embase databases and classified the articles depending on the epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNAs). Results: We present the different epigenetic modifications associated with BD or with mood-stabilizers. The major reported mechanisms were DNA methylation, histone methylation and acetylation, and non-coding RNAs. Overall, the assessments are poorly harmonized and the results are more limited than in other psychiatric disorders (e.g. schizophrenia). However, the nature of BD and its treatment offer excellent opportunities for epigenetic research: clear impact of environmental factors, clinical variation between manic or depressive episodes resulting in possible identification of state and traits biomarkers, documented impact of mood-stabilizers on the epigenome. Conclusion: Epigenetic is a growing and promising field in BD that may shed light on its pathophysiology or be useful as biomarkers of response to mood-stabilizer.

... The product of the FANCI gene is a member of the Fanconi anaemia complementation (FANC) group 46 . Genetic variation in FANC group has previously been found to be associated with psychiatric illness 47 . When considering both cases and controls, the top SNP is located near the gene SLC39A12. ...

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.

... All genome-wide studies reported that DNA methylation was significantly associated with depression. Hypermethylations were observed in six studies on the following genes: zinc finger and BTB domain containing 20 (ZBTB20), heterochromatin protein 1-binding protein 3 (HP1BP3), tetratricopeptide repeat domain 9B (TTC9B), and glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) [19][20][21][22][23][24] . ...

There has been a limited number of systematic reviews conducted to summarize the overview of the relationship between DNA methylation and depression, and to critically appraise the roles of major study characteristics in the accuracy of study findings. This systematic review aims to critically appraise the impact of study characteristics on the association between DNA methylation and depression, and summarize the overview of this association. Electronic databases and gray literatures until December 2017 were searched for English-language studies with standard diagnostic criteria of depression. A total of 67 studies were included in this review along with a summary of their study characteristics. We grouped the findings into etiological and treatment studies. Majority of these selected studies were recently published and from developed countries. Whole blood samples were the most studied common tissues. Bisulfite conversion, along with pyrosequencing, was widely used to test the DNA methylation level across all the studies. High heterogeneity existed among the studies in terms of experimental and statistical methodologies and study designs. As recommended by the Cochrane guideline, a systematic review without meta-analysis should be undertaken. This review has, in general, found that DNA methylation modifications were associated with depression. Subgroup analyses showed that most studies found BDNF and SLC6A4 hypermethylations to be associated with MDD or depression in general. In contrast, studies on NR3C1, OXTR, and other genes, which were tested by only few studies, reported mixed findings. More longitudinal studies using standardized experimental and laboratory methodologies are needed in future studies to enable more systematical comparisons and quantitative synthesis.

... LTCCs are formed by the principal χ1 subunits with auxiliary χ2δ and cytosolic β, γ subunits [3]. The β subunit is coded by CACNB2 genes, which are distributed only in hippocampal pyramidal, thalamic, and cerebellar Purkinje cells in the brain [3,18,19]. ...

• Fang Liu
• Xiaohong Gong
• Xudong Yao
• Lingling Cui
• Fei Wang

Background Calcium voltage-gated channel auxiliary subunit β2 is a protein that, in humans, is encoded by the CACNB2 gene. The β2 subunit is an auxiliary protein of voltage-gated calcium channels, which is predominantly expressed in hippocampal pyramidal neurons. A single-nucleotide polymorphism at the CACNB2 gene (rs11013860) has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural effects of rs11013860 expression are unknown. Thus, the current study investigated the mechanisms of how the CACNB2 gene influences hippocampal-cortical limbic circuits in patients with bipolar disorder (BD). Methods A total of 202 subjects were studied [69 BD patients and 133 healthy controls (HC)]. Participants agreed to undergo resting-state functional magnetic resonance imaging (rs-fMRI) and have blood drawn for genetic testing. Participants were found to belong to either a CC group homozygous for the C-allele (17 BD, 41 HC), or an A-carrier group carrying the high risk A-allele (AA/CA genotypes; 52 BD, 92 HC). Brain activity was assessed using resting-state functional connectivity (rs-FC) analyses. Results A main effect of genotype showed that the rs-FC of the AA/CA group was elevated more than that of the CC-group between the hippocampus and the regions of right-inferior temporal, fusiform, and left-inferior occipital gyri. Additionally, a significant diagnosis × genotype interaction was noted between the hippocampus and right pars triangularis. Furthermore, in BD patients, the AA/CA group showed lower rs-FC when compared to that of the CC group. Additionally, individuals from HC within the AA/CA group showed higher rs-FC than that of the CC group. Finally, within C-allele-carrying groups, individuals with BD showed significantly increased rs-FC compared to that of HC. Conclusions Our study demonstrates that BD patients with the CACNB2 rs11013860 AA/CA genotype may exhibit altered hippocampal-cortical connectivity.

... DNA methylation is dynamic and may change in response to some external factors, especially environments and medications [25][26][27]. Environmental factors play a crucial role in the pathogenesis of mood disorders [28]. Negative life events, known to be one of the most common stressors, are very likely to contribute to the onset of MDD [29]. ...

• Peipei Wang
• Cuizhen Zhang
• Qinyu Lv
• Chenxi Bao
• Weimin Cai

Purpose: The neurotrophin brain-derived neurotrophic factor (BDNF) has been found to be associated with both the pathophysiology of depression and antidepressants response. Gene expression differences were partly mediated by SNP, which might be identified as a predictor of antidepressant response. In the present study, we attempt to identify whether DNA methylation, another factor known to affect gene transcription, might also predict antidepressant response. Methods: A total of 85 depressed Chinese Han patients were followed-up 8 weeks after initiating escitalopram treatment. Treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The bisulfate sequencing was used to assess DNA methylation. Four single nucleotide polymorphisms (SNPs) in the BDNF gene were genotyped using PCR-RFLP or PCR sequencing. Results: We identified a DNA methylation predictor (P = 0.006-0.036) and a DNA methylation by LES interaction predictor (OR = 1.442 [1.057-1.968], P = 0.021) of general antidepressant treatment response. Lower mean BDNF DNA methylation was associated with impaired antidepressant response. Furthermore, the present data indicated that age, life stress, and SNPs genotype might be likely related to DNA methylation status. Average DNA methylation of BDNF at baseline was significantly lower than that at endpoint after 8 weeks of escitalopram treatment, which was based only on a subset of cases (n = 44). Conclusions: Our results suggest that BDNF DNA hypomethylation and its interaction with lower LES score might result in impaired antidepressant treatment response. The pharmacoepigenetic study could eventually help in finding epigenetic biomarkers of antidepressant response.

... In the current study, we could not find any DMPs which were ranked in the top 1000 and were overlapped with depression-associated DMPs reported in the previous studies using blood samples and the same array technology [52][53][54][55]. However, the methylation sites located in protocadherin (PCDH) family genes were reported as highly variable methylation sites according to depression in a previous study [16] and in the current study, we also found several CpG sites with Δβ > 5% and P < 0.05 in this region (Supplementary Table 4). ...

Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.

... Major depressive disorder (MDD) is a debilitating mental illness with an estimated lifetime prevalence of 16.6% in the USA (Kessler and Wang, 2008). Previous epigenome-scale MDD studies have largely focused on peripheral tissues such as blood (Byrne et al., 2013;Malki et al., 2016;Numata et al., 2015;Oh et al., 2015;Prados et al., 2015;Walker et al., 2016aWalker et al., , 2016b, with only a few studies examining epigenome-scale profiles in the brain (Murphy et al., 2017;Oh et al., 2015;Sabunciyan et al., 2012). Given the relative dearth of brain-based epigenomic studies of MDD, we conducted an epigenome-wide association study (EWAS) of MDD in brain-derived DNA using two analytic approaches, a standard differential methylation (DM) approach and a systems biology approach, weighted gene co-methylation network analysis (WGCNA). ...

We conducted an epigenome-wide association study of Major Depressive Disorder (MDD) in brain-derived DNA using two analytic approaches. DNA methylation data (GSE41826) was used in differential methylation (DM) analyses controlling for age, sex, suicide status, and post-mortem interval; and in weighted gene co-methylation network analyses (WGCNA) in probes mapping to transcription start sites. No probes in the DM analysis survived FDR correction. Nominally significant DM probes were enriched in synaptic function-related genes. WGCNA revealed one module correlated with MDD, enriched in genes associated with mitochondrial function. DM and WGCNA both showed enrichment of genes involved in transcription and DNA binding.

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Source: https://www.researchgate.net/figure/Bee-swarm-plot-showing-normalised-gene-expression-values-for-FANCI-in-the-married-in_fig2_291518327