DNA methylation analyses of the candidate genes identified by a methylome‐wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder

Sugawara, Hiroko; Murata, Y.; Ikegame, Tempei; Sawamura, Rie; Shimanaga, Shota; Takeoka, Yusuke; Takeo, Satoshi; Ikeda, Masashi; Yoshikawa, Akane; Nishimura, Fumichika; Kawamura, Yoshiya; Kakiuchi, Chihiro; Sasaki, Tsukasa; Iwata, Nakao; Hashimoto, Mamoru; Kasai, Kiyoto; Kato, Takeshi; Bundo, Miki; Iwamoto, Kazuya

doi:10.1111/pcn.12645

Cited by 30 publications

(21 citation statements)

References 43 publications

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“…DNA methylation can be either assessed over the entire genome (whole‐genome methylation profiling) as explained in an overview by Rakyan et al or by candidate studies designed to search specifically for DMRs or CpGs in specific genes or regions in the DNA . Three techniques are currently available for detection of methylation status at DMRs or CpGs: bisulphite sequencing, microarrays or bead chips and methyl‐sensitive cut counting (MSCC) …”

Section: Introductionmentioning

confidence: 99%

“…14 DNA methylation can be either assessed over the entire genome (whole-genome methylation profiling) as explained in an overview by Rakyan et al 17 or by candidate studies designed to search specifically for DMRs or CpGs in specific genes or regions in the DNA. 18 Three techniques are currently available for detection of methylation status at DMRs or CpGs: bisulphite sequencing, microarrays or bead chips and methyl-sensitive cut counting (MSCC). 19 Bisulphite sequencing exploits the current inability of DNA sequencing techniques to differentiate between methylcytosine and cytosine due to similar base pairing characteristics between both molecules.…”

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confidence: 99%

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Epigenome‐wide association studies in asthma: A systematic review

Edris

Dekker

Melén

et al. 2019

Clin Experimental Allergy

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Objective Asthma is a common chronic respiratory airway disease influenced by environmental factors and possibly their interaction with the human genome causing epigenetic changes. Epigenome‐wide association studies (EWAS) have mainly investigated DNA methylation and its association with disease or traits, exposure factors or gene expression. This systematic review aimed to identify all EWAS assessing differentially methylated sites associated with asthma in humans. Design Structured systematic literature search following PRISMA guidelines, Newcastle‐Ottawa Scale (NOS) for cohort studies was used for bias assessment. Data Sources We searched PubMed and Embase databases from 2005 to 2019. Eligibility Criteria Epigenome‐wide association studies testing association between differential methylation and asthma in humans. Results Overall, we identified 16 EWAS studies complying with our search criteria. Twelve studies were conducted on children, and 10 were conducted on sample sizes <150 subjects. Four hundred and nineteen CpGs were reported in children studies after correction for multiple testing. In the adult studies, thousands of differentially methylated sites were identified. Differential methylation in inflammatory‐related genes correlated with higher levels of gene expressions of inflammatory modulators in asthma. Differentially methylated genes associated with asthma included SMAD3, SERPINC1, PROK1, IL13, RUNX3 and TIGIT. Forty‐one CpGs were replicated at least once in blood samples, and 28 CpGs were replicated in nasal samples. Conclusion Although many differentially methylated CpGs in genes known to be involved in asthma have been identified in EWAS to date, we conclude that further studies of larger sample sizes and analyses of differential methylation between different phenotypes are needed in order to comprehensively evaluate the role of epigenetic factors in the pathophysiology and heterogeneity of asthma, and the potential clinical utility to predict or classify patients with asthma.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Epigenome‐wide association studies in asthma: A systematic review

Edris

Dekker

Melén

et al. 2019

Clin Experimental Allergy

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“…FAM63B (Mindy‐2) is a deubiquitinating enzyme found in the cerebellum and in the pineal body . Epigenetic alterations to FAM63B have been associated with schizophrenia and bipolar disorder …”

Section: Discussionmentioning

confidence: 99%

“…48 Epigenetic alterations to FAM63B have been associated with schizophrenia and bipolar disorder. 49,50 Methodological differences between the two autoantibody assays must be considered as explanations to why the herein identified candidate antigens could not be verified, including differences in protein folding, post-translational modification and immobilization of the antigen. These aspects are also relevant to a broader discussion on the difficulties in confirming suggested candidate autoantigens in NT1.…”

Section: Discussionmentioning

confidence: 99%

Screening for autoantibody targets in post‐vaccination narcolepsy using proteome arrays

et al. 2020

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Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin‐producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®‐vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two‐step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®‐vaccination. Using arrays of more than 9000 full‐length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first‐degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α‐MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®‐induced NT1.

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“…DNA methylation involves the addition of a methylgroup to the carbon-5 position of a cytosine residue (Razin and Cedar, 1991): this may be associated with increased or decreased gene expression depending on the genomic region in which it occurs (Jones, 2012;Watkeys et al, 2018). Both candidate-and genome-wide studies have revealed differential methylation of various sites in SZ (Hannon et al, 2016;Montano et al, 2016;Ruzicka et al, 2015;Yoshino et al, 2016), with some studies suggesting overlapping patterns of DNA methylation in BD (Dempster et al, 2011;Sugawara Poly-methylomic Profile Scores for schizophrenia et al, 2018), although there have been few replications at individual CpG sites (Pries et al, 2017;Teroganova et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Derivation of Poly-Methylomic Profile Scores for Schizophrenia

Watkeys

Cohen‐Woods

Quidé

et al. 2019

Preprint

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Schizophrenia (SZ) and bipolar disorder (BD) share numerous clinical and biological features as well as environmental risk factors that may be associated with altered DNA methylation.In this study we sought to construct a Poly-Methylomic Profile Score (PMPS) for SZ, representing the degree of epigenome-wide methylation according to previously published findings; we then examined its association with SZ and BD in an independent sample. DNA methylation for 57 SZ, 59 BD cases and 55 healthy controls (HCs) was quantified using the Illumina 450K methylation beadchip. We constructed five PMPSs for different p-value thresholds using summary statistics reported in a large epigenome-wide schizophrenia casecontrol association study, weighted by individual CpG effect sizes. All SZ PMPSs were significantly elevated in SZ cases relative to HCs, with the score calculated at the most stringent threshold accounting for the greatest amount of variance in SZ (compared to other PMPSs derived at more inclusive p-value thresholds). However, none of the PMPSs were associated with BD, or a combined cohort of BD and SZ cases relative to HCs. Results demonstrating elevated PMPSs in SZ relative to BD did not survive correction for multiple testing. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated among SZ, but not BD participants, suggests that epigenome-wide methylation patterns associated with schizophrenia may represent distinct pathophysiology that is yet to be elucidated. Whether this PMPS may be associated with neuroanatomical or other biological endophenotypes relevant to SZ and/or BD remains to be determined.Poly-methylomic Profile Scores for schizophrenia

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DNA methylation analyses of the candidate genes identified by a methylome‐wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder

Abstract: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.

Cited by 30 publications

References 43 publications

Epigenome‐wide association studies in asthma: A systematic review

Epigenome‐wide association studies in asthma: A systematic review

Screening for autoantibody targets in post‐vaccination narcolepsy using proteome arrays

Derivation of Poly-Methylomic Profile Scores for Schizophrenia

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