Differentially methylated regions in bipolar disorder and suicide

Gaine, Marie E.; Seifuddin, Fayaz; Sabunciyan, Sarven; Lee, Richard S.; Benke, Kelly S.; Monson, Eric; Zandi, Peter P.; Potash, James B.; Willour, Virginia L.

doi:10.1002/ajmg.b.32754

Cited by 20 publications

(20 citation statements)

References 78 publications

(101 reference statements)

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“…Protein analysis of the other two genes with high-impact variants, Asb14 and Arhgef38, also predicts changes in their function, yet neither ASB14 (ankyrin repeat and SOCS box containing 14) nor ARHGEF38 have been associated with any type or case of epilepsy. However, a recent study has related alterations in the methylation pattern of the Arhgef38 gene to changes in several pathways including axonal guidance signaling, calcium signaling, β-adrenergic signaling, and opioid signaling, in individuals with bipolar disorder [47].…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate-and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arh-gef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that PLOS ONE PLOS ONE | https://doi.

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Section: Discussionmentioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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“…By finding the closest DE expressed protein coding genes to DE ncRNAs between HFP and LFP chickens we were able to identify 21 putative eRNAs (Table 1). Among possible targets of these eRNA candidates are ARHGEF38 and SH3YL1, which have been linked to bipolar disorder and suicide [47,48], GLRA1 and MCTP2 were found to be associated with schizophrenia [49,50], and CHIR-B3, MHCIA7, MHCIY as well as MICA are genes involved in the immune system [51]. Thus, further experiments, like overexpression studies, will help to clarify the involvement of particular ncRNAs in FP.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the brain transcriptome in lines of laying hens divergently selected for feather pecking

et al. 2020

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Background: Feather pecking (FP) in laying hens reduces animal welfare and leads to economic losses for the layer industry. FP is considered a heritable condition that is influenced by dysregulation of neurotransmitter homeostasis, the gut microbiome, and the immune system. To identify genes and biological pathways responsible for FP behavior we compared the brain transcriptomes of 48 hens divergently selected for FP. In addition, we tested if high feather peckers (HFP) and low feather peckers (LFP) respond differently to light since light has been shown to trigger FP behavior. Results: Of approximately 48 million reads/sample an average of 98.4% were mapped to the chicken genome (GRCg6a). We found 13,070 expressed genes in the analyzed brains of which 423 showed differential expression between HFP and LFP. Genes of uncertain function and non-coding RNAs were overrepresented among those transcripts. Functional analyses revealed the involvement of cholinergic signaling, postsynaptic activity, membrane channels, and the immune system. After the light stimulus, 28 genes were found to be differentially expressed. These included an interaction cluster of core components of the circadian clock. However, differences in the response to light between HFP and LFP were not detectable. Conclusions: Genes involved in cholinergic signaling, channel activity, synaptic transmission, and immune response were found to be involved in FP behavior. We propose a model in which the gut microbiota modulates the immune system, which in turn affects cholinergic signaling. This might have an influence on monoamine signaling with possible involvement of GABA or glutamate signaling.

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“…More recently, Gaine et al, (2019) aimed at identifying aberrant DNA methylation patterns associated with bipolar disorder and suicidal behavior. They examined the genomic DNA methylation status of CpG sites in the prefrontal cortex (BA46) of 50 individuals with bipolar disorder (23 died by suicide and 27 died of other causes).…”

Section: Dna Methylation Studies In Suicide Victimsmentioning

confidence: 99%

Epigenetic studies in suicidal ideation and behavior

Dada

Qian

Al-Chalabi

et al. 2021

Psychiatric Genetics

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Most psychiatric disorders are associated with an elevated risk of suicide. Suicidal behavior is the product of the interaction of many risk factors, such as genetics and environmental factors. Hence, epigenetics research may help to understand the mechanisms leading to suicidal ideation and behavior. This review will discuss epigenetic studies in both suicidal ideation and behavior. Epigenetic modifications are likely to be important in both suicidal ideation and behavior. Most of the reviewed studies found significant epigenetic modifications linked with suicidal behavior rather than ideation. Although sizable research has been carried out on this topic, most studies have been done on small-scale samples, and future research is required in larger samples with better clinical characterization of suicide phenotypes to investigate these epigenetic modifications further.

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Differentially methylated regions in bipolar disorder and suicide

Cited by 20 publications

References 78 publications

Analysis of gene variants in the GASH/Sal model of epilepsy

Analysis of gene variants in the GASH/Sal model of epilepsy

Analysis of the brain transcriptome in lines of laying hens divergently selected for feather pecking

Epigenetic studies in suicidal ideation and behavior

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