Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation

Thygesen, Johan Hilge; Zambach, Sine; Ingason, Andrés; Lundin, Per; Hansen, Thomas Folkmann; Bertalan, Marcelo; Rosengren, Anders; Bjerre, Ditte; Ferrero-Miliani, Laura; Rasmussen, Henrik Berg; Parnas, Josef; Werge, Thomas

doi:10.1016/j.schres.2015.08.037

Cited by 12 publications

(5 citation statements)

References 55 publications

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“…13b ). In line with this hypothesis, HDAC4/SynGAP1 and MEF2A are associated with ASD 32 and schizophrenia 69 , respectively, and HDAC4 modulation shows promise in treating neurodegenerative disorders 70 . However, it should be noted that ARID1B-related pathologies may be associated with larger transcriptional changes surrounding HDAC4/MEF2A because HDAC4 acts on many other nuclear/cytoplasmic proteins (in addition to MEF2A) 70 , 71 , and MEF2A-dependent suppression of excitatory synapses involves multiple upstream regulators (in addition to NMDA receptors) and downstream targets (in addition to SynGAP1 and Arc) 52 , 72 .…”

Section: Discussionmentioning

confidence: 68%

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

Kim

Cho

et al. 2022

Nat Commun

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Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that Arid1b-happloinsufficient (Arid1b+/–) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of Arid1b+/– mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult Arid1b+/– mice through transcriptional reprogramming.

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Section: Discussionmentioning

confidence: 68%

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

Kim

Cho

et al. 2022

Nat Commun

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“…WGS data was generated in three independent research projects [ 4 , 7 , 9 ]. In short, genomic DNA was isolated from frozen whole-blood in EDTA tubes with no DNA amplification or enrichment.…”

Section: Data Descriptionmentioning

confidence: 99%

“…The DanMAC5 data described in this Data note can be freely and openly accessed on www.danmac5.dk . Please see references [ 4 , 7 – 9 ] for details and links to the original studies.…”

mentioning

confidence: 99%

DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals

et al. 2023

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Objectives Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega.dataset:EGAD00001009756) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. Data description Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants.

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“…MEF2A may also regulate the expression of genes related to thought disorders. Mutations in the MEF2 binding sites of the two schizophrenia related genes QKI (HGNC: 21100) and PDE10A (HGNC: 8772) have been associated with formal thought disorder [96]. Halting the degradation of the ubiquitinated MEF2A by neurotoxins induces the characteristics of Parkinson's disease in an animal model [82], indicating that accumulation of inactive MEF2A is also one of the causes of neurodegenerative diseases.…”

Section: The Role Of Mef2a In Neuron Survival Differentiation and Neu...mentioning

confidence: 99%

Myocyte Enhancer Factor 2A Plays a Central Role in the Regulatory Networks of Cellular Physiopathology

Liu¹,

Ou²,

Fang³

et al. 2022

Aging and disease

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Cell regulatory networks are the determinants of cellular homeostasis. Any alteration to these networks results in the disturbance of cellular homeostasis and induces cells towards different fates. Myocyte enhancer factor 2A (MEF2A) is one of four members of the MEF2 family of transcription factors (MEF2A-D). MEF2A is highly expressed in all tissues and is involved in many cell regulatory networks including growth, differentiation, survival and death. It is also necessary for heart development, myogenesis, neuronal development and differentiation. In addition, many other important functions of MEF2A have been reported. Recent studies have shown that MEF2A can regulate different, and sometimes even mutually exclusive cellular events. How MEF2A regulates opposing cellular life processes is an interesting topic and worthy of further exploration. Here, we reviewed almost all MEF2A research papers published in English and summarized them into three main sections: 1) the association of genetic variants in MEF2A with cardiovascular disease, 2) the physiopathological functions of MEF2A, and 3) the regulation of MEF2A activity and its regulatory targets. In summary, multiple regulatory patterns for MEF2A activity and a variety of co-factors cause its transcriptional activity to switch to different target genes, thereby regulating opposing cell life processes. The association of MEF2A with numerous signaling molecules establishes a central role for MEF2A in the regulatory network of cellular physiopathology.

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Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation

Cited by 12 publications

References 55 publications

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals

Myocyte Enhancer Factor 2A Plays a Central Role in the Regulatory Networks of Cellular Physiopathology

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