Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
24 08 2020
24 08 2020
Historique:
received:
11
03
2020
accepted:
28
07
2020
revised:
15
07
2020
entrez:
26
8
2020
pubmed:
26
8
2020
medline:
22
6
2021
Statut:
epublish
Résumé
Recent genome-wide studies have begun to identify gene variants, expression profiles, and regulators associated with neuroticism, anxiety disorders, and depression. We conducted a set of experimental cell culture studies of gene regulation by micro RNAs (miRNAs), based on genome-wide transcriptome, proteome, and miRNA expression data from twenty postmortem samples of lateral amygdala from donors with known neuroticism scores. Using Ingenuity Pathway Analysis and TargetScan, we identified a list of mRNA-protein-miRNA sets whose expression patterns were consistent with miRNA-based translational repression, as a function of trait anxiety. Here, we focused on one gene from that list, which is of particular translational significance in Psychiatry: synaptic vesicle glycoprotein 2A (SV2A) is the binding site of the anticonvulsant drug levetiracetam ((S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide), which has shown promise in anxiety disorder treatments. We confirmed that SV2A is associated with neuroticism or anxiety using an original GWAS of a community cohort (N = 1,706), and cross-referencing a published GWAS of multiple cohorts (Ns ranging from 340,569 to 390,278). Postmortem amygdala expression profiling implicated three putative regulatory miRNAs to target SV2A: miR-133a, miR-138, and miR-218. Moving from association to experimental causal testing in cell culture, we used a luciferase assay to demonstrate that miR-133a and miR-218, but not miR-138, significantly decreased relative luciferase activity from the SV2A dual-luciferase construct. In human neuroblastoma cells, transfection with miR-133a and miR-218 reduced both endogenous SV2A mRNA and protein levels, confirming miRNA targeting of the SV2A gene. This study illustrates the utility of combining postmortem gene expression data with GWAS to guide experimental cell culture assays examining gene regulatory mechanisms that may contribute to complex human traits. Identifying specific molecular mechanisms of gene regulation may be useful for future clinical applications in anxiety disorders or other forms of psychopathology.
Identifiants
pubmed: 32839459
doi: 10.1038/s41398-020-00966-4
pii: 10.1038/s41398-020-00966-4
pmc: PMC7445165
doi:
Substances chimiques
Glycoproteins
0
MIRN138 microRNA, human
0
MIRN218 microRNA, human
0
Membrane Glycoproteins
0
MicroRNAs
0
Nerve Tissue Proteins
0
SV2A protein, human
148845-93-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
297Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : P30AG10161
Pays : International
Organisme : NIA NIH HHS
ID : RF1 AG036042
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : R01AG36042
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : R01AG15819
Pays : International
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR023680
Pays : United States
Organisme : National Science Foundation (NSF)
ID : BCS-0843346
Pays : International
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01AG034578
Pays : International
Organisme : NIA NIH HHS
ID : R01 AG034578
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : R01AG17917
Pays : International
Organisme : NIA NIH HHS
ID : R01 AG036042
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
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