A Rare Functional Noncoding Variant at the GWAS-Implicated MIR137/MIR2682 Locus Might Confer Risk to Schizophrenia and Bipolar Disorder

Duan, Jubao; Shi, Jianxin; Fiorentino, Alessia; Leites, Catherine; Chen, Xiangning; Moy, Winton; Chen, Jingchun; Alexandrov, Boian S.; Usheva, Anny; He, Deli; Freda, Jessica; O’Brien, Niamh; McQuillin, Andrew; Sanders, Alan R.; Gershon, Elliot S.; DeLisi, Lynn E.; Bishop, A. R.; Gurling, Hugh; Pato, Michele T.; Levinson, Douglas F.; Kendler, Kenneth S.; Pato, Carlos N.; Gejman, Pablo V.

doi:10.1016/j.ajhg.2014.11.001

Cited by 94 publications

(81 citation statements)

References 76 publications

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“…Abnormalities in dendrite arborization have been reported in several neuropsychiatric disorders. Surprisingly, our findings of increased dendrite arborization did not parallel previous postmortem findings in schizophrenia (41); despite this, the increased dendrite arborization associated with 16p11.2 duplication during development may lead to premature maturation of synapses, as has been shown when schizophrenia-associated MIR137 expression is reduced (42,43). However, 16p11.2 duplications are also associated with ASD and seizure disorder, and the cellular phenotypes we identified may be more reflective of these disorders (16,44,45), such as the hypothesized increased brain connectivity in ASD.…”

Section: Discussioncontrasting

confidence: 54%

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

Blizinsky

Díaz-Castro

Forrest

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein-protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.T he architecture of the dendritic arbors defines a pyramidal neuron's dendritic receptive field (1). Moreover, patterns of dendritic arborization are essential to the computational ability of the neuron (1). Generating and maintaining proper dendritic receptive fields is therefore crucial for neural circuit function that underlies complex behaviors. Conversely, alterations in dendrites occur in psychiatric disorders, including schizophrenia and autism spectrum disorder (ASD) (2).Psychiatric disorders have complex genetic architecture that is partly explained by rare variants with high penetrance (3, 4). Though incidences of these rare mutations are low (4-7), the accrued burden of rare variants on disease risk may account for a significant proportion of cases in linked disorders (8). The most well-characterized forms of rare variations are large genomic regional duplications or deletions known as copy number variations (CNVs). CNVs represent large genomic alterations, often encompassing multiple genes, which confer significant risk (odds ratio = 3-30) (9). The increased rare CNV burden is associated with numerous neurodevelopmental psychiatric conditions, including schizophrenia, ASD, and intellectual disability (5, 7, 10, 11). However, due to the large number of genes within CNVs, understanding the relationship between genotype and phenotypes and the rational identification of potential targets for reversing pathologically relevant phenotypes in CNV disorders has been challenging.Recently, much attention has been paid to recurrent microduplication or deletion at the 16p11.2 locus. The ∼600-kb 16p11.2 CNV region encompasses 29 known protein-coding genes and is a hot spot for chromosomal rearrangement (3); 16p11.2 CNVs have been linked to multiple disorders and phenotypes; CNVs of this region are associa...

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Section: Discussioncontrasting

confidence: 54%

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

Blizinsky

Díaz-Castro

Forrest

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Cis -acting miRNA QTLs ( cis -mirQTLs) are generally located in the transcription regulatory regions of the miRNA locus 58,59 . For example, an SNV that is associated with a risk of schizophrenia in the enhancer of mir-137 weakens binding of the transcription factor YY1, leading to decreased miR-137 expression 60 . The relatively high prevalence of cis -mirQTLs is illustrated by one study in which RNA-seq of small RNAs of more than 450 genetically diverse human LCLs from the 1000 Genomes Project revealed that 60 of the 644 expressed mi RNAs that were detected (approximately 9%) contained cis -mirQTLs 4 .…”

Section: Variants Affect Mirna-mediated Regulationmentioning

confidence: 99%

The roles of RNA processing in translating genotype to phenotype

Manning

Cooper

2016

Nat Rev Mol Cell Biol

179

141

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A goal of human genetics studies is to determine the mechanisms by which genetic variation produces phenotypic differences that affect human health. Efforts in this respect have previously focused on genetic variants that affect mRNA levels by altering epigenetic and transcriptional regulation. Recent studies show that genetic variants that affect RNA processing are at least equally as common as, and are largely independent from, those variants that affect transcription. We highlight the impact of genetic variation on pre-mRNA splicing and polyadenylation, and on the stability, translation and structure of mRNAs as mechanisms that produce phenotypic traits. These results emphasize the importance of including RNA processing signals in analyses to identify functional variants.

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“…Additionally, different SNPs (rs1625579; rs1198588, rs1702294) in the upstream region of the host gene for miR-137 have been strongly associated with SCZ (Cummings et al, 2013; Green et al, 2013; Psychosis Endophenotypes International et al, 2014; Ripke et al, 2013; Schizophrenia Psychiatric Genome-Wide Association Study, 2011; Whalley et al, 2012). Besides SNPs, variable number tandem repeats (VNTRs) and rare variants have been also reported within the same MIR137 locus (Duan et al, 2014; Strazisar et al, 2015; Warburton et al, 2015). Recently, Warnica et al reported CNVs at eight loci (1q21.1, 2q13, 12q21.31, 14q32.33, 15q11-15q13, 16p11.2, 16p13.11, and 19q13.42), which overlap with a total of 25 miRNAs (Warnica et al, 2015), providing abundant evidence for the potential contribution of disrupted miRNA levels to the underlying pathophysiology.…”

Section: Genetic Variants In Mirna-related Genesmentioning

confidence: 99%

Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: Past, present, and future

Alural

Genç

Haggarty

2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Neuropsychiatry disorders are common health problems affecting approximately 1% of the population. Twin, adoption, and family studies have displayed a strong genetic component for many of these disorders; however, the underlying pathophysiological mechanisms and neural substrates remain largely unknown. Given the critical need for new diagnostic markers and disease-modifying treatments, expanding the focus of genomic studies of neuropsychiatric disorders to include the role of non-coding RNAs (ncRNAs) is of growing interest. Of known types of ncRNAs, microRNAs (miRNAs) are 20–25-nucleotide, single-stranded, molecules that regulate gene expression through post-transcriptional mechanisms and have the potential to coordinately regulate complex regulatory networks. In this review, we summarize the current knowledge on miRNA alteration/dysregulation in neuropsychiatric disorders, with a special emphasis on schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). With an eye toward the future, we also discuss the diagnostic and prognostic potential of miRNAs for neuropsychiatric disorders in the context of personalized treatments and network medicine.

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A Rare Functional Noncoding Variant at the GWAS-Implicated MIR137/MIR2682 Locus Might Confer Risk to Schizophrenia and Bipolar Disorder

Cited by 94 publications

References 76 publications

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

The roles of RNA processing in translating genotype to phenotype

Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: Past, present, and future

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