Genome-wide schizophrenia variant at MIR137 does not impact white matter microstructure in healthy participants

Kelly, Sinéad; Morris, Derek W.; Mothersill, Omar; Rose, Emma Jane; Fahey, Ciara; O’Brien, Carol; O’Hanlon, Erik; Gill, Michael; Corvin, Aiden; Donohoe, Gary

doi:10.1016/j.neulet.2014.05.002

Cited by 15 publications

(13 citation statements)

References 35 publications

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“…A bioinformatics analysis of predicted and validated miR-137 target genes revealed a significant enrichment of these genes within the axonal guidance canonical pathway [1]. One target, ZNF804A , is a well-known schizophrenia candidate gene [25] that has been linked to reduced integrity of the corpus callosum [26], although its relationship to white matter integrity has varied across studies [27; 28]. Since many other miR-137 target genes are also schizophrenia risk genes [1], the role of these genes in white matter development and morphology lends support to our finding of MIR137HGrv genotype-by-diagnosis—rather than just genotype—effects on corpus callosum volume.…”

Section: Discussionmentioning

confidence: 99%

MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia

Patel

Kelly

Wright

et al. 2015

Neuroscience Letters

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Genome-wide association studies implicate the MIR137HG risk variant rs1625579 (MIR137HGrv) within the host gene for microRNA-137 as a potential regulator of schizophrenia susceptibility. We examined the influence of MIR137HGrv genotype on 17 subcortical and callosal volumes in a large sample of individuals with schizophrenia and healthy controls (n=841). Although the volumes were overall reduced relative to healthy controls, for individuals with schizophrenia the homozygous MIR137HGrv risk genotype was associated with attenuated reduction of mid-posterior corpus callosum volume (p=0.001), along with trend-level effects in the adjacent central and posterior corpus callosum. These findings are unique in the literature and remain robust after analysis in ethnically homogenous and single-scanner subsets of the larger sample. Thus, our study suggests that the mechanisms whereby MIR137HGrv works to increase schizophrenia risk are not those that generate the corpus callosum volume reductions commonly found in the disorder.

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Section: Discussionmentioning

confidence: 99%

MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia

Patel

Kelly

Wright

et al. 2015

Neuroscience Letters

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“… 4 , 5 In line with the proposed influence of microRNA-137 (miR-137) on proliferation, migration and maturation of neural cells, 6 , 7 , 8 mechanisms important to the cognitive process, one of three intronic variants in high LD identified in this region (rs1625579) has been associated with a number of cognitively relevant phenotypes. These include lower performance in verbal episodic memory and vigilant attention, 9 altered fronto-amygdala connectivity during a face processing task 10 and decreased white matter integrity, 11 , 12 although a number of other studies have reported conflicting findings, with no effects of the MIR137 risk allele 13 , 14 on brain structure.…”

Section: Introductionmentioning

confidence: 99%

MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

et al. 2017

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Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10−5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.

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“…Lett et al (2013) also reported that North American schizophrenia patients carrying the TT genotype of this variant have reduced brain white matter density, diminished hippocampal volume, and increased lateral ventricle volume. However, other studies have not supported an association between miR-137 rs1625579 and schizophrenia or white matter microstructure (Kelly et al, 2014;Rose et al, 2014;Wang et al, 2014). Therefore, no consistent conclusion has been reached regarding the effect of this SNP on schizophrenia.…”

Section: Introductionmentioning

confidence: 91%

Association between miR-137 polymorphism and risk of schizophrenia: a meta-analysis

Ou¹,

Liu²,

Xiao³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. miR-137, a brain-enriched microRNA, is involved in the control of neuronal proliferation, differentiation, and dendritic arborization, all of which are important for proper neurogenesis and relevant to schizophrenia. miR-137 is also known to regulate many genes implicated in schizophrenia risk. Although reports have associated the miR-137 polymorphism rs1625579 with this disease, their results have been inconsistent. The aim of this meta-analysis was to evaluate the relationship between rs1625579 and schizophrenia. Data were obtained from an electronic database, and pooled odds ratios (ORs) with 95% confidence intervals (95%CI) were used to test the association using the RevMan 5.3 software. Twelve case-control studies comprising 11,583 cases and 14,315 controls were included. An estimated lambda value of 0.46 was recorded, suggesting that a codominant model of inheritance was most likely. A statistically significant association was established under allelic (T vs G: OR = 1.15, 95%CI = 1.10-1.21, P < 0.001) and homogeneous codominant models (TT vs GG: OR = 1.32, 95%CI = 1.13-1.54, P < 0.001), but no such relationship was detected using the heterogeneous codominant model (GT vs GG: OR = 1.14, 95%CI = 0.97-1.34, P = 0.11). This meta-analysis demonstrates that the rs1625579 miR-137 genetic variant significantly increases schizophrenia risk.

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Genome-wide schizophrenia variant at MIR137 does not impact white matter microstructure in healthy participants

Cited by 15 publications

References 35 publications

MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia

MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia

MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

Association between miR-137 polymorphism and risk of schizophrenia: a meta-analysis

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