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Cited by 14MicroRNA in disease regulationGenetic Associations and EpidemiologyRNA Research and Splicing

Mapping the microRNA landscape in the older adult brain and its genetic contribution to neuropsychiatric conditions

Open access
Vattathil, Selina M., Gerasimov, Ekaterina S., Canon, Se Min, Lori, Adriana, Tan, Sarah Sze Min, Kim, Paul J., Liu, Yue, Lai, Eric C. +3 more·2024·Nature Aging
DOI 10.1038/s43587-024-00778-xPMC PMC11839474
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Abstract

MicroRNAs (miRNAs) play a crucial role in regulating gene expression and influence many biological processes. Despite their importance, understanding of how genetic variation affects miRNA expression in the brain and how this relates to brain disorders remains limited. Here we investigated these questions by identifying microRNA expression quantitative trait loci (miR-QTLs), or genetic variants associated with brain miRNA levels, using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex samples of 604 older adult donors of European ancestry. Here we show that nearly half (224 of 470) of the analyzed miRNAs have associated miR-QTLs, many of which fall in regulatory regions such as brain promoters and enhancers. We also demonstrate that intragenic miRNAs often have genetic regulation independent from their host genes. Furthermore, by integrating our findings with 16 genome-wide association studies of psychiatric and neurodegenerative disorders, we identified miRNAs that likely contribute to bipolar disorder, depression, schizophrenia and Parkinson’s disease. These findings advance understanding of the genetic regulation of miRNAs and their role in brain health and disease.

AI snapshot

Written from the paper’s full text.

TL;DR

The study mapped microRNA expression quantitative trait loci (miR-QTLs) in dorsolateral prefrontal cortex from 604 older adult donors and identified miR-QTLs for 224 of 470 tested miRNAs. Integrating these miR-QTLs with 16 GWAS of psychiatric and neurodegenerative traits implicated four miRNAs consistent with causal roles in bipolar disorder, major depression, PTSD, schizophrenia, and Parkinson’s disease.

Key findings

  • Using MirGeneDB annotations, miR-QTLs were identified for 224 of 470 tested miRNAs (48%) at FDR < 1%; the median expression variance explained per conditionally independent miR-QTL was 4.1% (IQR 2.7%–7.8%), and 18 eMiRs had a miR-QTL explaining >20% of expression variance.
  • miR-QTLs were enriched in brain promoters and enhancers, but intragenic miRNAs often did not share QTLs with their host genes: among 106 miRNA–host pairs with both miR-QTLs and host eQTLs, 17 showed colocalization (coloc PP.H4 > 0.5) and 89 did not.
  • Integration with 16 GWAS identified 49 unique miRNAs associated with one or more brain traits in miRWAS; four miRNAs met all four criteria for a causal role: miR-92b-3p in Parkinson’s disease, miR-1908-5p in bipolar disorder and major depressive disorder, miR-499a-5p in bipolar disorder and schizophrenia, and miR-190b-5p in PTSD.
  • Of ~59,000 miRNA–predicted target pairs, 11 shared miR-QTLs and pQTLs; five had significant SMR results after Bonferroni correction, four had HEIDI P-values suggesting causality or pleiotropy rather than linkage, and luciferase assays supported interaction for all four tested pairs.

Methods

  • Genome-wide small RNA sequencing and genotyping were performed on post-mortem dlPFC samples from 604 older adult ROS/MAP donors of European ancestry; all were over 70 years old at death, with median age of death 90 years. miR-QTL mapping used PLINK2 linear regression with covariates including miRNA batch, PMI, RIN, age at death, cognitive diagnosis, study, sex, genotype platform, 10 genetic PCs, and 15 surrogate variables; miR-QTLs were defined at q-value < 0.01, followed by LD clumping and conditional analysis.
  • miRNA reads were mapped in parallel to miRBase and MirGeneDB; downstream analyses used the MirGeneDB set. Integration with GWAS used FUSION miRWAS, coloc, and SMR/HEIDI across five neurodegenerative and eleven psychiatric traits. pQTL and SMR analyses used dlPFC proteomic data from up to 716 ROS/MAP and Arizona Study of Aging participants, and luciferase assays were conducted in HEK 293T cells.
  • Promoter/enhancer enrichment was tested against cell-type-specific annotations from Nott et al. and PsychEncode; cross-tissue comparisons used published blood and fetal neocortex miR-QTL results.

Limitations

  • The paper states: findings would be strengthened by replication in an independent sample, but no comparable independent brain miRNA dataset was available; all participants were of European ancestry; brain miRNA genetic regulation may differ across adulthood stages; analyses were limited to dlPFC and may not generalize to other brain regions; some tested miRNAs had modest expression in bulk dlPFC and need cell-type-specific quantification; and focusing on MirGeneDB may have missed some true miRNAs.
  • Evident from the text: bulk tissue limits cell-type-specific inference, and the observed depletion of miR-QTLs in microglia enhancers is likely an artifact of microglia being a minor cell type in bulk samples. Cross-tissue comparisons are also confounded by differences in sample size, miRNA quantification, number of miRNAs considered, and analytic approach.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s43587-024-00778-x

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

2 of 50 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    miR-QTLs were enriched in PsychEncode bulk prefrontal cortex enhancers (Mantel-Haenszel common odds ratio = 1.32, 95% CI = [1.20,1.45], p = 1.3 × 10−8).

    “miR-QTLs were enriched in this set of enhancers (Mantel-Haenszel common odds ratio = 1.32, 95% CI = [1.20,1.45], p = 1.3 × 10−8)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [32] Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018). source

      The Enhancers section (page unavailable) identifies a reference set of 79,056 prefrontal cortex enhancers, supporting the identification of the enhancer set. The QTL analysis section discusses enrichment of other QTL types at genomic elements, but our copy does not report miR-QTL enrichment or the stated odds ratio, confidence interval, and p-value. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    miR-1908-5p is relevant to bipolar disorder despite its relatively low abundance.

    “Notable among those, miR-1908–5p was previously observed to be differentially expressed in blood in the acute bipolar state compared to remission state62, which suggests that miR-1908–5p is relevant to bipolar disorder despite its relatively low abundance.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Bennett, D. A. et al. Religious Orders Study and Rush Memory and Aging Project. J. Alzheimers Dis. 64, S161–S189 (2018). source

      The Materials section discusses miRNA data from the Religious Orders Study and Rush Memory and Aging Project, but does not identify miR-1908-5p or address bipolar disorder. Searches for miR-1908-5p, acute bipolar state versus remission, and low abundance found no passage supporting the observation attributed to this source. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
  • Findingown data

    For all except 44 of ~59,000 miRNA-protein pairs, the protein is trans (>500 Kb from or on a different chromosome) to the miRNA.

    “For all except 44 of ~59,000 miRNA-protein pairs, the protein is trans (> 500 Kb from or on a different chromosome) to the miRNA.”
    Quote in the paperSubstantial claim
  • Findingown data

    The tested miRNAs in the MirGeneDB set included 75% (470 out of 624) of the tested miRNAs from the miRBase set.

    “Furthermore, the tested miRNAs in the MirGeneDB set included 75% (470 out of 624) of the tested miRNAs from the miRBase set.”
    Quote in the paperNot a substantial claim
  • Findingown data

    miR-QTLs were more likely to be upstream than downstream of the miRNA gene (809 versus 570, binomial P = 1.32×10−10).

    “Among the remaining miRNAs, miR-QTLs were more likely to be upstream than downstream of the miRNA gene (809 versus 570, two-sided binomial test P-value = 1.32×10−10)”
    Quote in the paperNot a substantial claim
  • May combine two claims. 36
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 55

  • May combine two claims.

    Findingown data

    One miRNA had pQTLs for two genes (miR-1307-5p with LYPLA2 and PPFIA3), and two miRNAs from the same precursor (miR-1307-3p and −5p) both had pQTLs for predicted target PPFIA3.

    “One miRNA had pQTLs for two genes (miR-1307–5p with LYPLA2 and PPFIA3), and two miRNAs from the same precursor (miR-1307–3p and −5p) both had pQTLs for predicted target PPFIA3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the 76 eMiRs identified in whole blood, 55 were tested in our study and 30 (55%) were identified as eMiRs.

    “Conversely, of the 76 eMiRs identified in whole blood, 55 were tested in our study and we identified 55% of those (30 of 55) as eMiRs (Supplementary Figure 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Huan, T. et al. Genome-wide identification of microRNA expression quantitative trait loci. Nat. Commun. 6, 6601 (2015). source

  • May combine two claims.

    Findingown data

    Three index miR-QTLs were located within the miRNA precursor sequence, including one located within the mature miRNA.

    “Three index miR-QTLs were located within the miRNA precursor sequence, including one located within the mature miRNA (Supplementary Table 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Colocalization or lack thereof was consistent at the eQTL and pQTL level for 37 miRNA-host gene pairs, while colocalization was found at the eQTL level only for 8 pairs and pQTL level only for 5 pairs.

    “Colocalization or lack thereof was consistent at the eQTL and pQTL level for 37 miRNA-host gene pairs, while colocalization was found at the eQTL level only for 8 pairs and pQTL level only for 5 pairs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 224 eMiRs identified, 73 were tested in whole blood and 30 (41%) were identified as eMiRs in that context.

    “Of the 224 eMiRs we identified, 73 were tested in whole blood and 41% of those (30 of 73) were identified as eMiRs in that context.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Huan, T. et al. Genome-wide identification of microRNA expression quantitative trait loci. Nat. Commun. 6, 6601 (2015). source

  • The quote only partly states this claim.

    Findingown data

    Using miRBase to map miRNA reads, miR-QTLs were identified for 326 miRNAs at FDR < 1%.

    “Considering SNPs within 500kb of the precursor sequences, we tested 1,315,257 SNP-miRNA pairs and observed miR-QTLs for 326 miRNAs at false discovery rate (FDR) < 1% (unadjusted P-value < 2.98 × 10−4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 11 miRNA-target pairs involved 10 mature miRNAs from nine precursors, and 10 unique target genes.

    “These 11 pairs involved 10 mature miRNAs from nine precursors, and 10 unique target genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Genetic PCs are strongly correlated with genotype platform.

    “We observed that the genetic PCs are strongly correlated with genotype platform.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our analysis used bulk tissue, and microglia are a minor cell type in our samples.

    “Our analysis, on the other hand, used bulk tissue, and microglia are a minor cell type in our samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-1908-5p mediates the association between its miR-QTLs and FADS1 but does not mediate the association between its miR-QTLs and TMEM258.

    “Using SMR for two molecular traits, we found evidence that miR-1908–5p mediates the association between its miR-QTLs and FADS1 but does not mediate the association between its miR-QTLs and TMEM258 (Supplementary Table 17).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    miR-QTLs are significantly depleted in microglia enhancers.

    “Unexpectedly, we observed significant depletion of miR-QTLs in microglia enhancers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Sample size varied across different proteins from 76 to 716 participants due to differences in missingness rate across proteins.

    “Sample size varied across different proteins from 76 to 716 participants due to differences in missingness rate across proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Of the 716 participants included in the pQTL and SMR analysis, 565 are from the ROS/MAP cohort and 511 of those overlap the 604 participants included in the miR-QTL analysis.

    “Of the 716 participants included in the pQTL and SMR analysis, 565 are from the ROS/MAP cohort and 511 of those overlap the 604 participants included in the miR-QTL analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two miRNAs were causal in two brain traits: miR-1908-5p in both bipolar disorder and major depressive disorder, and miR-499a-5p in both bipolar disorder and schizophrenia.

    “Notably, two miRNAs were causal in two brain traits—miR-1908–5p in both bipolar disorder and major depressive disorder and miR-499a-5p in both bipolar disorder and schizophrenia (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    miR-1908-5p is located within FADS1 and is close to TMEM258, which are causal mRNAs in both bipolar disorder and major depression.

    “Specifically, miR-1908–5p, causal in both bipolar disorder and major depression, is located within FADS1 and is close to TMEM258, which are causal mRNAs in both bipolar disorder and major depression26 (Figure 5; Supplementary Table 17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Wingo, T. S. et al. Shared mechanisms across the major psychiatric and neurodegenerative diseases. Nat. Commun. 13, 4314 (2022). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The distribution of conditionally independent miR-QTLs per eMiR is similar to what was observed with miRBase.

    “The distribution of the conditionally-independent miR-QTLs per eMiR is similar to what we observed with miRBase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    672 samples with RIN ≥ 2.1 were selected for miRNA library preparation.

    “The average RIN score for all 743 RNA samples was 5.5; 672 samples with RIN ≥ 2.1 were selected for miRNA library preparation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The average RIN score for all 743 RNA samples was 5.5.

    “The average RIN score for all 743 RNA samples was 5.5; 672 samples with RIN ≥ 2.1 were selected for miRNA library preparation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    PC analysis showed that PC1 separates samples based on genotype source (WGS v. array).

    “The PC analysis showed that PC1 separates samples based on genotype source (WGS v. array).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    PC analysis confirmed that all samples cluster with the 1KG CEU population.

    “PC analysis also confirmed that all samples cluster with the 1KG CEU population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-1908-5p miR-QTLs colocalize with FADS1 eQTLs and the miRNA and transcript abundances are negatively correlated.

    “As mentioned in section 2.2, miR-1908–5p miR-QTLs colocalize with FADS1 eQTLs and the miRNA and transcript abundances are negatively correlated.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    miR-149-5p has its own intronic promoter.

    “For one of these pairs, miR-149–5p and host gene GPC1, previous work has shown that the miRNA targets the host gene in endothelial cells, has its own intronic promoter, and is activated independently of the host gene22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Chamorro-Jorganes, A., Araldi, E., Rotllan, N., Cirera-Salinas, D. & Suárez, Y. Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells. J. Cell Sci. 127, 1169–1178 (2014). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The QTL sharing detected is modest, but this is not surprising given the expected small effect sizes for trans-pQTLs.

    “While the QTL sharing we detected is modest, this is not surprising given the expected small effect sizes for trans-pQTLs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In both additional cases, the top SMR SNP is associated with miRNA and protein abundance in the same direction, which is not consistent with a causal role for the miRNA.

    “In both cases, the top SMR SNP is associated with the miRNA and protein abundance in the same direction, which is not consistent with a causal role for the miRNA.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    miR-149-5p is activated independently of host gene GPC1.

    “For one of these pairs, miR-149–5p and host gene GPC1, previous work has shown that the miRNA targets the host gene in endothelial cells, has its own intronic promoter, and is activated independently of the host gene22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Chamorro-Jorganes, A., Araldi, E., Rotllan, N., Cirera-Salinas, D. & Suárez, Y. Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells. J. Cell Sci. 127, 1169–1178 (2014). source

  • May combine two claims.

    Interpretationown data

    For the majority of intragenic miRNAs, the miR-QTL signal is not explained by host gene eQTLs, and miR-QTLs provide information complementary to eQTLs.

    “In any case, the findings show that for the majority of intragenic miRNAs, the miR-QTL signal is not explained by host gene eQTLs, and miR-QTLs provide information that is complementary to that from eQTLs.”
    • Also stated in: § Abstract · plain
      “intragenic miRNAs often did not share QTLs with their host gene”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    We observe significant sharing of miRNA genetic regulation between contexts, but important differences in study design and power limit further inference.

    “Taken together, we observe significant sharing of miRNA genetic regulation between contexts, but important differences in study design and power limits further inference.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The detected miR-QTLs in each study reflect not only differences in miRNA genetic regulation across contexts but also the sensitivity and specificity of each study.

  • Classified as probably not a substantial claim.

    Premisecitation

    miR-149-5p targets host gene GPC1 in endothelial cells.

    “For one of these pairs, miR-149–5p and host gene GPC1, previous work has shown that the miRNA targets the host gene in endothelial cells, has its own intronic promoter, and is activated independently of the host gene22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Chamorro-Jorganes, A., Araldi, E., Rotllan, N., Cirera-Salinas, D. & Suárez, Y. Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells. J. Cell Sci. 127, 1169–1178 (2014). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We removed very lowly-expressed miRNAs, defined as < 1 RPM for > 50% of samples.

    “We removed very lowly-expressed miRNAs, which we defined as those with < 1 RPM for > 50% of samples.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    We focused on GWAS summary statistics results from samples of individuals with European ancestry.

    “We focused on GWAS summary statistics results from samples of individuals with European ancestry (Supplementary Table 13).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miR-1908-5p was previously observed to be differentially expressed in blood in the acute bipolar state compared to remission state.

    “Notable among those, miR-1908–5p was previously observed to be differentially expressed in blood in the acute bipolar state compared to remission state62, which suggests that miR-1908–5p is relevant to bipolar disorder despite its relatively low abundance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Bennett, D. A. et al. Religious Orders Study and Rush Memory and Aging Project. J. Alzheimers Dis. 64, S161–S189 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Linear regression was performed to compare luminescence between experimental conditions adjusting for plate effects.

    “Linear regression was performed to compare luminescence between experimental conditions adjusting for plate effects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Sample outliers with respect to population structure were removed using EIGENSTRAT.

    “Sample outliers with respect to population structure were removed using EIGENSTRAT69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006). source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Surrogate variables were estimated from normalized counts using R package 'sva', with number set at 15 based on num.sv function.

    “Surrogate variables (SVs) were estimated from the normalized counts using R package ‘sva’. The number of SVs to estimate was set at 15 based on the results of the num.sv function, and SVs were estimated with a randomly-generated binary variable as the variable of interest and miRNA batch, PMI, RIN, age at death, cognitive diagnosis at death, study (ROS v. MAP), and sex as adjustment variables.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For miRNAs with multiple precursors that were less than 500 Kb apart, SNPs that fell in the padding region for multiple precursors were tested only once for the miRNA.

    “For miRNAs with multiple precursors that were less than 500 Kb apart, SNPs that fell in the padding region for multiple precursors were tested only once for the miRNA.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    We calculated the top ten genetic PCs using PLINK2 to be used as covariates in the miR-QTL analysis.

    “We calculated the top ten genetic PCs using PLINK273 to be used as covariates in the miR-QTL analysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The integration of genome-wide miRNA profiles with GWAS results used multiple independent and complementary approaches.

    “we integrated the genome-wide miRNA profiles with results from GWAS of these brain traits using multiple independent and complementary approaches (Figure 1).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Second degree and closer relatives were removed using KING.

    “Second degree and closer relatives were removed using KING72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Manichaikul, A. et al. Robust relationship inference in genome-wide association studies. Bioinformatics 26, 2867–2873 (2010). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Clinical diagnosis at death was based on the opinion of a neurologist with expertise in dementia who had access to select clinical but not postmortem data.

    “Clinical diagnosis at death was based on the opinion of a neurologist with expertise in dementia who had access to select clinical but not postmortem data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These findings demonstrate that miR-QTLs can be used to prioritize putative trans-pQTLs and provide additional support for predicted interactions.

    “While further investigation is necessary to confirm endogenous repression activity and the observed QTL associations, these findings are an initial demonstration of how miR-QTLs can be used to prioritize putative trans-pQTLs and provide additional support for predicted interactions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study expects to have captured the strongest miR-QTLs; larger studies would be expected to identify additional miR-QTLs with smaller effect sizes.

    “We expect to have captured the strongest miR-QTLs; larger studies would be expected to identify additional miR-QTLs with smaller effect sizes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationcitation

    We have high confidence in the validity of the miRNAs we did consider, which improves the signal in our observations and increases the confidence that our results provide a solid foundation to build on in future downstream analyses.

    “The trade-off for this choice is that we have high confidence in the validity of the miRNAs we did consider, which improves the signal in our observations and increases the confidence that our results provide a solid foundation to build on in future downstream analyses11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Fromm, B., Zhong, X., Tarbier, M., Friedländer, M. R. & Hackenberg, M. The limits of human microRNA annotation have been met. RNA 28, 781–785 (2022). source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    MiRNAs included in the analysis met the abundance threshold, had gene coordinate information, had at least one precursor gene located on an autosome, and had at least one common (MAF >5%) SNP within the test window.

    “MiRNAs included in the analysis met the abundance threshold described above, had gene coordinate information in the coordinate file, had at least one precursor gene located on an autosome, and had at least one common (MAF >5%) SNP within the test window.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    For miRWAS, we restricted the SNPs to the set of 1,190,321 SNPs in the linkage disequilibrium reference panel provided by FUSION.

    “For the miRWAS analysis, we restricted the SNPs to the set of 1,190,321 SNPs in the linkage disequilibrium reference panel provided by FUSION35.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Proteomic profiles were represented by residuals after regressing out effects of batch, PMI, age at death, and cognitive diagnosis.

    “Proteomic profiles were represented by residuals after regressing out effects of batch, PMI, age at death, and cognitive diagnosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Except for miR-1908-5p, the other three causal miRNAs are causal mediators independent of nearby causal transcripts and proteins.

    “In summary, except for miR-1908–5p, the other three causal miRNAs are causal mediators independent of nearby causal transcripts and proteins and provide additional valuable biological insights into the pathogenesis of these psychiatric and neurodegenerative diseases.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The test window for each mature miRNA included the precursor sequence(s) plus 500 Kb symmetric padding around each precursor sequence.

    “The test window for each mature miRNA included the precursor sequence(s) plus 500 Kb symmetric padding around each precursor sequence.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Samples included in the analysis passed all genotyping and miRNA data QC, had normal cognition, MCI, AD, or other dementia at death, and were of European ancestry.

    “Samples included in the analysis passed all genotyping and miRNA data QC, had normal cognition, MCI, AD, or other dementia at death, and were of European ancestry.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Our observations fill a gap in the available resources for studying the role of miRNAs in the human brain.

    “Nevertheless, our observations fill a gap in the available resources for studying the role of miRNAs in the human brain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Brain miRNA genetic regulation may differ across stages of adulthood.

    “Third, brain miRNA genetic regulation may differ across stages of adulthood and ought to be tested in future studies that include participants from a wider age range.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Initial genotype filtering excluded samples with genotype missingness >5% or self-identified race other than White, and variants with HWE P<1e-8, missingness >5%, MAF <1%, or not SNP.

    “Specifically, samples were excluded if they had genotype missingness >5% or were from participants who self-identified their race as other than White, and variants were excluded if they had evidence of deviation from Hardy Weinberg equilibrium (P-value < 1×10−8), genotype missingness >5%, minor allele frequency <1%, or were not a single nucleotide polymorphism (SNP).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We iteratively removed samples that were greater than 5 SD from the mean within the respective batch for total read count, trimmed read rate, and mapped read rate.

    “First, we iteratively removed samples that were greater than 5 standard deviations (SD) from the mean within the respective batch for total read count, trimmed read rate, and mapped read rate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analysis was limited to European ancestry participants because of small sample sizes for participants from other genetic ancestries.

    “The analysis was limited to these participants because of small sample sizes for participants from other genetic ancestries.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    All participants provided informed consent, and the studies were approved by an Institutional Review Board.

    “All participants provided informed consent, underwent annual cognitive evaluations, were organ donors, and signed an Anatomical Gift Act and repository consent to allow their data and biospecimens to be repurposed. An Institutional Review Board of Rush University Medical Center approved both studies and we have complied with all relevant ethical regulations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The large sample enabled us to conduct well-powered miR-QTL analysis and to successfully integrate these results with GWAS data to identify miRNAs contributing to the pathogenesis of psychiatric and neurodegenerative diseases.

    “This enabled us to conduct well-powered miR-QTL analysis and to successfully integrate these results with GWAS data to identify miRNAs contributing to the pathogenesis of psychiatric and neurodegenerative diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The miR-92b we identified to be causal in Parkinson's disease has been shown to target PTEN, promote neurite development, and maintain neuroblast self-renewal.

    “Notably, the miR-92b we identified to be causal in Parkinson’s disease has been shown to target PTEN, promote neurite development58, and maintain neuroblast self-renewal59.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Yuva-Aydemir, Y. et al. Downregulation of the host gene jigr1 by miR-92 is essential for neuroblast self-renewal in Drosophila. PLoS Genet. 11, e1005264 (2015). source
    • cites [59] Cano-Gamez, E. & Trynka, G. From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases. Front. Genet. 11, 424 (2020). source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    The findings would be strengthened by replication in an independent sample.

    “First, the findings would be strengthened by replication in an independent sample.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Imputation was performed to 1000 Genome Project Phase 3 using Michigan Imputation Server, and SNPs with R2>0.3 were retained.

    “For samples with array-based genotypes, imputation was performed to 1000 Genome Project Phase 370 using the Michigan Imputation Server71, and SNPs with R2>0.3 were retained.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012). source

      Not checked in the free run.

    • cites [71] Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Four unique miRNAs are consistent with a causal role in Parkinson's disease (miR-92b-3p), bipolar disorder (miR-1908-5p and miR-499a-5p), major depressive disorder (miR-1908-5p), post-traumatic stress disorder (miR-190b-5p), and schizophrenia (miR-499a-5p).

    “Further imposing the remaining three criteria described above, we found four unique miRNAs to be consistent with a causal role in Parkinson’s disease (miR-92b-3p), bipolar disorder (miR-1908–5p and miR-499a-5p), major depressive disorder (miR-1908–5p), post-traumatic stress disorder (miR-190b-5p), and schizophrenia (miR-499a-5p) (Table 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each miRNA mimic/3'-UTR reporter construct pair was transfected in quadruplicate on each plate.

    “Each miRNA mimic/3’-UTR reporter construct pair was transfected in quadruplicate on each plate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    We limited this analysis to SNPs within 50 Kb of miRNA genes to reduce confounding between distance to nearest gene and probability that a genomic region harbors a promoter.

    “We limited this analysis to SNPs within 50 Kb of miRNA genes because doing so reduces the potential effect of confounding between distance to nearest gene and probability that a genomic region harbors a promoter60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Chandra, V. et al. Promoter-interacting expression quantitative trait loci are enriched for functional genetic variants. Nat. Genet. 53, 110–119 (2021). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Differences in power due to sample size are likely the most salient and make direct comparisons challenging to interpret.

    “Differences in power due to sample size are likely the most salient and make direct comparisons challenging to interpret.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    For the three trans pairs, the top SMR SNP is associated with miRNA and protein abundance in opposite directions, which is consistent with the QTL acting in trans on protein abundance through its cis effect on miRNA abundance.

    “Furthermore, for these three pairs, the top SMR SNP is associated with miRNA and protein abundance in opposite directions, which is consistent with the QTL acting in trans on the protein abundance through its cis effect on miRNA abundance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Our analyses were conducted using samples from a specific brain region (dlPFC) and our observations may not be characteristic of other brain regions.

    “Fourth, our analyses were conducted using samples from a specific brain region (dlPFC) and our observations may not be characteristic of other brain regions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Samples that were greater than 4 SD from the mean of either of the first two PCs were removed.

    “Principal components (PCs) were estimated, and samples that were greater than 4 SD from the mean of either of the first two PCs were removed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    All participants were over 70 years old at the time of death, and the median age of death was 90 years.

    “All participants were over 70 years old at the time of death, and the median age of death was 90 years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Some of the tested miRNAs had modest expression in our dlPFC bulk tissue samples.

    “Fifth, some of the tested miRNAs had modest expression in our dlPFC bulk tissue samples and their cell type-specific expression levels need to be quantified in relevant cell types.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    We performed parallel runs of the miR-QTL analysis using reads mapped independently to two sets of miRNA annotations - miRBase (Release 22.1) and MirGeneDB (version 2.1).

    “Importantly, we performed parallel runs of the miR-QTL analysis using reads mapped independently to two sets of miRNA annotations – either the popular miRBase database (Release 22.1) or the curated MirGeneDB database (version 2.1).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Significant difference was defined as P-value < 0.05.

    “Significant difference was defined as P-value < 0.05.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Surrogate variables were designed to capture as much as possible the potentially unknown, unmeasured, or hidden confounding variables, including cell type heterogeneity.

    “These surrogate variables were designed to capture as much as possible the potentially unknown, unmeasured, or hidden confounding variables, including cell type heterogeneity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This study presents the first evidence for the contribution of miR-1908-5p in major depression, miR-190b-5p in post-traumatic stress disorder, miR-499a-5p in schizophrenia, and miR-92b-3p in Parkinson's disease.

    “We present here the first evidence for the contribution of miR-1908–5p in major depression, miR-190b-5p in post-traumatic stress disorder, miR-499a-5p in schizophrenia, and miR-92b-3p in Parkinson’s disease, to our knowledge.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For miRNAs mapped to multiple precursors, we kept the entry with the highest total count across samples.

    “For miRNAs mapped to multiple precursors, we kept the entry with the highest total count across samples.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    We examined the relationship of genetic regulation of miRNAs and their downstream targets using proteomic data.

    “Second, we examined the relationship of genetic regulation of miRNAs and their downstream targets using proteomic data.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    miR-1908-5p likely contributes to bipolar disorder and major depression through its effect on FADS1 mRNA expression but acts independently from TMEM258.

    “These findings suggest that miR-1908–5p likely contributes to bipolar disorder and major depression through its effect on FADS1 mRNA expression but acts independently from TMEM258.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Raw counts were normalized for library size and transformed to log2 counts using EdgeR.

    “The raw counts were then normalized for library size and transformed to log2 counts using EdgeR.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    We filtered 11 samples to focus analysis on individuals of European ancestry based on genetic data.

    “We then filtered 11 samples to focus analysis on individuals of European ancestry based on genetic data.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Before merging, variants with MAF < 5% in each dataset were removed.

    “Before merging, variants with MAF < 5% in each dataset were removed.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    SVs were estimated with a randomly-generated binary variable as the variable of interest and miRNA batch, PMI, RIN, age at death, cognitive diagnosis at death, study, and sex as adjustment variables.

    “Surrogate variables (SVs) were estimated from the normalized counts using R package ‘sva’. The number of SVs to estimate was set at 15 based on the results of the num.sv function, and SVs were estimated with a randomly-generated binary variable as the variable of interest and miRNA batch, PMI, RIN, age at death, cognitive diagnosis at death, study (ROS v. MAP), and sex as adjustment variables.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Proteomic data may better capture the effect of miRNA post-transcriptional regulation on target genes than transcriptomic data.

    “Proteomic data may better capture the effect of miRNA post-transcriptional regulation on target genes than transcriptomic data, which is more commonly used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The power of this analysis is tied to the relatively large sample size for the miRNA profiles, and there is not an independent comparable brain miRNA dataset for replication at this time.

    “The power of this analysis is tied to the relatively large sample size for the miRNA profiles, and there is not an independent comparable brain miRNA dataset for replication at this time.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Samples were randomized into batches of 8 for miRNA library preparation based on RIN, PMI, sex, cognitive diagnosis, amyloid, tangles, depression, education, and sense of life purpose.

    “Based on RIN, PMI, sex, cognitive diagnosis, amyloid, tangles, depression, education, and sense of life purpose, samples were randomized into batches of 8 for miRNA library preparation.”
    Quote in the paperNot a substantial claim
81 of 81

  • The paper relies on this without support.

    How GWAS risk loci confer risk in psychiatric and neurologic diseases remains unclear.

    “GWAS have identified many risk loci for brain illnesses; however, how these loci confer risk in these psychiatric and neurologic diseases remain unclear.”

  • The paper relies on this without support.

    Integrating GWAS signals with gene expression and QTL data from a reference set is a powerful strategy for identifying genes associated with complex traits in the absence of expression measures in the larger GWAS participants.

    “Recently, integrating GWAS signals with gene expression and QTL data from a reference set has become a powerful strategy for identifying genes that are associated with complex traits in the absence of expression measures in the larger GWAS participants.”

  • The paper relies on this without support.

    The detected miR-QTLs in each study reflect not only differences in miRNA genetic regulation across contexts but also the sensitivity and specificity of each study.

    “It is important to recognize that the detected miR-QTLs in each study reflect not only differences in miRNA genetic regulation across contexts but also the sensitivity and specificity of each study.”

  • The paper relies on this without support.

    miRNAs may share QTLs with nearby genes due to linkage disequilibrium, pleiotropy, or mediation.

    “Since miRNAs may share QTLs with nearby genes due to linkage disequilibrium, pleiotropy, or mediation, we examined whether the causal role could be attributed to the above identified miRNAs instead of their nearby genes.”

  • The paper relies on this without support.

    QTLs for master regulators such as miRNAs can potentially have an outsized effect since they can influence the expression of many other genes.

    “QTLs for master regulators such as miRNAs can potentially have an outsized effect since they can influence the expression of many other genes.”

  • The paper relies on this without support.

    MirGeneDB contains less than 30% of the annotations in miRBase due to its more stringent inclusion criteria.

    “MirGeneDB contains less than 30% of the annotations in miRBase due to its more stringent inclusion criteria.”

  • The paper relies on this without support.

    The relative proportions of the cell type in bulk tissue does not create a bias in the promoter and enhancer distributions across cell types.

    “The promoter and enhancer detection was done using pooled sorted single nuclei31, so the relative proportions of the cell type in bulk tissue does not create a bias in the promoter and enhancer distributions across cell types.”

  • The authors state this as an assumption.

    SNP allele dosage has an additive effect on miRNA abundance.

    “The effect of SNP allele dosage (assuming an additive effect) on miRNA abundance was estimated for each SNP-miRNA pair in turn using the --glm function from PLINK2.”

  • The paper relies on this without support.

    SMR association can arise from causality or pleiotropy of a single SNP that affects both the exposure and outcome, or from linkage of SNPs with distinct effects on the exposure and outcome.

    “SMR association can arise from causality or pleiotropy of a single SNP that affects both the exposure and outcome, or from linkage of SNPs with distinct effects on the exposure and outcome.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The miR-33 family is associated with lipid metabolism in the brain, and the miR-181b family was implicated in myelin-assisted axon regeneration.

    “The miR-33 family is associated with lipid metabolism in the brain 58 , and the miR-181b family was implicated in myelin-assisted axon regeneration 59 .”

    From Human brain microRNAs exhibit cell-type specificity and age dependence (2026) · cites this paper as [59]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentχ²(1) = 4.3reported p = .038 · recomputed p = .038

    “X2(1, N = 173) = 4.3, p = .038”

1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Two miRNA-host-gene pairs are unaccounted for

    Minor

    Proteomics data were available for 52 pairs, but the three reported colocalization categories account for only 50 (37 + 8 + 5). The outcomes for two pairs are not explained.

    Reported 52 · recomputed 50

1 of 1

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Authors
Vattathil, S. M., Gerasimov, E. S., Canon, S. M., Lori, A., Tan, S. S. M., Kim, P. J., Liu, Y., Lai, E. C., Bennett, D. A., Wingo, T. S., & Wingo, A. P.
Affiliations
  • University of California, Davis (US)
  • Emory University (US)
  • Rush University Medical Center (US)
  • VA Northern California Health Care System (US)
Corresponding author
  • Wingo, Thomas S.
  • Wingo, Aliza P.
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2024-12-06
Volume
5
Issue
2
Pages
306-319
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-024-00778-x
PMC
PMC11839474
OpenAlex
W4405115868
Cited by
14
References
76
Citations by year
2026: 7 · 2025: 6 · 2024: 1
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nd)
Funders
  • U.S. Department of Veterans Affairs (IK4 BX005219)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (I01 BX003853, R01 AG056533, P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356, R01 AG075827, R01 AG072120)
  • U.S. Department of Health & Human Services | National Institutes of Health (P30-CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
microRNA expression, dorsolateral prefrontal cortex, regulatory elements, enhancers, promoter, neuropsychiatric disorders, bipolar disorder, depression, schizophrenia, Parkinson's disease, neurodegenerative diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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