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Cited by 304Genetic Associations and EpidemiologyGenomics and Chromatin DynamicsBioinformatics and Genomic Networks

A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles

Open access
Sey, Nancy Y. A., Hu, Benxia, Mah, Won, Fauni, Harper, McAfee, Jessica Caitlin, Rajarajan, Prashanth, Brennand, Kristen J., Akbarian, Schahram +1 more·2020·Nature Neuroscience
DOI 10.1038/s41593-020-0603-0PMC PMC7131892

Published version of a preprint

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Abstract

Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism associations to nearest genes. Here we developed a platform, Hi-C-coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified neurobiologically relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows and cell types implicated for each disorder. Psychiatric-disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas neurodegenerative-disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological principles of brain disorders. Sey et al. report a computational tool, H-MAGMA, that extracts neurobiological insights from brain-disorder GWAS by linking risk variants to their cognate genes using chromatin interaction profiles from human brain tissue.

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Claims the paper makes

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  • Findingown data

    H-MAGMA and two eQTL-based gene mapping tools, coloc and TWAS, show significant overlap.

    “We also found a significant overlap between H-MAGMA and two widely used expression quantitative trait loci (eQTL)-based gene mapping tools, coloc9 and TWAS10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014). source

      Not checked in the free run.

    • cites [10] 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.

  • Findingown data

    In SCZ, 72.6% of TWAS genes were also detected by H-MAGMA (OR=12.14, 95% CI=10.20-14.49, P=3.94x10-206).

    “72.6% of TWAS genes, Fisher’s exact test, OR=12.14, 95% CI=10.20–14.49, P=3.94x10–206”
    Quote in the paperSubstantial claim
  • Findingown data

    MS was an exception, displaying prenatal enrichment.

    “The only exception was MS, which displayed prenatal enrichment.”
    Quote in the paperNot a substantial claim
  • Findingown data

    BD- and ADHD-associated genes gradually increased during the prenatal stage with a peak at developmental stage 6 (19-22 PCW).

    “BD- and ADHD-associated genes were gradually increased during the prenatal stage with a peak at the developmental stage 6 (19–22 PCW).”
    Quote in the paperSubstantial claim
  • Findingown data

    cMAGMA and H-MAGMA linked 7.4M and 3.9M SNPs to genes, respectively.

    “In total, cMAGMA and H-MAGMA linked 7.4M and 3.9M SNPs to genes, respectively (Extended Data Fig. 1d).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    80% of intronic SNPs and 87% of intergenic SNPs associated with nearest genes also showed associations with distal genes.

    “The majority of non-coding SNPs associated with nearest genes showed additional association with distal genes, as 80% of intronic SNPs and 87% of intergenic SNPs showed associations with distal genes (Fig. 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using a DLPFC eQTL resource, 56% of intronic SNPs and 76% of intergenic SNPs did not show any association with nearest genes.

    “we additionally used an eQTL resource from the human DLPFC3, from which we found 56% of intronic SNPs and 76% of intergenic SNPs did not show any association with nearest genes (Extended Data Fig. 1a, Methods).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Genes associated with degenerative disorders except MS constantly and gradually increased during both prenatal and postnatal stages, suggesting they may become more susceptible upon aging.

    “Genes associated with degenerative disorders except MS constantly and gradually increased during both prenatal and postnatal stages, suggesting that these genes may become more susceptible upon aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes associated with psychiatric disorders were highly expressed during prenatal stages, while genes associated with degenerative disorders were highly expressed postnatally.

    “Genes associated with psychiatric disorders were highly expressed during prenatal stages, while genes associated with degenerative disorders were highly expressed postnatally (Fig. 2b–c, see Supplementary Data 3 for statistics).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only 20% of intronic SNPs and 5% of intergenic SNPs interact with nearest genes based on Hi-C.

    “We found that only 20% of intronic SNPs and 5% of intergenic SNPs interact with nearest genes based on Hi-C (Fig. 1b, Extended Data Fig. 1a, Methods).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cMAGMA, ASD- and BD-associated genes were postnatally enriched, AD-associated genes did not display postnatal enrichment, and ALS-associated genes were prenatally enriched.

    “This distinction between psychiatric and degenerative disorders was less clear in cMAGMA: ASD- and BD-associated genes were postnatally enriched, AD-associated genes did not display postnatal enrichment, and ALS-associated genes were prenatally enriched (Extended Data Fig. 3, Supplementary Data 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Psychiatric disorders showed strong heritability enrichment in brain tissues, while degenerative disorders lacked brain-specific enrichment.

    “Consistent with the previous findings6, psychiatric disorders showed strong enrichment in brain tissues, while degenerative disorders lacked brain-specific enrichment (Extended Data Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    H-MAGMA detected a much larger number of SCZ-associated genes, which explained a significant proportion of heritability (4.7% of SNPs explained 38.93% of heritability, Enrichment=8.23, P=7.17x10-53).

    “H-MAGMA detected a much larger number of genes to be associated with SCZ, which explained a significant proportion of heritability (4.7% of SNPs explained 38.93% of heritability, Enrichment = 8.23, Enrichment P= 7.17x10–53, Methods).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The majority of brain disorders displayed enrichment in glutamatergic signaling, while ASD, SCZ, and ALS displayed enrichment in GABAergic signaling.

    “Further, while the majority of brain disorders displayed enrichment in glutamatergic signaling, ASD, SCZ, and ALS displayed enrichment in GABAergic signaling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Multiple aspects of glial development were associated with brain disorders, with stronger enrichment in degenerative disorders.

    “In support of this finding, multiple aspects of glial development were also associated with brain disorders, with stronger enrichment in degenerative disorders (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Neurotransmitter and synaptic pathways were implicated in multiple brain disorders.

    “Not surprisingly, neurotransmitter and synaptic pathways were implicated in multiple brain disorders, supporting decades of studies highlighting the importance of synaptic function in psychiatric disorders19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Zoghbi, H. Y. & Bear, M. F. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4, a009886 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    All brain disorders showed postsynaptic associations, while ADHD, SCZ, MDD, and MS also exhibited presynaptic associations.

    “For example, all brain disorders showed postsynaptic associations, while a selected set of disorders (ADHD, SCZ, MDD, and MS) also exhibited presynaptic associations.”
    Quote in the paperNot a substantial claim

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    Findingown data

    Neuronal differentiation and neuronal apoptotic pathways were enriched in all brain disorders.

    “Neuronal differentiation and neuronal apoptotic pathways were also enriched in all brain disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Amyloid beta enrichment was found for AD and PD, and tau enrichment for MS and PD.

    “Additional interesting findings include amyloid beta enrichment for AD and PD, and tau enrichment for MS and PD (Table 1), supporting amyloid beta and tau pathology in degenerative disorders26,27.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Iqbal, K., Liu, F. & Gong, C.-X. Tau and neurodegenerative disease: the story so far. Nat. Rev. Neurol. 12, 15–27 (2016). source

      Not checked in the free run.

    • cites [27] Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    cMAGMA gave similar results to H-MAGMA but with discrepancies including astrocytic expression of ASD-associated genes, lack of astrocytic expression of PD- and ALS-associated genes, and lack of endothelial expression of MS-associated genes.

    “While cMAGMA gave a similar result to H-MAGMA, there were important discrepancies, which include astrocytic expression of ASD-associated genes, lack of astrocytic expression of PD- and ALS-associated genes, and lack of endothelial expression of MS-associated genes (Extended Data Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Selective enrichment in excitatory neurons prevailed across development, as adult neuronal expression profiles for psychiatric disorder-associated genes also indicated excitatory neuronal enrichment.

    “This selective enrichment in excitatory neurons prevailed across development, as adult neuronal expression profiles for psychiatric disorder-associated genes also indicated excitatory neuronal enrichment (Extended Data Fig. 4b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cell-type specific H-MAGMA recapitulated biological processes, cell-type specificities, and developmental trajectories of brain homogenate H-MAGMA.

    “Cell-type specific H-MAGMA recapitulated biological processes, cell-type specificities, and developmental trajectories of brain homogenate H-MAGMA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ASD- and BD-associated genes were neither differentially regulated in psychiatric disorders nor enriched for any disease-associated co-expression modules.

    “ASD- and BD-associated genes were neither differentially regulated in psychiatric disorders nor enriched for any disease-associated co-expression modules (Extended Data Fig. 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cell-type specific H-MAGMA recapitulated cellular expression profiles: excitatory neuronal expression of psychiatric disorder risk genes, microglial expression of AD- and MS-associated genes, and astrocytic expression of PD- and ALS-associated genes.

    “For example, we observed excitatory neuronal expression of psychiatric disorder risk genes, microglial expression of AD- and MS-associated genes, and astrocytic expression of PD- and ALS-associated genes (Fig. 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Psychiatric disorder-associated genes showed prenatal enrichment with a peak during mid-gestation, while degenerative disorder-associated genes were postnatally enriched with a gradual increase in expression across a lifespan.

    “Further, psychiatric disorder-associated genes showed prenatal enrichment with a peak during mid-gestation, while degenerative disorder-associated genes were postnatally enriched with a gradual increase in expression across a lifespan (Fig. 3b–c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    AD- and PD-associated genes were expressed in mature astrocytes, while ALS-associated genes were highly expressed in fetal astrocytes.

    “We found that AD- and PD-associated genes were expressed in mature astrocytes, while ALS-associated genes were highly expressed in fetal astrocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Psychiatric disorder-associated genes coalesced in neurons, while degenerative disorder-associated genes were highly expressed in glia (microglia for AD and MS, astrocytes for ALS and PD).

    “One striking difference between psychiatric and degenerative disorders was that psychiatric disorder-associated genes coalesced in neurons, while degenerative disorder-associated genes were highly expressed in glia (microglia for AD and MS, astrocytes for ALS and PD, Extended Data Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Gene-level overlaps recapitulated the previously reported genetic architecture of brain disorders: psychiatric disorders exhibited strong overlaps in ranked gene lists, whereas degenerative disorders did not display significant overlaps.

    “Gene-level overlaps recapitulated the previously reported genetic architecture of brain disorders25: psychiatric disorders exhibited strong overlaps in their ranked gene lists, whereas degenerative disorders did not display significant overlaps (Extended Data Fig. 7a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] The Brainstorm Consortium et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    AD-associated genes were significantly enriched for DEGs in microglia and oligodendrocytes, but not in neurons.

    “We found that AD-associated genes were significantly enriched for DEGs in microglia and oligodendrocytes, but not in neurons (Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pleiotropic genes were involved in gene regulation, synaptic function, and neuronal and dendritic development.

    “Pleiotropic genes were involved in gene regulation, synaptic function, and neuronal and dendritic development (Fig. 5b).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingcitation

    Consistent with previous findings, a substantial overlap was detected between H-MAGMA and eQTL-based gene mapping tools.

    “Consistent with the previous finding3,11, we detected a substantial overlap.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018). source

      Not checked in the free run.

    • cites [11] Gusev, A. et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat. Genet. 50, 538–548 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    SNPs mapped to proximal genes may also have distal associations, whereas SNPs mapped to distal genes have no association with proximal genes.

    “SNPs mapped to proximal genes may also have distal associations, while SNPs mapped to distal genes do not have any association with proximal genes.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Psychiatric disorder-associated genes showed neurodevelopmental and neuronal enrichment.

    “Since psychiatric disorder-associated genes showed neurodevelopmental and neuronal enrichment, we used fetal brain and neuronal H-MAGMA results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    1,841 genes are shared in more than four disorders and are defined as pleiotropic genes.

    “In the end, we obtained 1,841 genes that are shared in more than four disorders, and defined them as pleiotropic genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Psychiatric disorders show strong genetic relationships at both the genetic correlation and gene-level overlap levels.

    “Psychiatric disorders show strong genetic relationships both at the level of genetic correlations (bottom left, rg) and gene-level overlaps (top right, RRHO).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    MAGMA was developed to extract biological insights from GWAS by linking risk variants to their cognate genes.

    “Multi-marker Analysis of GenoMic Annotation (MAGMA) was initially developed to extract biological insights from GWAS by linking risk variants to their cognate genes2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MAGMA assigns SNPs to nearest genes, which has the pitfall that non-coding SNPs can regulate distal genes via long-range (>10 kb) regulatory interactions.

    “MAGMA assigns SNPs to the nearest genes, which has two major pitfalls. First, it is becoming increasingly recognized that non-coding SNPs can regulate distal genes via long range (>10 kb) regulatory interactions, whereby distal enhancers are brought into contact with the gene promoter3,4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018). source

      Not checked in the free run.

    • cites [4] Won, H. et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538, 523–527 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MAGMA does not account for tissue-specific regulatory relationships, whereas disease risk SNPs are enriched in regulatory elements of the disease-relevant tissue.

    “Second, MAGMA does not take into account tissue-specific regulatory relationships, whereas disease risk SNPs are enriched in regulatory elements of the disease-relevant tissue5,6.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015). source

      Not checked in the free run.

    • cites [6] Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    MAGMA aggregates SNP associations to gene-level associations while correcting for confounding factors such as gene length, minor allele frequency, and gene density.

    “It aggregates SNP associations to gene-level associations while correcting for confounding factors such as gene length, minor allele frequency, and gene density2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    By comparing H-MAGMA with cMAGMA, non-coding SNPs often interact with distal genes, necessitating functional genomic evidence in assigning SNPs to cognate genes.

    “By comparing H-MAGMA with cMAGMA, we found that non-coding SNPs often interact with distal genes, necessitating the use of functional genomic evidence in assigning SNPs to cognate genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Most common risk variants for brain disorders from GWAS lie in non-coding regions, which makes biological interpretation difficult.

    “Most risk variants for brain disorders identified by genome-wide association studies (GWAS) reside in non-coding genome, which makes deciphering biological mechanisms difficult.”
    • Also stated in: § Introduction · plain
      “the majority of common risk variants reside in non-coding regions of the genome1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Edwards, S. L., Beesley, J., French, J. D. & Dunning, A. M. Beyond GWASs: illuminating the dark road from association to function. Am. J. Hum. Genet. 93, 779–797 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    H-MAGMA advances cMAGMA by incorporating functional genomics evidence and allowing developmental stage and cell-type specific gene mapping.

    “H-MAGMA advances conventional MAGMA (hereafter referred to as cMAGMA) by incorporating relevant functional genomics evidence and allowing developmental stage and cell-type specific gene mapping.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Traditional Hi-C guided gene mapping restricts analysis to genome-wide significant loci, while H-MAGMA can leverage sub-threshold loci that explain a significant proportion of heritability.

    “While traditional Hi-C guided gene mapping restricts its analysis to genome-wide significant (GWS) loci7, H-MAGMA can leverage signals from sub-threshold loci that explain a significant proportion of heritability8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017). source

      Not checked in the free run.

    • cites [8] Shi, H., Kichaev, G. & Pasaniuc, B. Contrasting the genetic architecture of 30 complex traits from summary association data. Am. J. Hum. Genet. 99, 139–153 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Psychiatric disorders have a strong neurodevelopmental predisposition, in contrast with degenerative disorders which have a postnatal origin.

    “This result is consistent with a strong neurodevelopmental predisposition for psychiatric disorders, in contrast with degenerative disorders which have a postnatal origin.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Developmental stages 5 and 6 represent mid-gestation, when upper layer neurons are generated and neuronal differentiation including axonogenesis and dendritic arborization occurs.

    “Developmental stages 5 and 6 represent mid-gestation, the period during which upper layer neurons are generated and neuronal differentiation including axonogenesis and dendritic arborization takes place12,13.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Kang, H. J. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011). source

      Not checked in the free run.

    • cites [13] De La Torre-Ubieta, L., Won, H., Stein, J. L. L. & Geschwind, D. H. H. Advancing the understanding of autism disease mechanisms through genetics. Nat. Med. 22, 345–361 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These results collectively highlight synaptic dysfunction in brain disorders, with distinctions among disorders based on neurotransmitters and pre/post synaptic associations.

    “These results collectively highlight synaptic dysfunction in brain disorders, albeit we could detect distinctions among disorders based on neurotransmitters and pre/post synaptic associations.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    ASD postmortem brains exhibit cell-type specific gene expression signatures such as upregulation of glial genes and downregulation of neuronal genes.

    “For example, ASD postmortem brains exhibit cell-type specific gene expression signatures such as upregulation of glial genes and downregulation of neuronal genes30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Parikshak, N. N. et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540, 423–427 (2016). source

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

    Premisecitation

    Microglia are increasingly recognized as a central cell type contributing to AD etiology.

    “Microglia are increasingly recognized as a central cell type contributing to the etiology of AD32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Hansen, D. V., Hanson, J. E. & Sheng, M. Microglia in Alzheimer’s disease. J. Cell Biol. 217, 459–472 (2018). source

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

    Premisecitation

    Common variation in SCZ maps onto specific groups of cells including pyramidal neurons and medium spiny neurons.

    “Common variation in SCZ maps onto specific groups of cells including pyramidal neurons and medium spiny neurons31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Skene, N. G. et al. Genetic identification of brain cell types underlying schizophrenia. Nat. Genet. 50, 825–833 (2018). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Cross-disorder GWAS of eight psychiatric disorders identified more than a hundred GWS loci increasing risk for multiple disorders.

    “Cross-disorder GWAS of eight psychiatric disorders recently identified more than a hundred GWS loci increasing risk for multiple disorders, further providing evidence of widespread pleiotropy among psychiatric disorders14.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell 179, 1469–1482.e11 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    H-MAGMA links non-coding SNPs to target genes based on functional genomic evidence and adds cellular context by using chromatin interaction data from disease-relevant tissue and cell types.

    “Compared with cMAGMA, H-MAGMA (1) links non-coding SNPs to their target genes based on functional genomic evidence, and (2) adds relevant cellular context to gene mapping by using chromatin interaction data from disease-relevant tissue and cell types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Variants associated with chromatin accessibility capture stimulus-sensitive signals and explain a significant proportion of heritability, even more so than eQTLs.

    “Second, it has been recently shown that the variants associated with chromatin accessibility capture stimulus-sensitive signals and explain a significant proportion of heritability, even more so than eQTLs47,48.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Alasoo, K. et al. Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response. Nat. Genet. 50, 424–431 (2018). source

      Not checked in the free run.

    • cites [48] Gate, R. E. et al. Genetic determinants of co-accessible chromatin regions in activated T cells across humans. Nat. Genet. 50, 1140–1150 (2018). source

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

    Study design and conductreasoning

    Data collection and analysis were not performed blind to the conditions of the experiments.

    “(3) data collection and analysis were not performed blind to the conditions of the experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    No data points were excluded from analysis.

    “Since we used publicly available GWAS summary statistics, (1) no data points were excluded from analysis”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    No statistical methods were used to pre-determine the sample size.

    “(2) no statistical methods were used to pre-determine the sample size”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Similar cell-type specificity was reported by the interactome study, demonstrating robustness of the result using an orthogonal approach.

    “Similar cell-type specificity was reported by the interactome study, demonstrating the robustness of the result using an orthogonal approach49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Mohammadi, S., Davila-Velderrain, J. & Kellis, M. Reconstruction of cell-type-specific interactomes at single-cell resolution. Cell Syst. 9, 559–568.e4 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Pleiotropic genes were associated with neuronal development and synaptic plasticity, suggesting inappropriate neuronal activity and regulation may act as key components in the pathogenesis of psychiatric disorders.

    “Pleiotropic genes were associated with neuronal development and synaptic plasticity, suggesting that inappropriate neuronal activity and regulation may act as key components in the pathogenesis of psychiatric disorders.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The cMAGMA input file was made comparable to H-MAGMA by using the same gene model and SNP list, with a window of 35 kb upstream and 10 kb downstream of each gene.

    “We generated an input file for cMAGMA that is comparable to H-MAGMA. We used the same gene model (Gencode v26) and a SNP list used for H-MAGMA, and allowed a window of 35kb upstream and 10kb downstream of each gene as previously described16,52.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Network Pathway Analysis Subgroup of the Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci. 18, 199–209 (2015). source

      Not checked in the free run.

    • cites [52] Pardiñas, A. F. et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat. Genet. 50, 381–389 (2018). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Differentially expressed genes in postmortem brains with psychiatric disorders at FDR < 0.05 were obtained from Gandal et al., 2018.

    “Differentially expressed genes (DEG) in postmortem brains with psychiatric disorders were obtained from Gandal et al., 201840 (FDR<0.05).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Gandal, M. J. et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362, eaat8127 (2018). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Union disorder risk genes were used to ensure that developmental expression trajectories are not dictated by the developmental stage from which Hi-C data was obtained.

    “To ensure that developmental expression trajectories are not dictated by the developmental stage from which Hi-C data was obtained, we used union disorder risk genes.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Cell-type-specific differentially expressed genes in Alzheimer's disease postmortem brains were obtained from Mathys et al., 2019.

    “Cell-type specific DEG in AD postmortem brains was obtained from Mathys et al., 201924.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    H-MAGMA results were restricted to those from adult brain to match the developmental period and brain region of the eQTL database.

    “We restricted our H-MAGMA results to those derived from the adult brain so that we can match the developmental period (adult) and brain region (DLPFC) with the eQTL database.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    In comparing H-MAGMA outputs with gene lists harboring protein-disrupting variation, a generalized linear model controlled for exome length and the number of SNPs mapped to each gene.

    “In comparing H-MAGMA outputs (common variation) with the gene lists that harbor protein disrupting variation (rare variation), we used a generalized linear model controlling for the exome length (controlling for rare variation) and the number of SNPs mapped to each gene (controlling for common variation).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein-disrupting variation in brain disorders is dependent on the exon but not on gene length.

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

    Study design and conductcitation

    In comparing H-MAGMA outputs with differentially expressed genes, the gene-set analysis embedded in MAGMA used whole gene-level association statistics while controlling for covariates such as gene size and LD.

    “In comparing H-MAGMA outputs with DEG, we used the gene-set analysis embedded in MAGMA, which utilizes the whole gene-level association statistics while controlling for covariates such as gene size and LD2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015). source

      Not checked in the free run.

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

    Study design and conductnone given

    Neuronal Hi-C was used for psychiatric disorders and astrocytic Hi-C for degenerative disorders to verify developmental trajectories in a cell-type-specific manner.

    “To further verify the developmental trajectories in a cell-type specific fashion, we used neuronal Hi-C for psychiatric disorders and astrocytic Hi-C for degenerative disorders.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    110 schizophrenia risk genes with elevated burden of rare variation at FDR < 0.3 were obtained from Singh et al., 2016.

    “Schizophrenia risk genes with elevated burden of rare variation were obtained from Singh et al., 201666 (110 genes with FDR<0.3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016). source

      Not checked in the free run.

61 of 61

  • The paper relies on this without support.

    Protein-disrupting variation in brain disorders is dependent on the exon but not on gene length.

    “We took this alternative approach than using MAGMA gene-set analysis because protein disrupting variation in brain disorders was detected by exome-sequencing and is dependent on the exon, but not gene length.”

  • The paper relies on this without support.

    Non-coding genes have much lower expression values than protein-coding genes, which can dilute signals.

    “We restricted our analysis only on protein-coding genes, because (1) the majority of genes detected in the spatiotemporal transcriptomic atlas12, single cell expression datasets60–62, and gene ontologies were protein-coding genes, and (2) non-coding genes have much lower expression values compared with protein-coding genes, which can dilute the signals.”

  • The paper relies on this without support.

    The majority of genes detected in the spatiotemporal transcriptomic atlas, single-cell expression datasets, and gene ontologies are protein-coding genes.

    “We restricted our analysis only on protein-coding genes, because (1) the majority of genes detected in the spatiotemporal transcriptomic atlas12, single cell expression datasets60–62, and gene ontologies were protein-coding genes, and (2) non-coding genes have much lower expression values compared with protein-coding genes, which can dilute the signals.”

  • The paper relies on this without support.

    The complexity of linkage disequilibrium in the MHC region can override the overall pattern.

    “We also excluded genes within the MHC region due to the complexity of LD, which can override the overall pattern.”
4 of 4

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?

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Pleiotropic-gene threshold alternates between four and five disorders

    Minor

    The results introduce the gene set using a threshold of at least four psychiatric disorders, but then describe the 1,841 genes as shared in more than four. These thresholds differ for genes shared in exactly four disorders.

  • Stage 6 has two different age ranges

    Minor

    The results define developmental stage 6 as 19-22 post-conception weeks, but the Methods define it as 19-24 weeks.

2 of 2

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Authors
Sey, N. Y. A., Hu, B., Mah, W., Fauni, H., McAfee, J. C., Rajarajan, P., Brennand, K. J., Akbarian, S., & Won, H.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Won, Hyejung
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2020-03-09
Volume
23
Issue
4
Pages
583-593
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-020-0603-0
PMC
PMC7131892
OpenAlex
W3009063121
Semantic Scholar
f35ffcf138c22bfc43a0a99a2bb24338a41bf44b
Cited by
297
References
93
Citations by year
2026: 29 · 2025: 45 · 2024: 48 · 2023: 33 · 2022: 53 · 2021: 51 · 2020: 36
FWCI
26.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (5T32NS007431)
  • UNC | University of North Carolina at Chapel Hill (Helen Lyng White Fellowship)
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R56MH101454, R0MH106056, R00MH113823, DP2MH122403)
  • Brain and Behavior Research Foundation (NARSAD Young Investigator)
  • Simons Foundation (605259)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
Keywords
magma, brain disorders, risk genes, chromatin interactions, Hi-C, non-coding variants, mental illness, neurodegenerative diseases, gene regulatory relationships, developmental timing, excitatory neurons, brain cell types, gene expression, genome-wide association study
MeSH terms
Brain, Brain Diseases, Chromatin, Humans, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genomics

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