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Cited by 1,126Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Open access
ARUK Consortium, Sims, Rebecca, GERAD/PERADES, CHARGE, ADGC, EADI, van der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna +443 more·2017·Nature Genetics
DOI 10.1038/ng.3916PMC PMC5669039
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Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Integrity signals

Registry

Crossref · 10.1038/ng.3916

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

56 of 74 cited sources checked · 30 supported · 1 flagged · accuracy not yet measured

  • Findingown data

    Evidence for the previously reported TREM2 rare variant p.R47H was observed.

    “We also observed evidence for the previously reported9,11 TREM2 rare variant p.R47H (Table 2).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013). source
    • cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). source
  • Premisecitation

    Functional annotation indicates ABI3 participates in innate immunity through interferon signaling.

    “Functional annotation (Supplementary Table 21) suggests ABI3 (Supplementary Figure 14) plays a role in the innate immune response via interferon-mediated signaling40.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Fairfax, B.P. et al. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014). source

      The Results sections on IFNβ signaling and IRF2-modulated gene targets discuss interferon-related innate immune networks, but neither links them to ABI3. Searches for ABI3, its expanded name, and ABI3 with interferon-mediated signaling found no passage in our copy supporting the specific claim about ABI3. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Premisecitation

    Previous analysis of normal brain co-expression networks identified 4 gene modules enriched for common variants associated with late-onset Alzheimer's disease risk.

    “Previous analysis of normal brain co-expression networks identified 4 gene modules that are enriched for common variants associated with LOAD risk2,3711.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [2] Lambert, J.-C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013). source

      The paper’s Abstract discusses pathways enriched for Alzheimer’s disease GWAS association signals, but does not describe an analysis of normal-brain co-expression networks or identify four gene modules. Searches for “co-expression modules,” “four gene modules,” and “brain expression modules” found no passage establishing the attributed finding. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [3711]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    Eight gene pathway clusters were previously identified as significantly enriched in Alzheimer's disease-associated common variants.

    “We previously identified 8 gene pathway clusters significantly enriched in AD-associated common variants36.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013). source

      The Results section (“Pathway analyses”; page unavailable) reports significant enrichment of gene ontology terms and a diabetes pathway among SNPs associated with CSF tau or phosphorylated tau. It does not report eight gene pathway clusters enriched in Alzheimer’s disease-associated common variants; the measured associations and the claimed count differ. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Findingcitation

    TREM2, ABI3 and PLCG2 have a common expression pattern in human brain cortex, with high expression in microglia and limited expression in neurons, oligodendrocytes, astrocytes and endothelial cells.

    “TREM2, ABI3 and PLCG2 have a common expression pattern in human brain cortex, with high expression in microglia cells and limited expression in neurons, oligodendrocytes, astrocytes and endothelial cells (Supplementary Figure 12)38.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016). source

      The Results section, “Transcriptomes of acutely purified human neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells” (page unavailable), describes cortical cell-type RNA-seq data. But neither that passage nor searches for TREM2, ABI3, and PLCG2 yielded a passage reporting their relative expression across those cells, so the claimed pattern cannot be verified from our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 29
  • May combine two claims. 37
  • The quote only partly states this claim. 1

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

    Premisecitation

    Nearly 30 late-onset Alzheimer's disease susceptibility loci are known, and risk is significantly polygenic.

    “Nearly 30 LOAD susceptibility loci2-12 are known, and risk is significantly polygenic13.”
    Quote in the paperNot a substantial claim8 of 10 sources checked
    • cites [2] Lambert, J.-C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013). source

      The Abstract reports 11 previously identified LOAD susceptibility loci and 11 newly identified loci, supporting this paper’s contribution to the cited group of susceptibility-locus findings. It does not establish the sentence’s total of nearly 30 loci. The separate claim that risk is significantly polygenic is attached to citation 13, not to this paper. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [3] Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009). source
    • cites [4] Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1099 (2009). source

      The paper reports genome-wide significant associations for CLU and PICALM, supporting its use among citations for late-onset Alzheimer’s susceptibility loci. It does not establish that nearly 30 loci were known; it says only APOE had previously been established unequivocally. The separate citation 13, not this paper, is attached to the polygenic-risk clause. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [5] Escott-Price, V. et al. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS One 9, e94661 (2014). source
    • cites [6] Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011). source

      The Abstract (page unavailable) identifies five new Alzheimer’s disease susceptibility genes and discusses several previously identified loci, so this paper supports the existence of multiple susceptibility loci. It does not establish the cited total of nearly 30. The separate claim that risk is significantly polygenic is attached to citation 13, not to this paper. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [7] Naj, A.C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011). source

      The citation is attached to the susceptibility-loci count, not the separate claim about polygenic risk. In the paper’s discussion (section labeled Abstract in our copy), the authors state that, with their findings, there are now ten known LOAD susceptibility loci—not nearly 30. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [8] Ruiz, A. et al. Toward fine mapping and functional characterization of genome-wide association study–identified locus rs74615166 (TRIP4) for Alzheimer's disease. Alzheimers Dement. 10, 257–P258 (2014). source
    • cites [9] Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013). source
    • cites [10] Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012). source
    • cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). source

  • May combine two claims.

    Premisecitation

    Deletions and missense mutations in PLCG2 affect the cSH2 autoinhibitory region and produce mixed loss- and gain-of-function signaling.

    “Genomic deletions (PLAID) and missense mutations (APLAID) affect the cSH2 autoinhibitory regulatory region. The result is a complex mix of loss and gain of function in cellular signalling39.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Milner, J.D. PLAID: a syndrome of complex patterns of disease and unique phenotypes. J. Clin. Immunol. 35, 527–530 (2015). source

      The PLAID discussion (indexed under Abstract; no page given) says the deletions span the autoregulatory cSH2 domain and that PLAID involves a mix of loss- and gain-of-function signaling. It also places the APLAID missense mutation in the same region, but reports enhanced signaling for APLAID rather than the same mixed response. The mixed-signaling conclusion is therefore supported for PLAID, not clearly for both conditions. (LLM, conf=0.84)

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

    Findingcitation

    A different suggestive common variant signal in another late-onset Alzheimer's disease case-control study was observed (P=6.3×10-7).

    “We also observed a different suggestive common variant signal in another LOAD case-control study (P=6.3×10-7)2.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Lambert, J.-C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013). source

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

    Premisecitation

    PLCG2 variants cause Antibody Deficiency and Immune Dysregulation (PLAID) and Autoinflammation and PLAID (APLAID).

    “PLCG2 variants also cause Antibody Deficiency and Immune Dysregulation (PLAID) and Autoinflammation and PLAID (APLAID)39.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Milner, J.D. PLAID: a syndrome of complex patterns of disease and unique phenotypes. J. Clin. Immunol. 35, 527–530 (2015). source

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

    Premisecitation

    A common variant late-onset Alzheimer's disease association near TREM2 was previously reported in a GWAS of cerebrospinal fluid tau and P-tau.

    “We previously reported a common variant LOAD association near TREM2, in a GWAS of cerebrospinal fluid tau and P-tau36.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013). source

      The Results (Novel loci associated with CSF tau and ptau levels; page unavailable) identify a common variant in TREML2 near TREM2 associated with CSF biomarker levels. But the paper does not establish that this common variant is associated with late-onset Alzheimer’s disease risk: the Discussion reports no AD-risk association for the lead variant at the locus, while identifying a separate rare TREM2 variant that increases risk. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Recent sequencing studies identified a number of genes with rare variants associated with Alzheimer's disease.

    “Recent sequencing studies identified a number of genes that have rare variants associated with AD9-11,18-24.”
    Quote in the paperNot a substantial claim7 of 10 sources checked
    • cites [9] Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013). source
    • cites [10] Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012). source
    • cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). source
    • cites [18] Vardarajan, B.N. et al. Coding mutations in SORL1 and Alzheimer disease. Ann. Neurol. 77, 215–227 (2015). source
    • cites [19] Vardarajan, B.N. et al. Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Ann. Neurol. 78, 487–498 (2015). source
    • cites [20] Steinberg, S. et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nat. Genet. 47, 445–447 (2015). source
    • cites [21] Logue, M.W. et al. Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans. Alzheimers Dement. 10, 609–618 (2014). source
    • cites [22] Jun, G. et al. PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ann. Neurol. 76, 379–392 (2014). source

      The Introduction reports an association between Alzheimer disease and SNPs in PLXNA4, and the Results identify an associated PLXNA4 SNP with a minor allele frequency of 0.04. But the Methods describe array genotyping and imputation, not sequencing, and this paper does not report sequencing studies identifying rare variants in a number of Alzheimer-associated genes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [23] Hunkapiller, J. et al. A rare coding variant alters UNC5C function and predisposes to Alzheimer's disease. Alzheimers Dement. 9, 853 (2013). source
    • cites [24] Wetzel-Smith, M.K. et al. A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death. Nat. Med. 20, 1452–1457 (2014). source

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

    Premisecitation

    ABI3 contributes to actin cytoskeleton organization via the WAVE2 complex, which regulates pathways for T-cell activation.

    “ABI3 plays a significant role in actin cytoskeleton organization through participation in the WAVE2 complex41, a complex that regulates multiple pathways leading to T-cell activation42.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [41] Sekino, S. et al. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun. Signal. 13, 41 (2015). source
    • cites [42] Nolz, J.C. et al. The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16, 24–34 (2006). source

  • May combine two claims.

    Findingown data

    151 genes present in 2 or more of these 4 modules showed strong enrichment for late-onset Alzheimer's disease-associated common variants (P=4.0×10-6) and for rare variants described here (MAF<1%) (P=1.17×10-6).

    “We identified 151 genes present in 2 or more of these 4 modules and these showed a strong enrichment for LOAD-associated common variants (P=4.0×10-6)36 and for rare variants described here (MAF<1%)(Supplementary Table 15P=1.17×10-6).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013). source

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

    Premisecitation

    In the common variation dataset, defining genes without surrounding genomic sequence produced the most significant excess of enriched pathways.

    “Genes were defined without surrounding genomic sequence, as this yielded the most significant excess of enriched pathways in the common variation dataset11.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). source

      The Methods sections describe TREM2 variant analysis and a meta-analysis of genomewide association studies, but do not compare gene definitions or report pathway enrichment. Searches for the claimed excess of enriched pathways and for genes defined without surrounding genomic sequence found no passage addressing either point. Page numbers were not available in our copy. (LLM, conf=0.75)

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

    Premisecitation

    Loss-of-function mutations in CSF1R cause hereditary diffuse leukoencephalopathy with spheroids, a white matter disease linked to microglial dysfunction.

    “Loss-of function mutations in CSF1R cause hereditary diffuse leukoencephalopathy with spheroids, a white matter disease related to microglial dysfunction48.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2011). source

      The Abstract identifies CSF1R mutations in families with HDLS, describes HDLS as a white matter disease, and suggests a role for microglial dysfunction. It says the functional findings suggest HDLS may result from a partial loss of CSF1R function; the claim presents loss of function as established. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SPI1 is a central transcription factor in microglial activation, has a significant gene-wide association with Alzheimer's disease, and lies near genome-wide significant signals from IGAP.

    “SPI1 is a central transcription factor in microglial activation state that has a significant gene-wide association with AD5 and is in the proximity of GWS signals identified by IGAP2.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [5] Escott-Price, V. et al. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS One 9, e94661 (2014). source
    • cites [2] Lambert, J.-C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013). source

      The paper’s Table 2 (Statistical analysis; page unavailable) reports a genome-wide significant Alzheimer’s disease signal at CELF1. Our copy does not identify SPI1 or establish that it lies near that signal; searches for SPI1 and PU.1 found no relevant passage. The microglial-activation and gene-wide-association parts of the citing sentence carry a different citation, so this verdict concerns the IGAP signal claim. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    TREM2 risk variants lie in exon 2, predicted to encode the conserved extracellular ligand-binding region; disruption there may weaken or eliminate TREM2 signaling and reduce TREM2 function.

    “TREM2 risk variants are located within exon 2, which is predicted to encode the conserved ligand binding extracellular region of the protein. Any disruption in this region may attenuate or abolish TREM2 signaling, resulting in the loss or decrease in TREM2 function47.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [47] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015). source

      The Results section (‘R47H mutation impairs Trem2 recognition of lipid ligands’; page not provided) reports reduced ligand-evoked reporter activation, supporting decreased TREM2 function for that variant. It does not identify exon 2 or describe a conserved ligand-binding region. It also says R47H did not detectably affect TREM2 signaling when stimulated with an antibody, so the claim that disruption there may abolish signaling goes beyond these findings. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SYK regulates Aβ production and tau hyperphosphorylation, is affected by the INPP5D/CD2AP complex encoded by two late-onset Alzheimer's disease-associated genes, and phosphorylates PLCG2.

    “SYK regulates Aβ production and tau hyperphosphorylation54, is affected by the INPP5D/CD2AP complex55 encoded by two LOAD associated genes2, and mediates phosphorylation of PLCG256.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [54] Paris, D. et al. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and tau hyperphosphorylation. J. Biol. Chem. 289, 33927–33944 (2014). source
    • cites [55] Bao, M. et al. CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. J. Immunol. 189, 786–792 (2012). source
    • cites [56] Kurosaki, T. & Tsukada, S. BLNK: connecting Syk and Btk to calcium signals. Immunity 12, 1–5 (2000). source

  • May combine two claims.

    Premisecitation

    Nilvadipine, an anti-hypertensive drug in a phase III Alzheimer's disease trial, targets SYK and TYROBP, a hub gene in an Alzheimer's disease-related brain expression network that encodes the TREM2 complex protein DAP12.

    “Notably, the anti-hypertensive drug Nilvadipine, currently in a phase III AD clinical trial, targets SYK as well as TYROBP, a hub gene in an AD-related brain expression network38, that encodes the TREM2 complex protein DAP12.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016). source

      The Results sections discuss human astrocyte gene expression, and the supplied References do not establish the claimed Alzheimer’s disease-related network. Searches for Nilvadipine, SYK, TYROBP, TREM2 and DAP12 found no passage in our copy addressing the drug targets or TYROBP’s claimed network role. No page numbers were available for these passages. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In the same brain tissue, four CpG sites showed differential methylation and two H3K9ac sites adjacent to PLCG2 and ABI3 showed lower acetylation, both associated with increased global neuritic plaque and tangle burden (FDR < 0.05).

    “From the same brain tissue, we examined methylation (n=714)16 and H3K9ac acetylation (n=676) data and found differential methylation at four CpG sites and lower acetylation at two H3K9ac sites adjacent to PLCG2 and ABI3 in relation to increased global neuritic plaque and tangle burden (FDR < 0.05).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Schork, N.J., Murray, S.S., Frazer, K.A. & Topol, E.J. Common vs. rare allele hypotheses for complex diseases. Curr. Opin. Genet. Dev. 19, 212–219 (2009). source

      The cited paper’s section on neuropsychiatric disease discusses rare copy-number variations, not brain-tissue methylation or H3K9ac. Searches for PLCG2, ABI3, the CpG and acetylation findings, and the reported sample sizes found no passage addressing them in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In microglia, TREM2-DAP12 promotes an M2-like activation state and helps recognize membrane debris and amyloid deposits, leading to microglial activation and proliferation.

    “In microglia, TREM2-DAP12 induces an M2-like activation44 and participates in recognition of membrane debris and amyloid deposits resulting in microglial activation and proliferation45-47.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [44] Neumann, H. & Takahashi, K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J. Neuroimmunol. 184, 92–99 (2007). source
    • cites [45] Painter, M.M. et al. TREM2 in CNS homeostasis and neurodegenerative disease. Mol. Neurodegener. 10, 43 (2015). source

      The Conclusion (page unavailable) says TREM2-DAP12 supports debris clearance and a transcriptional profile associated with enhanced myeloid-cell proliferation. The phagocytosis section reports microglial uptake of apoptotic neuronal membranes and Aβ. The copy does not establish an M2-like state or show that TREM2-DAP12 recognizes amyloid deposits and thereby causes microglial activation and proliferation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [46] Ulrich, J.D. et al. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol. Neurodegener. 8, 13 (2013). source

      The Background and Results and discussion sections address apoE, amyloid-β, and microdialysis, not TREM2-DAP12 signaling. Searches for TREM2-DAP12, M2-like activation, and recognition of membrane debris or amyloid deposits found no passage addressing the attributed microglial mechanism. No page numbers are available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [47] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015). source

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

    Premisecitation

    Pharmacological targeting of CSF1R inhibits microglial proliferation and shifts the microglial inflammatory profile toward an anti-inflammatory phenotype in murine models.

    “Pharmacological targeting of CSF1R inhibits microglial proliferation and shifts the microglial inflammatory profile to an anti-inflammatory phenotype in murine models53.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain 139, 891–907 (2016). source

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

    Premisecitation

    Activated microglia surround plaques, a finding consistently seen in Alzheimer's disease brain and Alzheimer's disease transgenic mouse models.

    “Activated microglial cells surround plaques49,50, a finding consistently observed in AD brain and AD transgenic mouse models51.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [49] Perlmutter, L.S., Barron, E. & Chui, H.C. Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease. Neurosci. Lett. 119, 32–36 (1990). source
    • cites [50] Wisniewski, H.M., Wegiel, J., Wang, K.C. & Lach, B. Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol. 84, 117–127 (1992). source
    • cites [51] Schwab, C., Klegeris, A. & McGeer, P.L. Inflammation in transgenic mouse models of neurodegenerative disorders. Biochim. Biophys. Acta 1802, 889–902 (2010). source

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

    Premisecitation

    The 151 genes appearing in at least two of the four co-expression modules were especially strongly enriched for IGAP GWAS association.

    “The 151 genes present in 2 or more of these 4 modules were particularly strongly enriched for IGAP GWAS association41.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Sekino, S. et al. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun. Signal. 13, 41 (2015). source

      The Results passages describe NESH/Abi-3, WAVE2, and cell-spreading experiments, not gene co-expression modules or GWAS enrichment. Searches for the 151-gene claim and for IGAP GWAS returned no passage addressing either point in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    High TREM2 expression has been shown to correlate with increasing neuritic plaque burden.

    “Similarly, high TREM2 expression has been shown to correlate with increasing neuritic plaque burden17.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Surakka, I. et al. The impact of low-frequency and rare variants on lipid levels. Nat. Genet. 47, 589–597 (2015). source

      The Results section on biological profiling discusses CD300LG and TM6SF2 expression, not TREM2 expression or neuritic plaques (page unavailable). Searches for TREM2, neuritic plaques, and plaque burden found no passage in our copy reporting the claimed correlation; the References mention TREM molecules only in connection with lipid recognition. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    TREM2 rs143332484/p.R62H is a novel genome-wide significant Alzheimer's disease variant with P=1.55×10-14, OR=1.67, MAF 0.0143 in cases and 0.0089 in controls.

    “and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene.”
    • Also stated in: § Abstract · plain
      “we report the first evidence for GWS association at TREM2 coding variant p.R62H (P=1.55×10-14, OR=1.67), with a MAF of 0.0143 in cases and 0.0089 in controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PLCG2 rs72824905/p.P522R is a protective Alzheimer's disease variant with P=5.38×10-10, OR=0.68, MAF 0.0059 in cases and 0.0093 in controls.

    “a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093)”
    • Also stated in: § Abstract · plain
      “The first is a missense variant p.P522R (P=5.38×10-10, OR=0.68) in Phospholipase C Gamma 2 (PLCG2)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Removing p.R47H and p.R62H from the analysis diminished the TREM2 gene-wide association, but a signal remained (PSKAT-O=6.3×10-3, PBurden=4.1×10-3).

    “Removal of p.R47H and p.R62H variants from the analysis diminished the gene-wide association but the signal remains interesting (PSKAT-O=6.3×10-3, PBurden=4.1×10-3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The ABI3 p.F209 variant shows consistent evidence for increasing late-onset Alzheimer's disease risk across all stages, with MAF 0.011 in cases and 0.008 in controls.

    “The p.F209 variant shows consistent evidence for increasing LOAD risk across all stages, with a MAF of 0.011 in cases and 0.008 in controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PLCG2 p.P522R is associated with decreased risk of late-onset Alzheimer's disease, with MAF 0.0059 in cases and 0.0093 in controls.

    “This variant is associated with decreased risk of LOAD, showing a MAF of 0.0059 in cases and 0.0093 in controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PLCG2, ABI3, and TREM2 are up-regulated in late-onset Alzheimer's disease human cortex and in two APP mouse models.

    “PLCG2, ABI3, and TREM2 are up-regulated in LOAD human cortex and in two APP mouse models.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Pathway analyses on the rare variant data using all 9,816 pathways found top pathways related to lipoprotein particles, cholesterol efflux, B-cell differentiation and immune response, areas also enriched when common variants are analyzed.

    “The top pathways are related to lipoprotein particles, cholesterol efflux, B-cell differentiation and immune response, areas of biology also enriched when common variants are analyzed37(Supplementary Table 16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] International Genomics of Alzheimer's Disease Consortium (IGAP).. Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimers Dement. 11, 658–671 (2015).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    Gene-wide analysis of PLCG2 showed nominal evidence for association at P=1.52×10-4, and no other independent association at this gene was found.

    “Gene-wide analysis showed nominal evidence for association at P=1.52×10-4 (Supplementary Tables 10 & 11) and we found no other independent association at this gene (Supplementary Figure 5).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The reference allele p.P522 is conserved across several species.

    “The reference allele (p.P522) is conserved across several species (Supplementary Figure 4).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The reference allele for ABI3 p.S209F is conserved across multiple species.

    “The reference allele is conserved across multiple species (Supplementary Figure 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 56-gene subset is strongly enriched for association signals from the previous common variant analysis (P=5.0×10-6) and this rare variant gene-set analysis (P=1.08×10-7).

    “This subset is strongly enriched for association signals from both the previous common variant analysis (P=5.0×10-6, Supplementary Table 17) and this rare variant gene-set analysis (P=1.08×10-7, Supplementary Table 15).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TREM2 p.R62H and p.R47H are not in linkage disequilibrium, and conditional analyses confirmed they are independent risk variants.

    “These variants are not in linkage disequilibrium (Supplementary Table 14) and conditional analyses confirmed that p.R62H and p.R47H are independent risk variants (Supplementary Figure 11).”
    Quote in the paperSubstantial claim

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

    Findingown data

    B4GALNT2, adjacent to ABI3, contained an independent suggestive association that failed to replicate in subsequent stages (Pcombined=1.68×10-4).

    “The B4GALNT2 gene, adjacent to ABI3, contained an independent suggestive association (Supplementary Figure 8), but this failed to replicate in subsequent stages (Pcombined=1.68×10-4)(Supplementary Table 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 56-gene interaction network is enriched for immune response genes and contains TREM2, PLCG2, ABI3, SPI1, INPP5D, CSF1R, SYK and TYROBP.

    “The 56-gene interaction network identified here is enriched in immune response genes and includes TREM2, PLCG2, ABI3, SPI1, INPP5D, CSF1R, SYK and TYROBP (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both the 151-gene set and the 56-gene subset are highly significantly enriched for association with rare variants having MAF<1% (P=1.17×10-6 and P=1.08×10-7, respectively).

    “Both the set of 151 genes (P=1.17×10-6) and the subset of 56 genes (P =1.08×10-7) show highly significant enrichment for association in the rare variants with MAF<1%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The top pathways in the rare variant analysis relate to immune response, B-cell differentiation, cholesterol efflux, and lipoprotein particles, and closely parallel the common variant results.

    “The top pathways are related to lipoprotein particles, cholesterol efflux, B-cell differentiation and immune response, and closely parallel the common variant results (Supplementary Table 16).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Under a conservative analysis that excluded the APOE region and corrected for possible LD between genes, both the 151-gene set and the 56-gene subset remained significantly enriched (P=5.15×10-5 and P=2.98×10-7, respectively).

    “Both the set of 151 genes (P=5.15×10-5) and the subset of 56 genes (P=2.98×10-7) show significant enrichment under a conservative analysis excluding the APOE region and correcting for possible LD between the genes (Supplementary Table 17).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After omitting TREM2, both the set of 151 genes and the subset of 56 genes still showed significant enrichment of signal (P=2.78×10-3 and P=0.010, respectively).

    “Both the set of 151 genes (P=2.78×10-3) and the subset of 56 genes (P=0.010) (Supplementary Table 18) still showed significant enrichment of signal”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Late-onset Alzheimer's disease has a significant genetic component, with heritability estimated at 58-79%.

    “Late-onset AD (LOAD) has a significant genetic component (h2=58-79%1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006). source

  • May combine two claims.

    Interpretationown data

    The remaining 95 genes only have nominally significant enrichment for either common or rare variants, suggesting the 56-gene network is driving the enrichment.

    “The remaining 95 genes only have nominally-significant enrichment for either common or rare variants (Supplementary Tables 15 & 17), suggesting that the 56-gene (Supplementary Table 18) network is driving the enrichment.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    PLCG2 produces a transmembrane signaling enzyme, PLCγ2, which breaks down PIP2 into IP3 and DAG.

    “PLCG2 (Supplementary Figure 13) encodes a transmembrane signaling enzyme (PLCγ2) that hydrolyses the membrane phospholipid PIP2”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Activation of the receptor triggers Syk and ZAP70 signaling, which activates PI3K and modulates PLCγ2.

    “Receptor activation results in activation of Syk and ZAP70 signaling which in turn activates PI3K activity and influences PLCγ2 activity43.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Xing, J., Titus, A.R. & Humphrey, M.B. The TREM2–DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective. Res. Rep. Biochem. 5, 89–100 (2015).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    Three independent analysts verified the meta-analysis results.

    “Three independent analysts confirmed the meta-analysis results.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Genotyping and quality control for all samples were done without knowledge of disease status.

    “All sample genotyping and quality control was performed blind to participant’s disease status.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Stage 2 variants were filtered for call rate and Hardy-Weinberg equilibrium in cases or controls.

    “Variants were filtered based on call rate excluding variants with >10% missingness and HWE excluding variants with PHWE<1×10-5 in either cases or controls.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Stage 1 variants were filtered for call rate, genotype cluster separation, and Hardy-Weinberg equilibrium.

    “Variants were filtered based on call rate excluding variants with >1% missingness, genotype cluster separation excluding variants with a separation score < 0.4 and Hardy-Weinberg equilibrium (HWE) excluding variants with PHWE < 1×10-4.”
    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

    Ten principal components were extracted with EIGENSTRAT, and the first three were included as covariates because they most affected the genomic control inflation factor.

    “Ten principal components (PCs) were extracted using EIGENSTRAT, including the first three PCs as covariates had the maximum impact on the genomic control inflation factor, λ2.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    The expression findings for PLCG2 and ABI3 agree with prior reports of high expression in monocytes, spleen, and whole blood (ROADmap project) and in microglia (Zhang et al.).

    “These findings are consistent with the high levels of expression of both PLCG2 and ABI3 in peripheral monocytes, spleen, and whole blood reported by the ROADmap project and in microglia as reported by Zhang et al15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001). source

  • May combine two claims.

    Study design and conductreasoning

    The protein interaction network procedure uses only protein interaction data and is agnostic to genetic association strength, so genetic association in the 56 network genes can be compared with the original 151 genes without bias.

    “Note that the procedure for generating the protein interaction network relies only on protein interaction data, and is agnostic to the strength of GWAS or rare-variant association for each gene. Thus the strength of genetic association in the set of 56 network genes can be tested relative to that in the original set of 151 genes without bias.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    For rare variants, additional exonic sites with lower MAF or effect size, and intronic or intergenic sites, may exist.

    “For rare variants, there may be additional exonic sites with lower MAF or effect size, and/or intronic and intergenic sites.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    TREM2 encodes a transmembrane receptor found on the plasma membrane of brain microglia.

    “TREM2 encodes a transmembrane receptor present in the plasma membrane of brain microglia”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The remaining heritability may come from many common variants with small effects.

    “The remaining heritability may be due to a large number of common variants of small effect size.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Concordance between stage 3 imputed and exome chip genotypes exceeded 99% overall and averaged above 88.5% for alternate allele genotypes.

    “overall concordance was >99%, while concordance among alternate allele genotypes (heterozygotes and alternate allele homozygotes) was >88.5% on average (N=13,000 samples).”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    The conservative secondary analysis, which removed the APOE region and the less significant gene from each pair of pathway genes within 1 Mb, removes potential bias in the enrichment test from LD between genes and from dropping less significant genes.

    “This highly conservative procedure removes any potential bias in the enrichment test both from LD between the genes, and also from dropping less significant genes from the analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    With two groups of 100, a two-sample t-test, and equal standard deviations, power is 80% to detect effect sizes of 0.40, 0.49, and 0.59 at p<0.05, 0.01, and 0.001, respectively.

    “Assuming two samples of 100 per group, two-sample t-test, same standard deviation, we will have 80% power to detect effect sizes of 0.40, 0.49 and 0.59 at p<0.05, 0.01 and 0.001, respectively, where effect size is the difference in means between two groups divided by the within-group standard deviation.”
    Quote in the paperNot a substantial claim
55 of 55

  • The paper relies on this without support.

    Prior work on normal brain co-expression networks found four modules enriched for common AD-risk variants in the IGAP GWAS.

    “Previous analysis of normal brain co-expression networks identified 4 gene modules that were enriched for common variants associated with AD risk in the IGAP GWAS.”

  • The paper relies on this without support.

    All four co-expression modules were enriched for immune-related genes.

    “Each of these 4 modules was also found to be enriched for immune-related genes.”

  • The paper relies on this without support.

    Cell number changes occur with AD neuropathology.

    “to account for cell number changes that occur with AD neuropathology.”
3 of 3

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?

  • Over 70 loci are associated with conferring risk for late-onset Alzheimer's disease.

    “In recent years, genome wide association studies (GWASs) and analyses of rare-coding variants have identified over 70 loci associated with conferring risk for late-onset AD (LOAD).”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [3]

    The paper’s introductory passage (indexed under Abstract; page unavailable) says that nearly 30 late-onset Alzheimer’s disease susceptibility loci were known, not over 70. It reports additional rare-variant associations, but does not give a total approaching the claimed figure. (LLM, conf=0.89)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • A 56-protein interaction network of enriched rare coding variants and common variants with late-onset AD gene-wide significance identified SPI1 as a central hub gene.

    “In addition, a 56-protein interaction network consisting of strongly enriched rare coding variants (p = 1.08 × 10–7, and common variants with Late-Onset AD gene-wide significance (p = 2.98 × 10–7) identified SPI1 as a central hub gene5.”

    From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [5]

    The Online Methods (Protein interaction Analysis; Gene-set enrichment analysis of the protein network, page unavailable) describe a 56-gene interaction network and report P=1.08×10⁻⁷ for rare-variant enrichment. But P=2.98×10⁻⁷ is from a conservative rare-variant analysis, not the common-variant analysis. The paper says SPI1 is in the network and is a central transcription factor in microglial activation; it does not identify SPI1 as the network’s central hub gene. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Studies investigating PU.1 in human microglia suggest there are shared Spi1/PU.1 dose dependent pathways in microglia.

    “However, studies investigating PU.1 in human microglia suggest there are shared Spi1/PU.1 dose dependent pathways in microglia.”

    From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [5]

    The passage on the 56-gene interaction network (section labeled Abstract; page unavailable) includes SPI1 and describes it as a central transcription factor in microglial activation. It does not report studies of PU.1 in human microglia or establish shared, SPI1/PU.1 dose-dependent pathways. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • SPI1 binding sites are located near other AD risk genes or regulatory elements.

    “In addition to SPI1 binding sites being located near other AD risk genes or regulatory elements5,7,8, SPI1 risk alleles associated with a higher gene expression have been shown to lower the age of onset in AD7.”

    From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [5]

    The paper’s discussion of the 56-gene interaction network (labeled Abstract in our copy; page unavailable) says that SPI1 is near genome-wide significant AD-associated signals. It does not say that SPI1 binding sites are near other AD risk genes or regulatory elements; proximity of the SPI1 gene is a different claim. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Previous work has identified that Spi1 is able to influence multiple gene networks in microglia and has been proposed as central to a network of AD risk genes conserved between species.

    “Previous work has identified that Spi1 is able to influence multiple gene networks in microglia5,7,31 and has been proposed as central to a network of AD risk genes that are conserved between species50.”

    From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [5]

    The paper describes SPI1 as a central transcription factor in microglial activation and includes it in a 56-gene interaction network enriched for AD risk signals (section labeled Abstract; page not provided). It does not say that SPI1 is central to that network or that the network is conserved between species. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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.

  • Stage 1 analysis includes more cases than were reported as genotyped

    Minor

    The paper reports 16,097 Stage 1 cases genotyped, but later says 16,160 cases were included in the unadjusted Stage 1 analysis. The reported control counts also differ between those descriptions.

  • Conflicting Stage 1 meta-analysis methods for low-frequency variants

    Minor

    The main text says low-frequency variants were combined with SeqMeta, while the methods say they were meta-analysed with METAL.

2 of 2

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1371/journal.pgen.1004792

    Info

    The cited work was retracted on 2021-11-04 (notice 10.1371/journal.pgen.1009895), not before this paper was published (2017-07-17).

    Cited work 10.1371/journal.pgen.1004792 · retracted 2021-11-04 · notice 10.1371/journal.pgen.1009895 · this paper published 2017-07-17

1 of 1

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Authors
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., Raybould, R., Bis, J. C., Martin, E. R., Grenier-Boley, B., Heilmann-Heimbach, S., Chouraki, V., Kuzma, A. B., Sleegers, K., Vronskaya, M., Ruiz, A., Graham, R. R., Olaso, R., Hoffmann, P., Grove, M. L., Vardarajan, B. N., Hiltunen, M., Nöthen, M. M., White, C. C., Hamilton-Nelson, K. L., Epelbaum, J., Maier, W., Choi, S.-H., Beecham, G. W., Dulary, C., Herms, S., Smith, A. V., Funk, C. C., Derbois, C., Forstner, A. J., Ahmad, S., Li, H., Bacq, D., Harold, D., Satizabal, C. L., Valladares, O., Squassina, A., Thomas, R., Brody, J. A., Qu, L., Sánchez-Juan, P., Morgan, T., Wolters, F. J., Zhao, Y., Garcia, F. S., Denning, N., Fornage, M., Malamon, J., Naranjo, M. C. D., Majounie, E., Mosley, T. H., Dombroski, B., Wallon, D., Lupton, M. K., Dupuis, J., Whitehead, P., Fratiglioni, L., Medway, C., Jian, X., Mukherjee, S., Keller, L., Brown, K., Lin, H., Cantwell, L. B., Panza, F., McGuinness, B., Moreno-Grau, S., Burgess, J. D., Solfrizzi, V., Proitsi, P., Adams, H. H., Allen, M., Seripa, D., Pastor, P., Cupples, L. A., Price, N. D., Hannequin, D., Frank-García, A., Levy, D., Chakrabarty, P., Caffarra, P., Giegling, I., Beiser, A. S., Giedraitis, V., Hampel, H., Garcia, M. E., Wang, X., Lannfelt, L., Mecocci, P., Eiriksdottir, G., Crane, P. K., Pasquier, F., Boccardi, V., Henández, I., Barber, R. C., Scherer, M., Tarraga, L., Adams, P. M., Leber, M., Chen, Y., Albert, M. S., Riedel-Heller, S., Emilsson, V., Beekly, D., Braae, A., Schmidt, R., Blacker, D., Masullo, C., Schmidt, H., Doody, R. S., Spalletta, G., Jr, W. T. L., Fairchild, T. J., Bossù, P., Lopez, O. L., Frosch, M. P., Sacchinelli, E., Ghetti, B., Yang, Q., Huebinger, R. M., Jessen, F., Li, S., Kamboh, M. I., Morris, J., Sotolongo-Grau, O., Katz, M. J., Corcoran, C., Dunstan, M., Braddel, A., Thomas, C., Meggy, A., Marshall, R., Gerrish, A., Chapman, J., Aguilar, M., Taylor, S., Hill, M., Fairén, M. D., Hodges, A., Vellas, B., Soininen, H., Kloszewska, I., Daniilidou, M., Uphill, J., Patel, Y., Hughes, J. T., Lord, J., Turton, J., Hartmann, A. M., Cecchetti, R., Fenoglio, C., Serpente, M., Arcaro, M., Caltagirone, C., Orfei, M. D., Ciaramella, A., Pichler, S., Mayhaus, M., Gu, W., Lleó, A., Fortea, J., Blesa, R., Barber, I. S., Brookes, K., Cupidi, C., Maletta, R. G., Carrell, D., Sorbi, S., Moebus, S., Urbano, M., Pilotto, A., Kornhuber, J., Bosco, P., Todd, S., Craig, D., Johnston, J., Gill, M., Lawlor, B., Lynch, A., Fox, N. C., Hardy, J., Albin, R. L., Apostolova, L. G., Arnold, S. E., Asthana, S., Atwood, C. S., Baldwin, C. T., Barnes, L. L., Barral, S., Beach, T. G., Becker, J. T., Bigio, E. H., Bird, T. D., Boeve, B. F., Bowen, J. D., Boxer, A., Burke, J. R., Burns, J. M., Buxbaum, J. D., Cairns, N. J., Cao, C., Carlson, C. S., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Carroll, S. L., Diaz, C. C., Chui, H. C., Clark, D. G., Cribbs, D. H., Crocco, E. A., DeCarli, C., Dick, M., Duara, R., Evans, D. A., Faber, K. M., Fallon, K. B., Fardo, D. W., Farlow, M. R., Ferris, S., Foroud, T. M., Galasko, D. R., Gearing, M., Geschwind, D. H., Gilbert, J. R., Graff-Radford, N. R., Green, R. C., Growdon, J. H., Hamilton, R. L., Harrell, L. E., Honig, L. S., Huentelman, M. J., Hulette, C. M., Hyman, B. T., Jarvik, G. P., Abner, E., Jin, L.-W., Jun, G., Karydas, A., Kaye, J. A., Kim, R., Kowall, N. W., Kramer, J. H., LaFerla, F. M., Lah, J. J., Leverenz, J. B., Levey, A. I., Li, G., Lieberman, A. P., Lunetta, K. L., Lyketsos, C. G., Marson, D. C., Martiniuk, F., Mash, D. C., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McKee, A. C., Mesulam, M., Miller, B. L., Miller, C. A., Miller, J. W., Morris, J. C., Murrell, J. R., Myers, A. J., O'Bryant, S., Olichney, J. M., Pankratz, V. S., Parisi, J. E., Paulson, H. L., Perry, W., Peskind, E., Pierce, A., Poon, W. W., Potter, H., Quinn, J. F., Raj, A., Raskind, M., Reisberg, B., Reitz, C., Ringman, J. M., Roberson, E. D., Rogaeva, E., Rosen, H. J., Rosenberg, R. N., Sager, M. A., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seeley, W. W., Smith, A. G., Sonnen, J. A., Spina, S., Stern, R. A., Swerdlow, R. H., Tanzi, R. E., Thornton-Wells, T. A., Trojanowski, J. Q., Troncoso, J. C., Van Deerlin, V. M., Van Eldik, L. J., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Wilhelmsen, K. C., Williamson, J., Wingo, T. S., Woltjer, R. L., Wright, C. B., Yu, C.-E., Yu, L., Garzia, F., Golamaully, F., Septier, G., Engelborghs, S., Vandenberghe, R., De Deyn, P. P., Fernadez, C. M., Benito, Y. A., Thonberg, H., Forsell, C., Lilius, L., Kinhult-Stählbom, A., Kilander, L., Brundin, R., Concari, L., Helisalmi, S., Koivisto, A. M., Haapasalo, A., Dermecourt, V., Fievet, N., Hanon, O., Dufouil, C., Brice, A., Ritchie, K., Dubois, B., Himali, J. J., Keene, C. D., Tschanz, J., Fitzpatrick, A. L., Kukull, W. A., Norton, M., Aspelund, T., Larson, E. B., Munger, R., Rotter, J. I., Lipton, R. B., Bullido, M. J., Hofman, A., Montine, T. J., Coto, E., Boerwinkle, E., Petersen, R. C., Alvarez, V., Rivadeneira, F., Reiman, E. M., Gallo, M., O'Donnell, C. J., Reisch, J. S., Bruni, A. C., Royall, D. R., Dichgans, M., Sano, M., Galimberti, D., St George-Hyslop, P., Scarpini, E., Tsuang, D. W., Mancuso, M., Bonuccelli, U., Winslow, A. R., Daniele, A., Wu, C.-K., Peters, O., Nacmias, B., Riemenschneider, M., Heun, R., Brayne, C., Rubinsztein, D. C., Bras, J., Guerreiro, R., Al-Chalabi, A., Shaw, C. E., Collinge, J., Mann, D., Tsolaki, M., Clarimón, J., Sussams, R., Lovestone, S., O'Donovan, M. C., Owen, M. J., Behrens, T. W., Mead, S., Goate, A. M., Uitterlinden, A. G., Holmes, C., Cruchaga, C., Ingelsson, M., Bennett, D. A., Powell, J., Golde, T. E., Graff, C., De Jager, P. L., Morgan, K., Ertekin-Taner, N., Combarros, O., Psaty, B. M., Passmore, P., Younkin, S. G., Berr, C., Gudnason, V., Rujescu, D., Dickson, D. W., Dartigues, J.-F., DeStefano, A. L., Ortega-Cubero, S., Hakonarson, H., Campion, D., Boada, M., Kauwe, J. K., Farrer, L. A., Van Broeckhoven, C., Ikram, M. A., Jones, L., Haines, J. L., Tzourio, C., Launer, L. J., Escott-Price, V., Mayeux, R., Deleuze, J.-F., Amin, N., Holmans, P. A., Pericak-Vance, M. A., Amouyel, P., van Duijn, C. M., Ramirez, A., Wang, L.-S., Lambert, J.-C., Seshadri, S., Williams, J., & Schellenberg, G. D.
Affiliations
  • Cardiff University (GB)
  • Erasmus MC (NL)
  • Inserm (FR)
  • Icelandic Heart Association (IS)
  • University of Miami (US)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • University of Washington (US)
  • Boston University (US)
  • University of Antwerp (BE)
  • Fundació ACE (ES)
  • Genentech
  • University of Bonn (DE)
  • Columbia University Irving Medical Center (US)
  • University of Eastern Finland (FI)
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2017-07-17
Volume
49
Issue
9
Pages
1373-1384
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3916
PMC
PMC5669039
OpenAlex
W2592518050
Cited by
1,126
References
72
Citations by year
2026: 65 · 2025: 96 · 2024: 93 · 2023: 115 · 2022: 112 · 2021: 148 · 2020: 126 · 2019: 118 · 2018: 127 · 2017: 17
FWCI
73.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
  • PubMed Central (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • HAL (Le Centre pour la Communication Scientifique Directe) (submittedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, rare coding variants, PLCγ2, ABI3, TREM2, microglia, innate immunity, genetic susceptibility
MeSH terms
Alzheimer Disease, Amino Acid Sequence, Gene Frequency

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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