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

In the paper

“Nearly 30 LOAD susceptibility loci2-12 are known, and risk is significantly polygenic13.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The citation is attached to the statement about LOAD susceptibility loci, not the separately cited polygenic-risk claim. The Abstract (page not provided) reports genome-wide significant associations at CLU and PICALM, making this paper a study identifying loci that contribute to the cited body of evidence; it need not itself establish the collective count of nearly 30. (LLM, conf=0.88)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Supported

  Citation 13 is attached to the polygenic-risk claim, not the nearly-30-loci count. The Introduction describes late-onset Alzheimer’s disease as genetically complex, and the Results report 60 nominally significant loci replicated at Stage 2—significantly more than expected by chance (p = 4.6×10⁻¹²). (LLM, conf=0.90)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Disputed

  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.

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Supported

  Citation 13 is attached to the claim that risk is polygenic, not to the count of nearly 30 loci. The passage labeled Abstract > Conclusions says that a number of common variants are associated with late-onset Alzheimer’s disease and identifies APOE ε4 as a particularly important one, supporting the claim that multiple genetic variants contribute to risk. No page number is available in our copy. (LLM, conf=0.85)

  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
• ?Not checked — no full text of the sourcecites [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
• Supported

  Citation 13 is attached to the polygenic-risk claim, not the count of nearly 30 loci. The paper describes late-onset Alzheimer’s disease as having a strong genetic component and identifies APOE alongside several other risk loci (passage indexed under Abstract > CONCLUSIONS; page unavailable). Its Discussion also anticipates additional genetic risk variants. Together, these support the claim that risk involves multiple genes. (LLM, conf=0.86)

  cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [39] Milner, J.D. PLAID: a syndrome of complex patterns of disease and unique phenotypes. J. Clin. Immunol. 35, 527–530 (2015). sourceExperimental — accuracy not yet measured

In the paper

“We also observed a different suggestive common variant signal in another LOAD case-control study (P=6.3×10-7)2.”

What the sources say

• Supported

  The paper’s main text (indexed under Abstract; page unavailable) reports a suggestive association signal for rs9381040 at P = 6.3 × 10⁻⁷ in its combined stage 1 and stage 2 analysis. It locates the signal near TREML2 and TREM2, distinguishing it from the previously reported rare TREM2 variant. (LLM, conf=0.93)

  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

In the paper

“PLCG2 variants also cause Antibody Deficiency and Immune Dysregulation (PLAID) and Autoinflammation and PLAID (APLAID)39.”

What the sources say

• Supported

  The passage on PLAID states that heterozygous PLCG2 deletions are responsible for most patients’ disease. The passage on APLAID states that a heterozygous PLCG2 missense mutation causes APLAID. The paper expands APLAID differently from the citing sentence, but supports the attributed causal claim. (LLM, conf=0.93)

  cites [39] Milner, J.D. PLAID: a syndrome of complex patterns of disease and unique phenotypes. J. Clin. Immunol. 35, 527–530 (2015). source

In the paper

“We previously reported a common variant LOAD association near TREM2, in a GWAS of cerebrospinal fluid tau and P-tau36.”

What the sources say

• Partly supported

  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)

  cites [36] Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013). sourceExperimental — accuracy not yet measured

In the paper

“Recent sequencing studies identified a number of genes that have rare variants associated with AD9-11,18-24.”

What the sources say

• Supported

  The Results (Association of Variant with Alzheimer’s Disease; page not provided) report that whole-genome sequencing identified a rare TREM2 variant significantly associated with Alzheimer’s disease. This paper supplies one example for the citing sentence’s collectively cited claim about genes with rare associated variants. (LLM, conf=0.91)

  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
• ?Not checked — no full text of the sourcecites [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
• Supported

  The Results report a strong association between the rare TREM2 R47H variant and Alzheimer's disease. The Discussion identifies whole-exome sequencing as the approach used, so this paper supports the sentence as one example among the cited sequencing studies, not as evidence that this study identified several genes. (LLM, conf=0.91)

  cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). source
• Supported

  The Results report rare SORL1 variants associated with Alzheimer’s disease, and the Methods describe the study’s targeted re-sequencing. In this multi-citation sentence, the paper supports SORL1 as one example of the genes identified; it does not need to identify every gene covered by the other citations. (LLM, conf=0.90)

  cites [18] Vardarajan, B.N. et al. Coding mutations in SORL1 and Alzheimer disease. Ann. Neurol. 77, 215–227 (2015). source
• Supported

  The Discussion reports that targeted sequencing identified rare variants in several genes, including BIN1, EPHA1, CD2AP, and ABCA7, with statistically significant associations in the studied late-onset Alzheimer disease cohorts. It also concludes that multiple rare coding mutations occur in genes at Alzheimer disease–associated loci. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [20] Steinberg, S. et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nat. Genet. 47, 445–447 (2015). source
• Supported

  The Results report that whole-exome sequencing identified two rare AKAP9 variants associated with Alzheimer’s disease in African American participants. This paper therefore provides an example of the sequencing studies described in the multiply cited sentence; it need not establish the full number of genes identified across those studies. (LLM, conf=0.92)

  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
• Partly supported

  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)

  cites [22] Jun, G. et al. PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ann. Neurol. 76, 379–392 (2014). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [23] Hunkapiller, J. et al. A rare coding variant alters UNC5C function and predisposes to Alzheimer's disease. Alzheimers Dement. 9, 853 (2013). source
• Supported

  The paper reports identifying the rare UNC5C T835M variant through genome and exome sequencing, then finding an association with late-onset Alzheimer’s disease in a case-control analysis (main text, labelled “Abstract” in our copy; no page given). It supports the cited sentence as one example among the several studies cited, rather than as a study identifying multiple genes itself. (LLM, conf=0.91)

  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

In the paper

“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.”

What the sources say

• Supported

  The Background identifies NESH/Abi-3 as an Abi-family protein and describes the WAVE complex as regulating actin filament nucleation and network assembly. The Discussion says NESH/Abi-3 has a distinct role in actin cytoskeleton reorganization through its WAVE2-based complex. The T-cell activation clause is attached to citation 42, not this source. (LLM, conf=0.90)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

What the sources say

• Supported

  The citation follows the reference to LOAD-associated common variants. The Results section (‘Impact of the novel identified loci on other AD phenotypes’; page unavailable) reports an association between a common variant at 3q28 and Alzheimer’s disease risk. The 151-gene enrichment and its P value are presented as the citing authors’ analysis, not as a result attributed to this source. (LLM, conf=0.85)

  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

In the paper

“Genes were defined without surrounding genomic sequence, as this yielded the most significant excess of enriched pathways in the common variation dataset11.”

What the sources say

• ?Could not verify

  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)

  cites [11] Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). sourceExperimental — accuracy not yet measured

In the paper

“Loss-of function mutations in CSF1R cause hereditary diffuse leukoencephalopathy with spheroids, a white matter disease related to microglial dysfunction48.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Discussion (page unavailable) reports that the SPI1-MTCH2 gene cluster shows gene-based genome-wide significant association with Alzheimer’s disease. That supports the association claim attached to this source; the IGAP-proximity claim is attached to a different citation in the citing sentence. (LLM, conf=0.90)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

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

In the paper

“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.”

What the sources say

• Supported

  Citation 54 is attached to the first clause only. The paper states in its concluding discussion that Syk plays a key role in regulating Aβ production and Tau hyperphosphorylation. The INPP5D/CD2AP and PLCG2 clauses have separate citations and are not attributed to this source. (LLM, conf=0.95)

  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
• Supported

  Citation 55 attaches to the claim that the complex affects SYK, not to the separately cited Alzheimer’s disease or PLCG2 claims. The Results report that the CD2AP/SHIP1 complex regulates Syk ubiquitination and degradation; SHIP1 is the protein referred to as INPP5D in the citing sentence. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  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
• ?Not checked — no full text of the sourcecites [56] Kurosaki, T. & Tsukada, S. BLNK: connecting Syk and Btk to calcium signals. Immunity 12, 1–5 (2000). source

In the paper

“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.”

What the sources say

• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  cites [45] Painter, M.M. et al. TREM2 in CNS homeostasis and neurodegenerative disease. Mol. Neurodegener. 10, 43 (2015). sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction states that TREM2 signals through DAP12 and detects damage-associated lipids, enabling microglia to sense Aβ accumulation. The Results describe sensing lipids exposed by damaged cells and during Aβ deposition; the Discussion describes TREM2-supported microgliosis as microglial expansion and activation around plaques. The M2-like activation phrase carries a separate citation (44) and is not attributed to this source. (LLM, conf=0.88)

  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

In the paper

“Pharmacological targeting of CSF1R inhibits microglial proliferation and shifts the microglial inflammatory profile to an anti-inflammatory phenotype in murine models53.”

What the sources say

• Supported

  The Results section reports that CSF1R inhibition blocked microglial proliferation in APP/PS1 mice. It also reports reduced pro-inflammatory mediators and increased anti-inflammatory cytokines in those mice, supporting the described shift in inflammatory profile. (LLM, conf=0.92)

  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

In the paper

“Activated microglial cells surround plaques49,50, a finding consistently observed in AD brain and AD transgenic mouse models51.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Supported

  Section 2.2.1 states that activated microglia accumulate near Aβ plaques in several transgenic mouse strains, similarly to AD. This supports the cited comparison with AD brain; our copy does not provide a page number for the passage. (LLM, conf=0.93)

  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

In the paper

“The 151 genes present in 2 or more of these 4 modules were particularly strongly enriched for IGAP GWAS association41.”

What the sources say

• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Similarly, high TREM2 expression has been shown to correlate with increasing neuritic plaque burden17.”

What the sources say

• ?Could not verify

  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)

  cites [17] Surakka, I. et al. The impact of low-frequency and rare variants on lipid levels. Nat. Genet. 47, 589–597 (2015). sourceExperimental — accuracy not yet measured

In the paper

“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”

In the paper

“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)”

In the paper

“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).”

In the paper

“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”

In the paper

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

In the paper

“PLCG2, ABI3, and TREM2 are up-regulated in LOAD human cortex and in two APP mouse models.”

In the paper

“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).”

What the sources say

• ?Not matched

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

In the paper

“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).”

In the paper

“The reference allele (p.P522) is conserved across several species (Supplementary Figure 4).”

In the paper

“The reference allele is conserved across multiple species (Supplementary Figure 7).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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%.”

In the paper

“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).”

In the paper

“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).”

In the paper

“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”

In the paper

“Late-onset AD (LOAD) has a significant genetic component (h2=58-79%1).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006). source

In the paper

“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.”

In the paper

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

In the paper

“Receptor activation results in activation of Syk and ZAP70 signaling which in turn activates PI3K activity and influences PLCγ2 activity43.”

What the sources say

• ?Not matched

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

In the paper

“Three independent analysts confirmed the meta-analysis results.”

In the paper

“All sample genotyping and quality control was performed blind to participant’s disease status.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [15] Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001). source

In the paper

“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.”

In the paper

“For rare variants, there may be additional exonic sites with lower MAF or effect size, and/or intronic and intergenic sites.”

In the paper

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

In the paper

“The remaining heritability may be due to a large number of common variants of small effect size.”

In the paper

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

In the paper

“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.”

In the paper

“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.”