Publications by authors named "Mariet Allen"

57 Publications

Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans.

Alzheimers Dement 2021 Sep 5. Epub 2021 Sep 5.

Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA.

Not all apolipoprotein E (APOE) ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. Guided by the top ε4-attenuating signals from methylome-wide association analyses (N = 572, ε4+ and ε4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the ε4+ subgroups (N = 235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. Three out of the four significant CpG dinucleotides were captured by one principal component (PC1), which interacts with ε4 on AD, and is associated with expression of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (odds ratio = 2.39, 95% confidence interval = [1.64,3.46], P = 7.08 × 10 ). An epigenomic factor associated with a reduced proportion of activated microglia (epigenomic factor of activated microglia, EFAM) appears to attenuate the risk of ε4 on AD.
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http://dx.doi.org/10.1002/alz.12425DOI Listing
September 2021

EPIGENOMIC FEATURES RELATED TO MICROGLIA ARE ASSOCIATED WITH ATTENUATED EFFECT OF APOE ε4 ON ALZHEIMER'S DISEASE RISK IN HUMANS.

Alzheimers Dement 2020 12 7;16(Suppl 2). Epub 2020 Dec 7.

Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168 street, New York, NY, USA.

Not all ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. Guided by the top ε4-attenuating signals from methylome-wide association analyses (N=572, ε4+ and ε4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the ε4+ subgroups (N=235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. Three out of the four significant CpG dinucleotides were captured by one principle component (PC1), which interacts with ε4 on AD, and is associated with expression of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (OR=2.39, 95%CI=[1.64,3.46], =7.08x10). An epigenomic factor associated with a reduced proportion of activated microglia (microglial epigenomic factor 1) appears to attenuate the risk of ε4 on AD.
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http://dx.doi.org/10.1002/alz.043533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362904PMC
December 2020

Microglia show differential transcriptomic response to Aβ peptide aggregates ex vivo and in vivo.

Life Sci Alliance 2021 07 14;4(7). Epub 2021 Jun 14.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA

Aggregation and accumulation of amyloid-β (Aβ) is a defining feature of Alzheimer's disease pathology. To study microglial responses to Aβ, we applied exogenous Aβ peptide, in either oligomeric or fibrillar conformation, to primary mouse microglial cultures and evaluated system-level transcriptional changes and then compared these with transcriptomic changes in the brains of CRND8 APP mice. We find that primary microglial cultures have rapid and massive transcriptional change in response to Aβ. Transcriptomic responses to oligomeric or fibrillar Aβ in primary microglia, although partially overlapping, are distinct and are not recapitulated in vivo where Aβ progressively accumulates. Furthermore, although classic immune mediators show massive transcriptional changes in the primary microglial cultures, these changes are not observed in the mouse model. Together, these data extend previous studies which demonstrate that microglia responses ex vivo are poor proxies for in vivo responses. Finally, these data demonstrate the potential utility of using microglia as biosensors of different aggregate conformation, as the transcriptional responses to oligomeric and fibrillar Aβ can be distinguished.
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http://dx.doi.org/10.26508/lsa.202101108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321667PMC
July 2021

Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer's disease.

Acta Neuropathol Commun 2021 05 21;9(1):93. Epub 2021 May 21.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.

Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer's disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = -3.70 [95% CI -0.49--0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.
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http://dx.doi.org/10.1186/s40478-021-01199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147512PMC
May 2021

Modulating innate immune activation states impacts the efficacy of specific Aβ immunotherapy.

Mol Neurodegener 2021 05 6;16(1):32. Epub 2021 May 6.

Department of Neuroscience and Neurology, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, University of Florida, FL, 32611, Gainesville, USA.

Introduction: Passive immunotherapies targeting Aβ continue to be evaluated as Alzheimer's disease (AD) therapeutics, but there remains debate over the mechanisms by which these immunotherapies work. Besides the amount of preexisting Aβ deposition and the type of deposit (compact or diffuse), there is little data concerning what factors, independent of those intrinsic to the antibody, might influence efficacy. Here we (i) explored how constitutive priming of the underlying innate activation states by Il10 and Il6 might influence passive Aβ immunotherapy and (ii) evaluated transcriptomic data generated in the AMP-AD initiative to inform how these two cytokines and their receptors' mRNA levels are altered in human AD and an APP mouse model.

Methods: rAAV2/1 encoding EGFP, Il6 or Il10 were delivered by somatic brain transgenesis to neonatal (P0) TgCRND8 APP mice. Then, at 2 months of age, the mice were treated bi-weekly with a high-affinity anti-Aβ1-16 mAb5 monoclonal antibody or control mouse IgG until 6 months of age. rAAV mediated transgene expression, amyloid accumulation, Aβ levels and gliosis were assessed. Extensive transcriptomic data was used to evaluate the mRNA expression levels of IL10 and IL6 and their receptors in the postmortem human AD temporal cortex and in the brains of TgCRND8 mice, the later at multiple ages.

Results: Priming TgCRND8 mice with Il10 increases Aβ loads and blocks efficacy of subsequent mAb5 passive immunotherapy, whereas priming with Il6 priming reduces Aβ loads by itself and subsequent Aβ immunotherapy shows only a slightly additive effect. Transcriptomic data shows that (i) there are significant increases in the mRNA levels of Il6 and Il10 receptors in the TgCRND8 mouse model and temporal cortex of humans with AD and (ii) there is a great deal of variance in individual mouse brain and the human temporal cortex of these interleukins and their receptors.

Conclusions: The underlying immune activation state can markedly affect the efficacy of passive Aβ immunotherapy. These results have important implications for ongoing human AD immunotherapy trials, as they indicate that underlying immune activation states within the brain, which may be highly variable, may influence the ability for passive immunotherapy to alter Aβ deposition.
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http://dx.doi.org/10.1186/s13024-021-00453-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103631PMC
May 2021

Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer's disease.

Nat Commun 2021 04 19;12(1):2311. Epub 2021 Apr 19.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.
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http://dx.doi.org/10.1038/s41467-021-22399-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055900PMC
April 2021

Analysis of intraoperative human brain tissue transcriptome reveals putative risk genes and altered molecular pathways in glioma-related seizures.

Epilepsy Res 2021 Jul 18;173:106618. Epub 2021 Mar 18.

Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Background: The pathogenesis of glioma-related seizures (GRS) is poorly understood. Here in, we aim to identify putative molecular pathways that lead to the development of GRS.

Methods: We determined brain transcriptome from intraoperative human brain tissue of patients with either GRS, glioma without seizures (non-GRS), or with idiopathic temporal lobe epilepsy (iTLE). We performed transcriptome-wide comparisons between disease groups tissue from non-epileptic controls (non-EC) to identify differentially-expressed genes (DEG). We compared DEGs to identify those that are specific or common to the groups. Through a gene ontology analysis, we identified molecular pathways enriched for genes with a Log-fold change ≥1.5 or ≤-1.5 and p-value <0.05 compared to non-EC.

Results: We identified 110 DEGs that are associated with GRS vs. non-GRS: 80 genes showed high and 30 low expression in GRS. There was significant overexpression of genes involved in cell-to-cell and glutamatergic signaling (CELF4, SLC17A7, and CAMK2A) and down-regulation of genes involved immune-trafficking (CXCL8, H19, and VEGFA). In the iTLE vs GRS analysis, there were 1098 DEGs: 786 genes were overexpressed and 312 genes were underexpressed in the GRS samples. There was significant enrichment for genes considered markers of oncogenesis (GSC, MYBL2, and TOP2A). Further, there was down-regulation of genes involved in the glutamatergic neurotransmission (vesicular glutamate transporter-2) in the GRS vs. iTLE samples.

Conclusions: We identified a number of altered processes such as cell-to-cell signaling and interaction, inflammation-related, and glutamatergic neurotransmission in the pathogenesis of GRS. Our findings offer a new landscape of targets to further study in the fields of brain tumors and seizures.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106618DOI Listing
July 2021

Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer's disease.

Acta Neuropathol Commun 2021 03 16;9(1):43. Epub 2021 Mar 16.

Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark.

SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.
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http://dx.doi.org/10.1186/s40478-021-01140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962264PMC
March 2021

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

Acta Neuropathol 2021 05 26;141(5):667-680. Epub 2021 Feb 26.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
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http://dx.doi.org/10.1007/s00401-021-02289-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043857PMC
May 2021

Integrative functional genomic analysis of intron retention in human and mouse brain with Alzheimer's disease.

Alzheimers Dement 2021 06 21;17(6):984-1004. Epub 2021 Jan 21.

Institute for Systems Biology, Seattle, Washington, USA.

Intron retention (IR) has been implicated in the pathogenesis of complex diseases such as cancers; its association with Alzheimer's disease (AD) remains unexplored. We performed genome-wide analysis of IR through integrating genetic, transcriptomic, and proteomic data of AD subjects and mouse models from the Accelerating Medicines Partnership-Alzheimer's Disease project. We identified 4535 and 4086 IR events in 2173 human and 1736 mouse genes, respectively. Quantitation of IR enabled the identification of differentially expressed genes that conventional exon-level approaches did not reveal. There were significant correlations of intron expression within innate immune genes, like HMBOX1, with AD in humans. Peptides with a high probability of translation from intron-retained mRNAs were identified using mass spectrometry. Further, we established AD-specific intron expression Quantitative Trait Loci, and identified splicing-related genes that may regulate IR. Our analysis provides a novel resource for the search for new AD biomarkers and pathological mechanisms.
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http://dx.doi.org/10.1002/alz.12254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248162PMC
June 2021

Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome.

PLoS Genet 2021 01 8;17(1):e1009224. Epub 2021 Jan 8.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom.

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
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http://dx.doi.org/10.1371/journal.pgen.1009224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819609PMC
January 2021

Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy.

Acta Neuropathol Commun 2020 10 22;8(1):172. Epub 2020 Oct 22.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer's disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (n = 2008, n = 1037, n = 971) and Thal phase amyloid plaque scores (n = 1786, n = 1018, n = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46-4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = - 0.822, 95% CI - 1.439 to - 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = - 0.995, 95% CI - 1.773 to - 0.218, p = 0.012) than LBD-NP patients (ß = - 0.292, 95% CI - 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = - 0.638, 95% CI - 1.139 to - 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.
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http://dx.doi.org/10.1186/s40478-020-01050-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579984PMC
October 2020

Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions.

Sci Data 2020 10 12;7(1):340. Epub 2020 Oct 12.

Sage Bionetworks, Seattle, WA, 98121, USA.

The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).
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http://dx.doi.org/10.1038/s41597-020-00642-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550587PMC
October 2020

Correction to: Deciphering cellular transcriptional alterations in Alzheimer's disease brains.

Mol Neurodegener 2020 09 15;15(1):54. Epub 2020 Sep 15.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13024-020-00403-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490892PMC
September 2020

Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease.

Alzheimers Dement 2020 10 22;16(10):1372-1383. Epub 2020 Aug 22.

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

Introduction: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.

Methods: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aβ40], Aβ42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.

Results: Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.

Discussion: Refining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.
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http://dx.doi.org/10.1002/alz.12104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103951PMC
October 2020

Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology.

Alzheimers Dement 2020 09 5;16(9):1213-1223. Epub 2020 Aug 5.

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.

Introduction: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD).

Methods: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis.

Results: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [ F]Florbetapir positron emission tomography and CSF Aβ .

Discussion: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
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http://dx.doi.org/10.1002/alz.12092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541709PMC
September 2020

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

Cell Rep 2020 07;32(2):107908

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
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http://dx.doi.org/10.1016/j.celrep.2020.107908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428328PMC
July 2020

Deciphering cellular transcriptional alterations in Alzheimer's disease brains.

Mol Neurodegener 2020 07 13;15(1):38. Epub 2020 Jul 13.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer's disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.
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http://dx.doi.org/10.1186/s13024-020-00392-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359236PMC
July 2020

MAPT haplotype-stratified GWAS reveals differential association for AD risk variants.

Alzheimers Dement 2020 07 13;16(7):983-1002. Epub 2020 May 13.

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

Introduction: MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD).

Methods: Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci.

Results: We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance. The most significant H2 non-carrier-specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in "synaptic transmission" (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT.

Discussion: This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype-specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.
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http://dx.doi.org/10.1002/alz.12099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983911PMC
July 2020

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Acta Neuropathol 2019 08 27;138(2):237-250. Epub 2019 May 27.

Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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http://dx.doi.org/10.1007/s00401-019-02026-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660501PMC
August 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans.

Mol Neurodegener 2018 10 11;13(1):53. Epub 2018 Oct 11.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.

Background: Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer's disease (AD).

Methods: We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson's disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls). 1479 AD and 1491 controls were non-overlapping with a prior report.

Results: Using Fisher's exact test, there was significant association of both ABI3_rs616338-T (OR = 1.41, p = 0.044) and PLCG2_rs72824905-G (OR = 0.56, p = 0.008) with AD. These OR estimates were maintained in the non-overlapping replication AD-control analysis, albeit at reduced significance (ABI3_rs616338-T OR = 1.44, p = 0.12; PLCG2_rs72824905-G OR = 0.66, p = 0.19). None of the other cohorts showed significant associations that were concordant with those for AD, although the DLB cohort had suggestive findings (Fisher's test: ABI3_rs616338-T OR = 1.79, p = 0.097; PLCG2_rs72824905-G OR = 0.32, p = 0.124). PLCG2_rs72824905-G showed suggestive association with pathologically-confirmed MSA (OR = 2.39, p = 0.050) and PSP (OR = 1.97, p = 0.061), although in the opposite direction of that for AD. We assessed RNA sequencing data from 238 temporal cortex (TCX) and 224 cerebellum (CER) samples from AD, PSP and control patients and identified co-expression networks, enriched in microglial genes and immune response GO terms, and which harbor PLCG2 and/or ABI3. These networks had higher expression in AD, but not in PSP TCX, compared to controls. This expression association did not survive adjustment for brain cell type population changes.

Conclusions: We validated the associations previously reported with ABI3_rs616338-T and PLCG2_rs72824905-G in a Caucasian AD case-control cohort, and observed a similar direction of effect in DLB. Conversely, PLCG2_rs72824905-G showed suggestive associations with PSP and MSA in the opposite direction. We identified microglial gene-enriched co-expression networks with significantly higher levels in AD TCX, but not in PSP, a primary tauopathy. This co-expression network association appears to be driven by microglial cell population changes in a brain region affected by AD pathology. Although these findings require replication in larger cohorts, they suggest distinct effects of the microglial genes, ABI3 and PLCG2 in neurodegenerative diseases that harbor significant vs. low/no amyloid ß pathology.
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http://dx.doi.org/10.1186/s13024-018-0289-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190665PMC
October 2018

TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.

J Exp Med 2018 09;215(9):2247-2264

Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL

There is considerable interest in harnessing innate immunity to treat Alzheimer's disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor-based biologics represent a novel and safe Aβ-selective class of biotherapy in AD.
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http://dx.doi.org/10.1084/jem.20180484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122970PMC
September 2018

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy.

Acta Neuropathol 2018 11 22;136(5):709-727. Epub 2018 Aug 22.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP.
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http://dx.doi.org/10.1007/s00401-018-1900-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208732PMC
November 2018

An alternative transcript of the Alzheimer's disease risk gene SORL1 encodes a truncated receptor.

Neurobiol Aging 2018 11 28;71:266.e11-266.e24. Epub 2018 Jun 28.

Danish Research Institute of Translational Neuroscience (DANDRITE) Nordic-EMBL Partnership, Aarhus, Denmark. Electronic address:

SORL1 encodes a 250-kDa protein named sorLA, a functional sorting receptor for the amyloid precursor protein (APP). Several single nucleotide polymorphisms of the gene SORL1, encoding sorLA, are genetically associated with Alzheimer's disease (AD). In the existing literature, SORL1 is insufficiently described at the transcriptional level, and there is very limited amount of functional data defining different transcripts. We have characterized a SORL1 transcript containing a novel exon 30B. The transcript is expressed in most brain regions with highest expression in the temporal lobe and hippocampus. Exon 30B is spliced to exon 31, leading to a mature transcript that encodes an 829 amino acid sorLA receptor. This receptor variant lacks the binding site for APP and is unlikely to function in APP sorting. This transcript is expressed in equal amounts in the cerebellum from AD and non-AD individuals. Our data describe a transcript that encodes a truncated sorLA receptor, suggesting novel neuronal functions for sorLA and that alternative transcription provides a mechanism for SORL1 activity regulation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769419PMC
November 2018

TMEM106B haplotypes have distinct gene expression patterns in aged brain.

Mol Neurodegener 2018 07 3;13(1):35. Epub 2018 Jul 3.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Background: Single nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non-coding variants may also contribute to disease risk. It has been reported that the risk haplotype is associated with higher levels of TMEM106B and increased levels of TMEM106B cause cytotoxicity; however, the precise mechanism through which TMEM106B haplotypes contribute to neurodegeneration is unclear.

Methods: We utilized RNA sequencing data derived from temporal cortex (TCX) and cerebellum (CER) from 312 North American Caucasian subjects neuropathologically diagnosed with Alzheimer's disease, progressive supranuclear palsy, pathological aging or normal controls to analyze transcriptome signatures associated with the risk (TT) and protective (SS) TMEM106B haplotypes. In cohorts matched for disease phenotype, we used Analysis of Variance (ANOVA) to identify differentially expressed genes and Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene networks associated with the risk and protective TMEM106B haplotypes.

Results: A total of 110 TCX and 116 CER samples were included in the analyses. When comparing TT to SS carriers, we detected 593 differentially expressed genes in TCX and 7 in CER. Gene co-expression network analyses further showed that in both TCX and CER the SS haplotype was positively correlated with gene networks involved in synaptic transmission, whereas the TT haplotype was positively correlated with gene networks enriched for immune response. Gene expression patterns of 5 cell-type-specific markers revealed significantly reduced expression of the neuronal marker and relative increases in all other cell markers in TT as compared to SS carriers in TCX with a similar but non-significant trend in CER.

Conclusions: By comparing the common TMEM106B risk and protective haplotypes we identified significant and partly conserved transcriptional differences across TCX and CER and striking changes in cell-type composition, especially in TCX. These findings illustrate the profound effect of TMEM106B haplotypes on brain health and highlight the importance to better understand TMEM106B's function and dysfunction in the context of neurodegenerative diseases.
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http://dx.doi.org/10.1186/s13024-018-0268-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029036PMC
July 2018

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease.

Alzheimers Res Ther 2018 02 20;10(1):22. Epub 2018 Feb 20.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study.

Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.

Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10) and visual (P = 5.6 × 10) cortices.

Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
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http://dx.doi.org/10.1186/s13195-018-0349-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819208PMC
February 2018

Correction to: Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

Genome Med 2018 01 12;10(1). Epub 2018 Jan 12.

Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.

Correction: The original version of this article [1] unfortunately contained a typographical error. The 'Alzheimer's Disease Neuroimaging Initiative' was erroneously included as 'Alzheimer's Disease Neuroimaging Initative' in the author list of the article.
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http://dx.doi.org/10.1186/s13073-018-0516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765598PMC
January 2018
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