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article, disease, google, scholar, expression, association, psp, genes, abi, gene, variants, plcg, plcgrsg, cas, risk, controls, brain, diseases, dlb, cell, neurodegenerative, cohort, alzheimers, msa, abirst, control, microglial, module, study, data, temporal, cortex, model, table, observed, mayo, analysis, patients, pathology, clinic, coexpression, network, microglia, additional, lewy, significant, samples, networks, variant, trem,

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mild cognitive impairment nilüfer ertekin-taner african-american ad case o'donnell-luria ah auto-inhibitory domain leads protein-coding genetic variation nesh/abi-3-based wave2 complex caucasian case-control cohorts steele-richardson-olszewski syndrome extracellular signal-regulated kinase population-based linkage analyses amp-ad knowledge portal african-american control participants article download pdf nincds-adrda work group african-american ad cases african-american control maf late-stage neurodegeneration abi-1-based wave2 complex african-american cohort psp = progressive supranuclear palsy nspph-nsh2 linker domain late onset alzheimer' late-onset alzheimer' neurological disorders identified microglial gene-enriched microglial/innate immune module received research support privacy choices/manage cookies cerebellar immune/microglial module full access progressive supranuclear palsy ertekin-taner multiple system atrophy central nervous system lewy body research pairwise diagnostic group psp-affected brain regions rare coding variants received publishing royalties creative commons license reduced synapse/neuron loss candidate regulatory variant bulk brain tissue identifies human disease immune/microglial networks suggests wave regulatory complex abi33730xl genetic analyzer 1 cycle sequencing kit cell population variation

Questions {❓}

• DLB and PDD: a role for mutations in dementia and Parkinson disease genes?

Schema {🗺️}

WebPage:
      mainEntity:
         headline:ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans
         description:Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer’s disease (AD). 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. 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. 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.
         datePublished:2018-10-11T00:00:00Z
         dateModified:2018-10-11T00:00:00Z
         pageStart:1
         pageEnd:12
         license:http://creativecommons.org/publicdomain/zero/1.0/
         sameAs:https://doi.org/10.1186/s13024-018-0289-x
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            ABI3
            PLCG2
            Alzheimer’s disease (AD)
            Progressive supranuclear palsy (PSP)
            Parkinson’s disease (PD)
            Dementia with Lewy bodies (DLB)
            Multiple system atrophy (MSA)
            African-American
            Genetic association
            Expression
            Neurosciences
            Neurology
            Molecular Medicine
         image:
            https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs13024-018-0289-x/MediaObjects/13024_2018_289_Fig1_HTML.png
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            issn:
               1750-1326
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            name:BioMed Central
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               type:ImageObject
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         author:
               name:Olivia J Conway
               affiliation:
                     name:Mayo Clinic Florida
                     address:
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                        type:PostalAddress
                     type:Organization
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               name:Minerva M Carrasquillo
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                     address:
                        name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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                     address:
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               name:Samantha L Strickland
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               name:Thuy Nguyen
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               name:Ronald L Walton
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               name:Ronald C Petersen
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               name:John A Lucas
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               name:Dennis W Dickson
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                     address:
                        name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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               name:Nilüfer Ertekin-Taner
               url:http://orcid.org/0000-0003-4436-8889
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                     name:Mayo Clinic Florida
                     address:
                        name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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                     address:
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ScholarlyArticle:
      headline:ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans
      description:Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer’s disease (AD). 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. 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. 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.
      datePublished:2018-10-11T00:00:00Z
      dateModified:2018-10-11T00:00:00Z
      pageStart:1
      pageEnd:12
      license:http://creativecommons.org/publicdomain/zero/1.0/
      sameAs:https://doi.org/10.1186/s13024-018-0289-x
      keywords:
         ABI3
         PLCG2
         Alzheimer’s disease (AD)
         Progressive supranuclear palsy (PSP)
         Parkinson’s disease (PD)
         Dementia with Lewy bodies (DLB)
         Multiple system atrophy (MSA)
         African-American
         Genetic association
         Expression
         Neurosciences
         Neurology
         Molecular Medicine
      image:
         https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs13024-018-0289-x/MediaObjects/13024_2018_289_Fig1_HTML.png
      isPartOf:
         name:Molecular Neurodegeneration
         issn:
            1750-1326
         volumeNumber:13
         type:
            Periodical
            PublicationVolume
      publisher:
         name:BioMed Central
         logo:
            url:https://www.springernature.com/app-sn/public/images/logo-springernature.png
            type:ImageObject
         type:Organization
      author:
            name:Olivia J Conway
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Minerva M Carrasquillo
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Xue Wang
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Jenny M Bredenberg
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
                  type:Organization
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            name:Joseph S Reddy
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                  address:
                     name:Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
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            name:Samantha L Strickland
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            name:Curtis S Younkin
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                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            name:Jeremy D Burgess
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                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            name:Mariet Allen
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                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            name:Bradley F Boeve
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                     name:Department of Neurology, Mayo Clinic Minnesota, Rochester, USA
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            name:Ronald C Petersen
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            name:Tanis J Ferman
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            name:William P Cheshire
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                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
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            type:Person
            name:Jay A van Gerpen
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
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            name:Ryan J Uitti
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
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            type:Person
            name:Zbigniew K Wszolek
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
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            type:Person
            name:Owen A Ross
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            name:Dennis W Dickson
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            name:Neill R Graff-Radford
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
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            type:Person
            name:Nilüfer Ertekin-Taner
            url:http://orcid.org/0000-0003-4436-8889
            affiliation:
                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
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                  name:Mayo Clinic Florida
                  address:
                     name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
                     type:PostalAddress
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            email:[email protected]
            type:Person
      isAccessibleForFree:1
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      name:Molecular Neurodegeneration
      issn:
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      name:Mayo Clinic Florida
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         name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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            address:
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            address:
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            address:
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      name:Nilüfer Ertekin-Taner
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            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
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            name:Mayo Clinic Florida
            address:
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      email:[email protected]
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      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
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      name:Department of Neurology, Mayo Clinic Minnesota, Rochester, USA
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      name:Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, USA
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      name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA

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