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The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Yuetiva Deming, Fabia Filipello, Francesca Cignarella, Claudia Cantoni, Simon Hsu, Robert Mikesell, Zeran Li, Jorge L Del-Aguila, Umber Dube, Fabiana Geraldo Farias, Joseph Bradley, Bruno Benitez, John Budde, Laura Ibanez, Maria Victoria Fernandez, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dominantly Inherited Alzheimer Network (DIAN), Kaj Blennow, Henrik Zetterberg, Amanda Heslegrave, Per M Johansson, Johan Svensson, Bengt Nellgård, Alberto Lleo, Daniel Alcolea, Jordi Clarimon, Lorena Rami, José Luis Molinuevo, Marc Suarez-Calvet, Estrella Morenas-Rodríguez, Gernot Kleinberger, Michael Ewers, Oscar Harari, Christian Haass, Thomas J Brett, Celeste M. Karch, Laura Piccio, Carlos Cruchaga
doi: https://doi.org/10.1101/352179
Yuetiva Deming
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Fabia Filipello
2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
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Francesca Cignarella
2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
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Claudia Cantoni
2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
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Simon Hsu
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Robert Mikesell
2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
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Zeran Li
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Jorge L Del-Aguila
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Umber Dube
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Fabiana Geraldo Farias
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Joseph Bradley
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Bruno Benitez
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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John Budde
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Laura Ibanez
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Maria Victoria Fernandez
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Kaj Blennow
3Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
4Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
5Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
6UK Dementia Research Institute at UCL, London, UK.
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Henrik Zetterberg
3Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
4Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
5Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
6UK Dementia Research Institute at UCL, London, UK.
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Amanda Heslegrave
5Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
6UK Dementia Research Institute at UCL, London, UK.
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Per M Johansson
5Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
6UK Dementia Research Institute at UCL, London, UK.
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Johan Svensson
7Department of Anesthesiology and Intensive Care Medicine, Sahlgrenska University. Hospital, Mölndal, Sweden and Institute of Clinical Sciences, the Sahlgrenska Academy at the University of Gothenburg, Sweden
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Bengt Nellgård
8Department of Internal Medicine, Institute of Medicine, the Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
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Alberto Lleo
9Neurology Dept. Hospital de la Santa Creu i Sant Pau. Sant Antoni Ma Claret 167. Barcelona 08025. Spain
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Daniel Alcolea
9Neurology Dept. Hospital de la Santa Creu i Sant Pau. Sant Antoni Ma Claret 167. Barcelona 08025. Spain
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Jordi Clarimon
9Neurology Dept. Hospital de la Santa Creu i Sant Pau. Sant Antoni Ma Claret 167. Barcelona 08025. Spain
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Lorena Rami
10IDIBAPS. Alzheimer’s disease and other cognitive disorders unit, Neurology Service, ICN Hospital Clinic.
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José Luis Molinuevo
11Alzheimer’s disease and other cognitive disorders unit, Neurology Service, ICN Hospital Clinic i Universitari
12BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation. Barcelona, Spain
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Marc Suarez-Calvet
12BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation. Barcelona, Spain
13Biomedical Center (BMC), Biochemistry, Ludwig Maximilians-Universitat Munchen, Munich, Germany.
14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Estrella Morenas-Rodríguez
13Biomedical Center (BMC), Biochemistry, Ludwig Maximilians-Universitat Munchen, Munich, Germany.
14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Gernot Kleinberger
13Biomedical Center (BMC), Biochemistry, Ludwig Maximilians-Universitat Munchen, Munich, Germany.
14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Michael Ewers
15Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Germany
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Oscar Harari
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
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Christian Haass
13Biomedical Center (BMC), Biochemistry, Ludwig Maximilians-Universitat Munchen, Munich, Germany.
14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
16German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
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Thomas J Brett
17Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States
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Celeste M. Karch
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
18Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
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Laura Piccio
2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
18Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
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Carlos Cruchaga
1Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
18Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
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Abstract

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15×10−15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

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Posted June 20, 2018.
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The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk
Yuetiva Deming, Fabia Filipello, Francesca Cignarella, Claudia Cantoni, Simon Hsu, Robert Mikesell, Zeran Li, Jorge L Del-Aguila, Umber Dube, Fabiana Geraldo Farias, Joseph Bradley, Bruno Benitez, John Budde, Laura Ibanez, Maria Victoria Fernandez, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dominantly Inherited Alzheimer Network (DIAN), Kaj Blennow, Henrik Zetterberg, Amanda Heslegrave, Per M Johansson, Johan Svensson, Bengt Nellgård, Alberto Lleo, Daniel Alcolea, Jordi Clarimon, Lorena Rami, José Luis Molinuevo, Marc Suarez-Calvet, Estrella Morenas-Rodríguez, Gernot Kleinberger, Michael Ewers, Oscar Harari, Christian Haass, Thomas J Brett, Celeste M. Karch, Laura Piccio, Carlos Cruchaga
bioRxiv 352179; doi: https://doi.org/10.1101/352179
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The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk
Yuetiva Deming, Fabia Filipello, Francesca Cignarella, Claudia Cantoni, Simon Hsu, Robert Mikesell, Zeran Li, Jorge L Del-Aguila, Umber Dube, Fabiana Geraldo Farias, Joseph Bradley, Bruno Benitez, John Budde, Laura Ibanez, Maria Victoria Fernandez, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dominantly Inherited Alzheimer Network (DIAN), Kaj Blennow, Henrik Zetterberg, Amanda Heslegrave, Per M Johansson, Johan Svensson, Bengt Nellgård, Alberto Lleo, Daniel Alcolea, Jordi Clarimon, Lorena Rami, José Luis Molinuevo, Marc Suarez-Calvet, Estrella Morenas-Rodríguez, Gernot Kleinberger, Michael Ewers, Oscar Harari, Christian Haass, Thomas J Brett, Celeste M. Karch, Laura Piccio, Carlos Cruchaga
bioRxiv 352179; doi: https://doi.org/10.1101/352179

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