title: The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk.
abstract: OBJECTIVE
  Recently, 2 independent studies reported that a rare missense variant, rs75932628 (R47H), in exon 2 of the gene encoding the "triggering receptor expressed on myeloid cells 2" (TREM2) significantly increases the risk of Alzheimer disease (AD) with an effect size comparable to that of the APOE ε4 allele.
  
  
  METHODS
  In this study, we attempted to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in 2 independent Caucasian family cohorts consisting of 927 families (with 1,777 affected and 1,235 unaffected) and in 2 Caucasian case-control cohorts composed of 1,314 cases and 1,609 controls. In addition, we imputed genotypes in 3 independent Caucasian case-control cohorts containing 1,906 cases and 1,503 controls.
  
  
  RESULTS
  Meta-analysis of the 2 family-based and the 5 case-control cohorts yielded a p value of 0.0029, while the overall summary estimate (using case-control data only) resulted in an odds ratio of 1.67 (95% confidence interval 0.95-2.92) for the association between the TREM2 R47H and increased AD risk.
  
  
  CONCLUSIONS
  While our results serve to confirm the association between R47H and risk of AD, the observed effect on risk was substantially smaller than that previously reported.
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Basavaraj V
authors.initials: BV
authors.lastname: Hooli
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Parrado
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Wai-Ki
authors.initials: WK
authors.lastname: Yip
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Johannes T
authors.initials: JT
authors.lastname: Roehr
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Dandi
authors.initials: D
authors.lastname: Qiao
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.affiliation: From the MassGeneral Institute for Neurodegenerative Diseases (B.V.H., A.R.P., K.M., R.E.T.), Department of Neurology, Massachusetts General Hospital, Boston; Department of Biostatistics (W.-K.Y., D.Q., C.L.), Harvard School of Public Health, Boston, MA; Department of Vertebrate Genomics (T.L., J.T.R., L.B.), Max Planck Institute for Molecular Genetics, Berlin; Department of Psychiatry and Psychotherapy (F.J., A.R.), Institute for Medical Biometry, Informatics and Epidemiology (T.B.), and Institute of Human Genetics (A.R.), University of Bonn; German Center for Neurodegenerative Diseases (DZNE) (F.J., T.B.), Bonn; and Department of Psychiatry (O.P.), Charité University Medicine, Berlin, Germany. tanzi@helix.mgh.harvard.edu.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human