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October 07, 2014; 83 (15) Article

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk

Basavaraj V. Hooli, Antonio R. Parrado, Kristina Mullin, Wai-Ki Yip, Tian Liu, Johannes T. Roehr, Dandi Qiao, Frank Jessen, Oliver Peters, Tim Becker, Alfredo Ramirez, Christoph Lange, Lars Bertram, Rudolph E. Tanzi
First published September 3, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000855
Basavaraj V. Hooli
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.
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Antonio R. Parrado
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.
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Kristina Mullin
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.
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Wai-Ki Yip
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.
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Tian Liu
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.
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Johannes T. Roehr
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.
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Dandi Qiao
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.
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Frank Jessen
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.
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Oliver Peters
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.
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Tim Becker
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.
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Alfredo Ramirez
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.
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Christoph Lange
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.
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Lars Bertram
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.
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Rudolph E. Tanzi
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.
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Citation
The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk
Basavaraj V. Hooli, Antonio R. Parrado, Kristina Mullin, Wai-Ki Yip, Tian Liu, Johannes T. Roehr, Dandi Qiao, Frank Jessen, Oliver Peters, Tim Becker, Alfredo Ramirez, Christoph Lange, Lars Bertram, Rudolph E. Tanzi
Neurology Oct 2014, 83 (15) 1353-1358; DOI: 10.1212/WNL.0000000000000855

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Abstract

Objectives: 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.

GLOSSARY

AD=
Alzheimer disease;
ADNI=
Alzheimer's Disease Neuroimaging Initiative;
AgeCoDe=
German Study on Ageing, Cognition and Dementia in Primary Care Patients;
CI=
confidence interval;
FBAT=
family-based association test;
GSK=
GlaxoSmithKline;
GWAS=
genome-wide association study;
LOAD=
late-onset Alzheimer disease;
MAF=
minor allele frequency;
NIA=
National Institute on Aging;
NIA-LOAD=
National Institute on Aging Genetics Initiative for Late Onset Alzheimer's Disease;
NIMH=
National Institute of Mental Health;
OR=
odds ratio;
SNP=
single nucleotide polymorphism;
TGEN2=
Translational Genomics Research Institute series 2;
TREM2=
triggering receptor expressed on myeloid cells 2

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received November 21, 2013.
  • Accepted in final form July 15, 2014.
  • © 2014 American Academy of Neurology
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