publication . Article . Other literature type . 2017

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Cory C. Funk; Daniel H. Geschwind; Vivianna M. Van Deerlin; Aimee Pierce; Linda J. Van Eldik; Ronald C. Petersen; Daniel C. Marson; Lars Lannfelt; Sebastien Engelborghs; Martin R. Farlow; ...
Open Access English
  • Published: 01 Sep 2017
  • Publisher: Nature Publishing Group
Abstract
International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × ...
Subjects
free text keywords: Alzheimer's disease; Genome-wide association studies, [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Journal Article, Article, ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI, Microglia, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Immunologic, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Amino Acid Sequence, Sequence Homology, Amino Acid, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Phospholipase C gamma, Immunity, Innate, Protein Interaction Maps, Exome, R1, Genetics, Common disease-common variant, Linkage disequilibrium, TREM2, Genome-wide association study, Minor allele frequency, Alzheimer's disease, medicine.disease, medicine, Case-control study, Allele frequency, Biology
Funded by
NIH| UCLA Clinical and Translational Science Institute
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5UL1TR000124-04
  • Funding stream: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
,
NIH| Alzheimers Disease Neuroimaging Initiative
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01AG024904-01
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| UCLA Alzheimers Disease Research Center
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3P50AG016570-07S1
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01AG015928-01
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
CIHR
Project
  • Funder: Canadian Institutes of Health Research (CIHR)
160 references, page 1 of 11

1. Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK;

2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;

3. Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA;

4. Inserm, U1167, RID-AGE - Risk factors and molecular determinants of aging-related diseases, F59000 Lille, France;

5. Institut Pasteur de Lille, F-59000 Lille, France;

6. University Lille, U1167 - Excellence Laboratory LabEx DISTALZ, F-59000 Lille;

7. Icelandic Heart Association, Kopavogur, Iceland;

8. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA;

9. CEA / Institut de Génomique, Centre National de Génotypage, F-91057 Evry, France ;

10. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA;

11. Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida, USA;

12. Institute of Human Genetics, University of Bonn, Bonn, Germany;

13. Department of Genomics, Life & Brain Center, University of Bonn, 53127, Bonn, Germany;

14. Boston University School of Medicine, Boston, MA, USA;

15. Framingham Heart Study, Framingham, MA, USA;

160 references, page 1 of 11
Abstract
International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × ...
Subjects
free text keywords: Alzheimer's disease; Genome-wide association studies, [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Journal Article, Article, ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI, Microglia, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Immunologic, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Amino Acid Sequence, Sequence Homology, Amino Acid, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Phospholipase C gamma, Immunity, Innate, Protein Interaction Maps, Exome, R1, Genetics, Common disease-common variant, Linkage disequilibrium, TREM2, Genome-wide association study, Minor allele frequency, Alzheimer's disease, medicine.disease, medicine, Case-control study, Allele frequency, Biology
Funded by
NIH| UCLA Clinical and Translational Science Institute
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5UL1TR000124-04
  • Funding stream: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
,
NIH| Alzheimers Disease Neuroimaging Initiative
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01AG024904-01
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| UCLA Alzheimers Disease Research Center
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3P50AG016570-07S1
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01AG015928-01
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
CIHR
Project
  • Funder: Canadian Institutes of Health Research (CIHR)
160 references, page 1 of 11

1. Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK;

2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;

3. Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA;

4. Inserm, U1167, RID-AGE - Risk factors and molecular determinants of aging-related diseases, F59000 Lille, France;

5. Institut Pasteur de Lille, F-59000 Lille, France;

6. University Lille, U1167 - Excellence Laboratory LabEx DISTALZ, F-59000 Lille;

7. Icelandic Heart Association, Kopavogur, Iceland;

8. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA;

9. CEA / Institut de Génomique, Centre National de Génotypage, F-91057 Evry, France ;

10. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA;

11. Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida, USA;

12. Institute of Human Genetics, University of Bonn, Bonn, Germany;

13. Department of Genomics, Life & Brain Center, University of Bonn, 53127, Bonn, Germany;

14. Boston University School of Medicine, Boston, MA, USA;

15. Framingham Heart Study, Framingham, MA, USA;

160 references, page 1 of 11
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