期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 368, 期 2, 页码 117-127出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1211851
关键词
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资金
- Alzheimer's Research UK
- Medical Research Council (MRC)
- Wellcome Trust
- Wellcome Trust/MRC Joint Call in Neurodegeneration Award [WT089698]
- Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (which support the Mayo Alzheimer's Disease Research Center) [P50 AG016574, U01 AG006786, R01 AG18023]
- Washington University School of Medicine Alzheimer's Disease Research Center [2P50 AG005681-27, 5P30 NS069329-02, NIRG-11-200110, 1R01 AG041797-01]
- National Institute for Health Research Biomedical Research Unit in Dementia at University College London Hospitals, University College London
- Ontario Research Fund
- Canadian Institutes of Health Research
- National Institutes of Health Research
- Wellcome Trust Medical Research Council
- an anonymous charitable foundation
- Fondation pour la Recherche sur Alzheimer
- Alzheimer Society of Ontario
- Big Lottery
- Intramural Research Programs of the National Institute on Aging
- National Institute of Neurological Disease and Stroke
- National Institutes of Health (Department of Health and Human Services) [ZO1 AG000950-10]
- Alzheimers Research UK [ARUK-TRFUS2012-1, ARUK-NCG2012B-1, ART-SB2010A-1, ART-PPG2011A-14, ARUK-TRFUS2012-3, ART-BIG2009-1, ART-RF2007-3, ART-NCG2008A-1, ART-PG2010-1, ARUK-PG2014-1] Funding Source: researchfish
- Medical Research Council [G0300429, MC_G1000735, G1100695, G0701441, MC_U123160651, G0902227, G0801418B, MR/K013041/1, MC_U123192748, G0802462, G0701075] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10033] Funding Source: researchfish
- MRC [MC_U123192748, G0300429, MC_G1000735, G0701075, G0902227, G1100695, MC_U123160651, MR/K013041/1, G0802462, G0701441] Funding Source: UKRI
BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.)
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