TREM2 variants in Alzheimer's disease.

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.).

[1]  A. Singleton,et al.  Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. , 2012, JAMA neurology.

[2]  L. Hazrati,et al.  Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism , 2012, Neurobiology of Aging.

[3]  J. Hardy,et al.  Microglia, Alzheimer's Disease, and Complement , 2012, International journal of Alzheimer's disease.

[4]  Joseph K. Pickrell,et al.  A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes , 2012, Science.

[5]  R. Guerreiro,et al.  Complement receptor 1 (CR1) and Alzheimer's disease. , 2012, Immunobiology.

[6]  A. Singleton,et al.  Repeat expansion in C9ORF72 in Alzheimer's disease. , 2012, The New England journal of medicine.

[7]  D. G. Clark,et al.  Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease , 2011, Nature Genetics.

[8]  Nick C Fox,et al.  Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease , 2011, Nature Genetics.

[9]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[10]  A. Singleton,et al.  Towards a complete resolution of the genetic architecture of disease. , 2010, Trends in genetics : TIG.

[11]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[12]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[13]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[14]  L. Kiemeney,et al.  Corrigendum: Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer , 2009, Nature Genetics.

[15]  Nick C Fox,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes , 2009, Nature Genetics.

[16]  M. Hamshere,et al.  Meta-analysis of linkage studies for Alzheimer's disease—A web resource , 2009, Neurobiology of Aging.

[17]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[18]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[19]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[20]  Nick C Fox,et al.  Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease , 2009 .

[21]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[22]  I. Bechmann,et al.  TREM2 is upregulated in amyloid plaque‐associated microglia in aged APP23 transgenic mice , 2008, Glia.

[23]  L. Piccio,et al.  Blockade of TREM‐2 exacerbates experimental autoimmune encephalomyelitis , 2007, European journal of immunology.

[24]  H. Neumann,et al.  TREM2-Transduced Myeloid Precursors Mediate Nervous Tissue Debris Clearance and Facilitate Recovery in an Animal Model of Multiple Sclerosis , 2007, PLoS medicine.

[25]  H. Neumann,et al.  Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis , 2007, Journal of Neuroimmunology.

[26]  B. Melchior,et al.  Microglia and the control of autoreactive T cell responses , 2006, Neurochemistry International.

[27]  L. Peltonen,et al.  Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. , 2002, American journal of human genetics.

[28]  S. Turner,et al.  Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695* , 2001, The Journal of Biological Chemistry.

[29]  Ralph A. Nixon,et al.  Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease , 2000, Nature.

[30]  P. S. St George-Hyslop,et al.  A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. , 2000, Nature.

[31]  K. Welsh-Bohmer,et al.  APOE-ε4 count predicts age when prevalence of AD increases, then declines , 1999, Neurology.

[32]  B W Wyse,et al.  APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. , 1999, Neurology.

[33]  J. Rommens,et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene , 1995, Nature.

[34]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[35]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.