title: Coding variants in TREM2 increase risk for Alzheimer's disease.
abstract: The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer''s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [P = 9.17 × 10(-4), odds ratio (OR) = 2.63 (1.44-4.81)] and p.R62H [P = 2.36 × 10(-4), OR = 2.36 (1.47-3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [PSKAT-O = 5.37 × 10(-7); OR = 2.55 (1.80-3.67)]. The association of TREM2 variants with AD is still highly significant after excluding p.R47H [PSKAT-O = 7.72 × 10(-5); OR = 2.47 (1.62-3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P = 4.65 × 10(-2)) and p.R62H (P = 6.87 × 10(-3)) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Sheng Chih
authors.initials: SC
authors.lastname: Jin
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA, Hope Center Program on Protein Aggregation and Neurodegeneration and.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Breanna
authors.initials: B
authors.lastname: Cooper
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Skorupa
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Norton
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Hsu
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Yefei
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA, Hope Center Program on Protein Aggregation and Neurodegeneration and Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA, Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Ave., St. Louis, MO 63108, USA and Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA goatea@psychiatry.wustl.edu ccruchaga@wustl.edu.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA, Hope Center Program on Protein Aggregation and Neurodegeneration and goatea@psychiatry.wustl.edu ccruchaga@wustl.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics*; D012306:Risk; D016415:Sequence Alignment
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human