title: A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.
abstract: BACKGROUND
  We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.
  
  
  METHODS
  Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis.
  
  
  RESULTS
  A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10-3and 4.6 × 10-2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10-2and 3.5 × 10-3, Bonferroni-corrected P = 6.7 × 10-2and 7.1 × 10-3, respectively).
  
  
  CONCLUSIONS
  Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Burgess
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Strickland
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Aryal
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Michaela L
authors.initials: ML
authors.lastname: Kachadoorian
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Human Genetics Group, University of Nottingham, Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Curtis S
authors.initials: CS
authors.lastname: Younkin
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Nair
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
authors.forename: Pritha
authors.initials: P
authors.lastname: Chanana
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Serie
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Malphrus
authors.affiliation: Human Genetics Group, University of Nottingham, Nottingham, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Institute for Systems Biology, Seattle, WA, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Price
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.affiliation: Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA. Electronic address: taner.nilufer@mayo.edu.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D046228:Microarray Analysis; D005810:Multigene Family; D040641:Quantitative Trait Loci; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C473366:TREML1 protein, human
keywords: Alzheimer's disease; Regulatory variant; TREM2; TREML1; eQTL