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A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.

Alzheimers Dement. 2017 Jun;13(6):663-673. Epub 2016 Dec 08
Minerva M Carrasquillo 1 , Mariet Allen 1 , Jeremy D Burgess 1 , Xue Wang 2 , Samantha L Strickland 1 , Shivani Aryal 1 , Joanna Siuda 1 , Michaela L Kachadoorian 1 , Christopher Medway 3 , Curtis S Younkin 1 , Asha Nair 4 , Chen Wang 4 , Pritha Chanana 4 , Daniel Serie 2 , Thuy Nguyen 1 , Sarah Lincoln 1 , Kimberly G Malphrus 1 , Kevin Morgan 5 , Todd E Golde 6 , Nathan D Price 7 , Charles C White 8 , Philip L De Jager 9 , David A Bennett 10 , Yan W Asmann 2 , Julia E Crook 2 , Ronald C Petersen 11 , Neill R Graff-Radford 12 , Dennis W Dickson 1 , Steven G Younkin 1 , Nilüfer Ertekin-Taner 13
Minerva M Carrasquillo 1 , Mariet Allen 1 , Jeremy D Burgess 1 , Xue Wang 2 , Samantha L Strickland 1 , Shivani Aryal 1 , Joanna Siuda 1 , Michaela L Kachadoorian 1 , Christopher Medway 3 , Curtis S Younkin 1 , Asha Nair 4 , Chen Wang 4 , Pritha Chanana 4 , Daniel Serie 2 , Thuy Nguyen 1 , Sarah Lincoln 1 , Kimberly G Malphrus 1 , Kevin Morgan 5 , Todd E Golde 6 , Nathan D Price 7 , Charles C White 8 , Philip L De Jager 9 , David A Bennett 10 , Yan W Asmann 2 , Julia E Crook 2 , Ronald C Petersen 11 , Neill R Graff-Radford 12 , Dennis W Dickson 1 , Steven G Younkin 1 , Nilüfer Ertekin-Taner 13
+ et al

[No authors listed]

Author information
  • 1 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
  • 2 Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL, USA.
  • 3 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Human Genetics Group, University of Nottingham, Nottingham, UK.
  • 4 Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
  • 5 Human Genetics Group, University of Nottingham, Nottingham, UK.
  • 6 Department of Neuroscience, University of Florida, Gainesville, FL, USA.
  • 7 Institute for Systems Biology, Seattle, WA, USA.
  • 8 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.
  • 9 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.
  • 10 Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
  • 11 Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
  • 12 Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
  • 13 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA. Electronic address: taner.nilufer@mayo.edu.

摘要

INTRODUCTION: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 × 10-3 and 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 × 10-2 and 3.5 × 10-3, Bonferroni-corrected P = 6.7 × 10-2 and 7.1 × 10-3, respectively). DISCUSSION: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.

KEYWORDS: Alzheimer's disease, Regulatory variant, TREM2, TREML1, eQTL

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