title: TREM2 is associated with increased risk for Alzheimer's disease in African Americans.
abstract: BACKGROUND
  TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer's disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case-control analyses in a total of 906 LOAD cases vs. 2,487 controls.
  
  
  RESULTS
  We identified significant LOAD risk association with p.L211P (p=0.01, OR=1.27, 95%CI=1.05-1.54) and suggestive association with p.W191X (p=0.08, OR=1.35, 95%CI=0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk.
  
  
  CONCLUSIONS
  Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. shengchih.jin@yale.edu.
authors.forename: Sheng Chih
authors.initials: SC
authors.lastname: Jin
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Carrasquillo.Minerva@mayo.edu.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. bbenitez@DOM.wustl.edu.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. skorupat@psychiatry.wustl.edu.
authors.forename: Tara
authors.initials: T
authors.lastname: Skorupa
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. carrelld@psychiatry.wustl.edu.
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. pateld@psychiatry.wustl.edu.
authors.forename: Dwani
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Lincoln.Sarah@mayo.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. siddukrishnan1992@gmail.com.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Michaela.Kach@gmail.com.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kachadoorian
authors.affiliation: Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, 10032, USA. cr2101@cumc.columbia.edu.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. cr2101@cumc.columbia.edu.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.affiliation: Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, 10032, USA. rpm2@columbia.edu.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. rpm2@columbia.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30033, USA. thomas.wingo@emory.edu.|Division of Neurology, Atlanta Veterans Administration Medical Center, Atlanta, GA, 30033, USA. thomas.wingo@emory.edu.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wingo
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30033, USA. jlah@emory.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30033, USA. alevey@emory.edu.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. jrmurrel@iupui.edu.
authors.forename: Jill
authors.initials: J
authors.lastname: Murrell
authors.affiliation: Indiana University Center for Aging Research, Indianapolis, IN, 46202, USA. hhendri@iupui.edu.|Regenstrief Institute, Inc, 410 West 10th Street, Suite 2000, Indianapolis, IN, 46202, USA. hhendri@iupui.edu.
authors.forename: Hugh
authors.initials: H
authors.lastname: Hendrie
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. tforoud@iupui.edu.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. graffradford.neill@mayo.edu.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. alison.goate@mssm.edu.|Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, 660 S. Euclid Avenue B8111, St. Louis, MO, 63110, USA. alison.goate@mssm.edu.|Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue B8111, St. Louis, MO, 63110, USA. alison.goate@mssm.edu.|Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, St. Louis, MO, 63108, USA. alison.goate@mssm.edu.|Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA. alison.goate@mssm.edu.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. cruchagc@psychiatry.wustl.edu.|Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, 660 S. Euclid Avenue B8111, St. Louis, MO, 63110, USA. cruchagc@psychiatry.wustl.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Taner.Nilufer@mayo.edu.|Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Taner.Nilufer@mayo.edu.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
mesh_terms: D001741:Black or African American / Q000235:genetics*; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human