TY - JOUR
T1 - TREM2 is associated with increased risk for Alzheimer's disease in African Americans
AU - Jin, Sheng Chih
AU - Carrasquillo, Minerva M.
AU - Benitez, Bruno A.
AU - Skorupa, Tara
AU - Carrell, David
AU - Patel, Dwani
AU - Lincoln, Sarah
AU - Krishnan, Siddharth
AU - Kachadoorian, Michaela
AU - Reitz, Christiane
AU - Mayeux, Richard
AU - Wingo, Thomas S.
AU - Lah, James J.
AU - Levey, Allan I.
AU - Murrell, Jill
AU - Hendrie, Hugh
AU - Foroud, Tatiana
AU - Graff-Radford, Neill R.
AU - Goate, Alison M.
AU - Cruchaga, Carlos
AU - Ertekin-Taner, Nilüfer
N1 - Publisher Copyright:
© 2015 Jin et al.; licensee BioMed Central.
PY - 2015/4/10
Y1 - 2015/4/10
N2 - 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.
AB - 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.
KW - African-American
KW - Case-control
KW - Coding variants
KW - LOAD
KW - TREM2
UR - http://www.scopus.com/inward/record.url?scp=84929174352&partnerID=8YFLogxK
U2 - 10.1186/s13024-015-0016-9
DO - 10.1186/s13024-015-0016-9
M3 - Article
C2 - 25886450
AN - SCOPUS:84929174352
SN - 1750-1326
VL - 10
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 19
ER -