TREM2 is associated with increased risk for Alzheimer's disease in African Americans

Sheng Chih Jin, Minerva M. Carrasquillo, Bruno A. Benitez, Tara Skorupa, David Carrell, Dwani Patel, Sarah Lincoln, Siddharth Krishnan, Michaela Kachadoorian, Christiane Reitz, Richard Mayeux, Thomas S. Wingo, James J. Lah, Allan I. Levey, Jill Murrell, Hugh Hendrie, Tatiana Foroud, Neill R. Graff-Radford, Alison M. Goate, Carlos CruchagaNilüfer Ertekin-Taner

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number19
JournalMolecular Neurodegeneration
Volume10
Issue number1
DOIs
StatePublished - Apr 10 2015

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African Americans
Alzheimer Disease
Linkage Disequilibrium
Myeloid Cells
Mutation
Population
Genes

Keywords

  • African-American
  • Case-control
  • Coding variants
  • LOAD
  • TREM2

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., ... Ertekin-Taner, N. (2015). TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Molecular Neurodegeneration, 10(1), [19]. https://doi.org/10.1186/s13024-015-0016-9

TREM2 is associated with increased risk for Alzheimer's disease in African Americans. / Jin, Sheng Chih; Carrasquillo, Minerva M.; Benitez, Bruno A.; Skorupa, Tara; Carrell, David; Patel, Dwani; Lincoln, Sarah; Krishnan, Siddharth; Kachadoorian, Michaela; Reitz, Christiane; Mayeux, Richard; Wingo, Thomas S.; Lah, James J.; Levey, Allan I.; Murrell, Jill; Hendrie, Hugh; Foroud, Tatiana; Graff-Radford, Neill R.; Goate, Alison M.; Cruchaga, Carlos; Ertekin-Taner, Nilüfer.

In: Molecular Neurodegeneration, Vol. 10, No. 1, 19, 10.04.2015.

Research output: Contribution to journalArticle

Jin, SC, Carrasquillo, MM, Benitez, BA, Skorupa, T, Carrell, D, Patel, D, Lincoln, S, Krishnan, S, Kachadoorian, M, Reitz, C, Mayeux, R, Wingo, TS, Lah, JJ, Levey, AI, Murrell, J, Hendrie, H, Foroud, T, Graff-Radford, NR, Goate, AM, Cruchaga, C & Ertekin-Taner, N 2015, 'TREM2 is associated with increased risk for Alzheimer's disease in African Americans', Molecular Neurodegeneration, vol. 10, no. 1, 19. https://doi.org/10.1186/s13024-015-0016-9
Jin, Sheng Chih ; Carrasquillo, Minerva M. ; Benitez, Bruno A. ; Skorupa, Tara ; Carrell, David ; Patel, Dwani ; Lincoln, Sarah ; Krishnan, Siddharth ; Kachadoorian, Michaela ; Reitz, Christiane ; Mayeux, Richard ; Wingo, Thomas S. ; Lah, James J. ; Levey, Allan I. ; Murrell, Jill ; Hendrie, Hugh ; Foroud, Tatiana ; Graff-Radford, Neill R. ; Goate, Alison M. ; Cruchaga, Carlos ; Ertekin-Taner, Nilüfer. / TREM2 is associated with increased risk for Alzheimer's disease in African Americans. In: Molecular Neurodegeneration. 2015 ; Vol. 10, No. 1.
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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

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.

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