Citations 2
Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2 : A genome‐wide association study in over 12,000 non‐demented participants
Grenier‐Boley, Benjamin , Simino, Jeannette , Adams, Hieab H.H. , White, Charles C. , Terzikhan, Natalie, Cruchaga, Carlos , Knol, Maria J. , Li, Shuo , Schraen, Susanna, Grove, Megan L. , Satizábal, Claudia L. , Amin, Najaf , Younkin, Steven G., Initiative, Alzheimer's Disease Neuroimaging, Gottesman, Rebecca F., Buée, Luc , Uitterlinden, André G. , DeCarli, Charles , Bressler, Jan , DeStefano, Anita L. , Dartigues, Jean‐François, Boerwinkle, Eric , Tzourio, Christophe , Fornage, Myriam , Jager, Phil De, Reitz, Christiane, Mosley, Thomas H. , Lambert, Jean‐Charles , Duijn, Cornelia M. van , DeCarli, Charles , Younkin, Steven, Cruchaga, Carlos , Adams, Hieab H H , Satizabal, Claudia L , Tzourio, Christophe , van Duijn, Cornelia M , Damotte, Vincent , Lee, Sven J. van der , Chouraki, Vincent Antoine , Tosto, Giuseppe , Berr, Claudine , Initiative, Alzheimer's Disease Neuroimaging, Beiser, Alexa , Knopman, David S. , Yang, Qiong , Ikram, M. Arfan , Amouyel, Philippe , Jager, Philip L. De , Seshadri, Sudha
Alzheimer's & Dementia | May 18, 2021 | Volume: 17 | Issue: 10 | Pages: 1663-1674
Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.
A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression
Carrasquillo, Minerva M., Allen, Mariet , Burgess, Jeremy D. , Wang, Xue , Strickland, Samantha L. , Aryal, Shivani , Siuda, Joanna , Kachadoorian, Michaela, Medway, Christopher, Younkin, Curtis, Nair, Asha, Chanana, Pritha , Serie, Daniel, Nguyen, Thuy , Lincoln, Sarah, Malphrus, Kimberly G., Morgan, Kevin , Golde, Todd E. , Price, Nathan D. , White, Charles C. , Jager, Philip L. De , Bennett, David A. , Asmann, Yan W. , Petersen, Ronald , Graff‐Radford, Neill R., Younkin, Steven G., Ertekin‐Taner, Nilüfer , Kachadoorian, Michaela L, Younkin, Curtis S, Crook, Julia E. , Bennett, David A. , Carrasquillo, Minerva M. , Siuda, Joanna S. , Wang, Chen , Graff‐Radford, Neill R., Dickson, Dennis W. , Price, Nathan D
Alzheimer's & Dementia | December 8, 2016 | Volume: 13 | Issue: 6 | Pages: 663-673
AbstractIntroductionWe hypothesized that common Alzheimer's disease (AD)‐associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.MethodsExpression 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.ResultsA 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).DiscussionOur 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.