期刊
PLOS ONE
卷 8, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0064802
关键词
-
资金
- National Institutes of Health grant: National Institute on Aging [R01 AG018023, AG025711, AG017216, AG003949]
- National Institutes of Health grant: Mayo Alzheimer's Disease Research Center [P50 AG016574]
- National Institutes of Health grant: Mayo Alzheimer's Disease Patient Registry [U01AG006576]
- Wellcome Trust
- Medical Research Council (MRC)
- Alzheimer's Research United Kingdom (ARUK)
- Welsh Assembly Government
- Alzheimer's Society
- Ulster Garden Villages
- N. Ireland Research & Development Office
- Royal College of Physicians/Dunhill Medical Trust
- Trinity College group
- Bristol Research into Alzheimer's and Care of the Elderly
- OPTIMA group
- UCLH/UCL Biomedical Centre
- Lundbeck SA
- German Federal Ministry of Education and Research Competence Network Dementia and Competence Network Degenerative Dementia
- Alfried Krupp von Bohlen und Halbach-Stiftung
- Alzheimers Research UK [ARUK-PG2014-1, ART-RF2007-3] Funding Source: researchfish
- Medical Research Council [MR/K013041/1, G0801418B, MC_PC_14095, MC_U123160651, MC_U123192748, G0902227] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10084] Funding Source: researchfish
- MRC [MR/K013041/1, MC_U123160651, MC_U123192748, MC_PC_14095, G0902227] Funding Source: UKRI
GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61-0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82-0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5x10(-7) -9.3x10(-6)). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = -0.34, p = 0.0006) and senile plaque counts (r = -0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = -0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据