Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 20, Pages 4558-4571Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds296
Keywords
-
Funding
- Pfizer
- National Institutes of Health [P30-NS069329-01, R01-AG035083, P50 AG05681]
- Alzheimer's Association [MNIRG-11-205368]
- NIH [U01AG032984, P30 AG010129, K01 AG030514]
- Wellcome Trust [GR082604MA]
- Medical Research Council [G0300429]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Canadian Institutes of Health Research
- Dana Foundation
- MRC [G0902227, G0300429] Funding Source: UKRI
- Medical Research Council [G0300429, G0902227] Funding Source: researchfish
Ask authors/readers for more resources
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimers disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P 8.15 10(4)) but not plasma (P 0.071) APOE protein levels are significantly associated with CSF A(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF A(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with A(42) levels was independent of the APOE ?4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ?4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P 6.9 10(13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72 of the variability in CSF APOE protein levels, whereas the APOE ?4 genotype alone explains 8 of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value 10(6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P 4.49 10(9)).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available