期刊
TRANSLATIONAL PSYCHIATRY
卷 3, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/tp.2013.13
关键词
Alzheimer's disease; SORCS2; SORCS3; SORT1
类别
资金
- National Institutes of Health, National Institute on Aging (NIH-NIA) [U01AG032984, RC2AG036528, U01AG016976, U24AG021886, U24 AG026395, U24AG026390, P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG009029, R01 AG017173, R01 AG025259, P50 AG008702, R37 AG015473, P30 AG028377]
- Abbott
- AstraZeneca AB
- Bayer Schering Pharma AG
- Bristol-Myers Squibb
- Eisai Global Clinical Development
- Elan Corporation
- Genentech
- GE Healthcare
- GlaxoSmithKline
- Innogenetics
- Johnson and Johnson
- Eli Lilly and Co.
- Medpace, Inc.
- Merck and Co., Inc.
- Novartis AG
- Pfizer Inc
- F. Hoffman-La Roche
- Schering-Plough
- Synarc, Inc.
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Dana Foundation
- National Institute of Biomedical Imaging and Bioengineering
- NIA [U01 AG024904, RC2 AG036535, K01 AG030514]
- Alzheimer's Association [IIRG-08-89720, IIRG-05-14147]
- Veterans Affairs Administration
- Wellcome Trust
- Howard Hughes Medical Institute
- Canadian Institute of Health Research
- Evans Center for Interdisciplinary Biomedical Research ARC on 'Protein Trafficking and Neurodegenerative Diseases' at Boston University
- Ontario Research Fund
- Alzheimer Society of Canada
- Alzheimer Society of Ontario
- Paul B. Beeson Career Development Award [K23AG034550]
- NIA
- Canadian Institutes of Health Research
Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on gamma-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P <= 0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.
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