TY - JOUR
T1 - A genome-wide scan for common variants affecting the rate of age-related cognitive decline.
AU - De Jager, Philip L.
AU - Shulman, Joshua M.
AU - Chibnik, Lori B.
AU - Keenan, Brendan T.
AU - Raj, Towfique
AU - Wilson, Robert S.
AU - Yu, Lei
AU - Leurgans, Sue E.
AU - Tran, Dong
AU - Aubin, Cristin
AU - Anderson, Christopher D.
AU - Biffi, Alessandro
AU - Corneveaux, Jason J.
AU - Huentelman, Matthew J.
AU - Alzheimer's Disease Neuroimaging Initiative, Disease Neuroimaging Initiative
AU - Rosand, Jonathan
AU - Daly, Mark J.
AU - Myers, Amanda J.
AU - Reiman, Eric M.
AU - Bennett, David A.
AU - Evans, Denis A.
N1 - Funding Information:
The authors thank Sara Pulit for help with assembling a comprehensive list of SNPs associated with inflammatory diseases. The authors are also grateful to the participants in the Religious Orders Study, the Chicago Health and Aging Project, the Memory and Aging Project, and the Alzheimer's Disease Neuroimaging Initiative. This work is supported by the National Institutes of Health [ R01 AG030146 , P30 AG10161 , R01 AG17917 , R01 AG15819 , K08 AG034290 , P30 AG10161 and R01 AG11101 ], and the Illinois Department of Public Health. J.M.S. is additionally supported by the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center and Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer Inc. and Merck & Co. A.J.M. is supported by NIA grant R01 AG034504 and the Johnnie B Byrd Institute. M.J.H., J.C., and E.M.R. are supported by grants from Kronos Life Sciences Laboratories , the National Institute on Aging (Arizona Alzheimer's Disease Center P30 AG19610 , R01 AG023193 , Mayo Clinic Alzheimer's Disease Center P50 AG16574 and Intramural Research Program), the National Alzheimer's Coordinating Center ( U01 AG016976 ), and the state of Arizona. Additional funding was obtained from the NIH Neuroscience Blueprint ( U24NS051872 ), the ENDGAME Consortium ( U01HL084744 ), a National Institute on Aging grant to Carl Cotman (University of California, Irvine, P50 AG23173 ), National Institute on Aging ( K01AG024079 ) and the state of Arizona. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) ( National Institutes of Health grant U01 AG024904 ). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: 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., as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants; 1P30 AG010129 , K01 AG030514 , and the Dana Foundation.
PY - 2012/5
Y1 - 2012/5
N2 - Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury. Copyright Â
AB - Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury. Copyright Â
UR - http://www.scopus.com/inward/record.url?scp=84858334284&partnerID=8YFLogxK
M3 - Article
C2 - 22054870
AN - SCOPUS:84858334284
SN - 0197-4580
VL - 33
SP - 1017.e1-15
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 5
ER -