A genome-wide scan for common variants affecting the rate of age-related cognitive decline.

TitleA genome-wide scan for common variants affecting the rate of age-related cognitive decline.
Publication TypeJournal Article
Year of Publication2012
AuthorsDe Jager PL, Shulman JM, Chibnik LB, Keenan BT, Raj T, Wilson RS, Yu L, Leurgans SE, Tran D, Aubin C, Anderson CD, Biffi A, Corneveaux JJ, Huentelman MJ, Rosand J, Daly MJ, Myers AJ, Reiman EM, Bennett DA, Evans DA
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative
JournalNeurobiol Aging
Volume33
Issue5
Pagination1017.e1-15
Date Published2012 May
ISSN1558-1497
KeywordsAged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Cognition Disorders, Cyclic Nucleotide Phosphodiesterases, Type 7, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Mitochondrial Proteins, Risk Factors
Abstract

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.

DOI10.1016/j.neurobiolaging.2011.09.033
Alternate JournalNeurobiol. Aging
PubMed ID22054870
PubMed Central IDPMC3307898
Grant ListP50 AG16574 / AG / NIA NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
U24NS051872 / NS / NINDS NIH HHS / United States
K08 AG034290 / AG / NIA NIH HHS / United States
P30 AG010161-09 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 AG017917-01A1 / AG / NIA NIH HHS / United States
U01HL084744 / HL / NHLBI NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
U24 NS051872 / NS / NINDS NIH HHS / United States
K01 AG024079 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
R01 AG030146-04 / AG / NIA NIH HHS / United States
R01 AG023173 / AG / NIA NIH HHS / United States
1P30 AG010129 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
K01AG024079 / AG / NIA NIH HHS / United States
/ / Intramural NIH HHS / United States
P50 AG23173 / AG / NIA NIH HHS / United States
R01 AG11101 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
R01 AG034504 / AG / NIA NIH HHS / United States
R01 AG015819-14 / AG / NIA NIH HHS / United States
P30 AG19610 / AG / NIA NIH HHS / United States
K08 AG034290-01 / AG / NIA NIH HHS / United States
R01 AG011101 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
R01 NS059873 / NS / NINDS NIH HHS / United States
R01 AG023193 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States