title: A genome-wide scan for common variants affecting the rate of age-related cognitive decline.
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.
authors: Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA. pdejager@rics.bwh.harvard.edu
authors: Philip L
authors: PL
authors: De Jager
authors: Joshua M
authors: JM
authors: Shulman
authors: Lori B
authors: LB
authors: Chibnik
authors: Brendan T
authors: BT
authors: Keenan
authors: Towfique
authors: T
authors: Raj
authors: Robert S
authors: RS
authors: Wilson
authors: Lei
authors: L
authors: Yu
authors: Sue E
authors: SE
authors: Leurgans
authors: Dong
authors: D
authors: Tran
authors: Cristin
authors: C
authors: Aubin
authors: Christopher D
authors: CD
authors: Anderson
authors: Alessandro
authors: A
authors: Biffi
authors: Jason J
authors: JJ
authors: Corneveaux
authors: Matthew J
authors: MJ
authors: Huentelman
authors: Jonathan
authors: J
authors: Rosand
authors: Mark J
authors: MJ
authors: Daly
authors: Amanda J
authors: AJ
authors: Myers
authors: Eric M
authors: EM
authors: Reiman
authors: David A
authors: DA
authors: Bennett
authors: Denis A
authors: DA
authors: Evans
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D003072:Cognition Disorders / Q000453:epidemiology / Q000235:genetics*; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D012307:Risk Factors
chemical_list: D001057:Apolipoproteins E; D024101:Mitochondrial Proteins; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human