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

NEUROBIOLOGY OF AGING

卷:33

Article

De Jager, Philip L.^1,2,3,4  Shulman, Joshua M.^1,2,3,4  Chibnik, Lori B.^1,2,3,4  Keenan, Brendan T.^1,2,4  Raj, Towfique^1,2,3  Wilson, Robert S.⁵  Yu, Lei⁵  Leurgans, Sue E.⁵  Tran, Dong^1,2,3,4  Aubin, Cristin^1,2,3,4  Anderson, Christopher D.^4,6,7  Biffi, Alessandro^4,6,7  Corneveaux, Jason J.^8,9  Huentelman, Matthew J.^8,9  Rosand, Jonathan^3,4,6,7  Daly, Mark J.^3,4,6,7  Myers, Amanda J.^10,11  Reiman, Eric M.^8,9,12,13,14  Bennett, David A.⁵  Evans, Denis A.^5,15 

[1] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Inst Neurosci, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Psychiat, Program Translat NeuroPsychiat Genom, Inst Neurosci, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[5] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[6] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[8] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA

[9] Arizona Alzheimers Consortium, Phoenix, AZ USA

[10] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA

[11] Johnnie B Byrd Sr Alzheimers Ctr & Res Inst, Tampa, FL USA

[12] Univ Arizona, Banner Alzheimers Inst, Phoenix, AZ USA

[13] Univ Arizona, Dept Psychiat, Phoenix, AZ USA

[14] Univ Arizona, Dept Psychiat, Tucson, AZ USA

[15] Rush Univ, Med Ctr, Rush Inst Hlth Aging, Chicago, IL 60612 USA

关键词: Cognitive decline;    Genome-wide association study;    Alzheimer's disease;    Genetic risk score;   

DOI  :  10.1016/j.neurobiolaging.2011.09.033

来源: Elsevier

【 摘 要 】

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 x 10(-9); P-JOINT = 3.7 x 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 x 10(-5); P-REP = 9.4 x 10(-3); P-JOINT = 2.3 x 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. (C) 2012 Elsevier Inc. All rights reserved.

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