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

Philip L. De Jager, Joshua M. Shulman, Lori B. Chibnik, Brendan T. Keenan, Towfique Raj, Robert S. Wilson, Lei Yu, Sue E. Leurgans, Dong Tran, Cristin Aubin, Christopher D. Anderson, Alessandro Biffi, Jason J. Corneveaux, Matthew J. Huentelman, Disease Neuroimaging Initiative Alzheimer's Disease Neuroimaging Initiative, Jonathan Rosand, Mark J. Daly, Amanda J Myers, Eric M. Reiman, David A. BennettDenis A. Evans

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 (PDISC = 5.6 × 10-9; PJOINT = 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 (PDISC = 6.7 × 10-5; PREP = 9.4 × 10-3; PJOINT = 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.

Original languageEnglish (US)
Pages (from-to)1017.e1-1017.e15
JournalNeurobiology of Aging
Volume33
Issue number5
DOIs
StatePublished - Jan 1 2012

Fingerprint

Genome
Genome-Wide Association Study
Disease Susceptibility
Wounds and Injuries
Vascular Diseases
Neurodegenerative Diseases
Sample Size
Brain Injuries
Type 2 Diabetes Mellitus
Cognitive Dysfunction
Alzheimer Disease
Cardiovascular Diseases
Inflammation
Phenotype
Genes

Keywords

  • Alzheimer's disease
  • Cognitive decline
  • Genetic risk score
  • Genome-wide association study

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

De Jager, P. L., Shulman, J. M., Chibnik, L. B., Keenan, B. T., Raj, T., Wilson, R. S., ... Evans, D. A. (2012). A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiology of Aging, 33(5), 1017.e1-1017.e15. https://doi.org/10.1016/j.neurobiolaging.2011.09.033

A genome-wide scan for common variants affecting the rate of age-related cognitive decline. / De Jager, Philip L.; Shulman, Joshua M.; Chibnik, Lori B.; Keenan, Brendan T.; Raj, Towfique; Wilson, Robert S.; Yu, Lei; Leurgans, Sue E.; Tran, Dong; Aubin, Cristin; Anderson, Christopher D.; Biffi, Alessandro; Corneveaux, Jason J.; Huentelman, Matthew J.; Alzheimer's Disease Neuroimaging Initiative, Disease Neuroimaging Initiative; Rosand, Jonathan; Daly, Mark J.; Myers, Amanda J; Reiman, Eric M.; Bennett, David A.; Evans, Denis A.

In: Neurobiology of Aging, Vol. 33, No. 5, 01.01.2012, p. 1017.e1-1017.e15.

Research output: Contribution to journalArticle

De 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, Alzheimer's Disease Neuroimaging Initiative, DNI, Rosand, J, Daly, MJ, Myers, AJ, Reiman, EM, Bennett, DA & Evans, DA 2012, 'A genome-wide scan for common variants affecting the rate of age-related cognitive decline', Neurobiology of Aging, vol. 33, no. 5, pp. 1017.e1-1017.e15. https://doi.org/10.1016/j.neurobiolaging.2011.09.033
De Jager PL, Shulman JM, Chibnik LB, Keenan BT, Raj T, Wilson RS et al. A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiology of Aging. 2012 Jan 1;33(5):1017.e1-1017.e15. https://doi.org/10.1016/j.neurobiolaging.2011.09.033
De Jager, Philip L. ; Shulman, Joshua M. ; Chibnik, Lori B. ; Keenan, Brendan T. ; Raj, Towfique ; Wilson, Robert S. ; Yu, Lei ; Leurgans, Sue E. ; Tran, Dong ; Aubin, Cristin ; Anderson, Christopher D. ; Biffi, Alessandro ; Corneveaux, Jason J. ; Huentelman, Matthew J. ; Alzheimer's Disease Neuroimaging Initiative, Disease Neuroimaging Initiative ; Rosand, Jonathan ; Daly, Mark J. ; Myers, Amanda J ; Reiman, Eric M. ; Bennett, David A. ; Evans, Denis A. / A genome-wide scan for common variants affecting the rate of age-related cognitive decline. In: Neurobiology of Aging. 2012 ; Vol. 33, No. 5. pp. 1017.e1-1017.e15.
@article{ca2072a44c0f46bf808667bce32ba124,
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 (PDISC = 5.6 × 10-9; PJOINT = 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 (PDISC = 6.7 × 10-5; PREP = 9.4 × 10-3; PJOINT = 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.",
keywords = "Alzheimer's disease, Cognitive decline, Genetic risk score, Genome-wide association study",
author = "{De Jager}, {Philip L.} and Shulman, {Joshua M.} and Chibnik, {Lori B.} and Keenan, {Brendan T.} and Towfique Raj and Wilson, {Robert S.} and Lei Yu and Leurgans, {Sue E.} and Dong Tran and Cristin Aubin and Anderson, {Christopher D.} and Alessandro Biffi and Corneveaux, {Jason J.} and Huentelman, {Matthew J.} and {Alzheimer's Disease Neuroimaging Initiative}, {Disease Neuroimaging Initiative} and Jonathan Rosand and Daly, {Mark J.} and Myers, {Amanda J} and Reiman, {Eric M.} and Bennett, {David A.} and Evans, {Denis A.}",
year = "2012",
month = "1",
day = "1",
doi = "10.1016/j.neurobiolaging.2011.09.033",
language = "English (US)",
volume = "33",
pages = "1017.e1--1017.e15",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",
number = "5",

}

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.

PY - 2012/1/1

Y1 - 2012/1/1

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 (PDISC = 5.6 × 10-9; PJOINT = 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 (PDISC = 6.7 × 10-5; PREP = 9.4 × 10-3; PJOINT = 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.

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 (PDISC = 5.6 × 10-9; PJOINT = 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 (PDISC = 6.7 × 10-5; PREP = 9.4 × 10-3; PJOINT = 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.

KW - Alzheimer's disease

KW - Cognitive decline

KW - Genetic risk score

KW - Genome-wide association study

UR - http://www.scopus.com/inward/record.url?scp=85018059449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018059449&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2011.09.033

DO - 10.1016/j.neurobiolaging.2011.09.033

M3 - Article

C2 - 22054870

AN - SCOPUS:84858334284

VL - 33

SP - 1017.e1-1017.e15

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

IS - 5

ER -