ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Peter T. Nelson, Steven Estus, Erin L. Abner, Ishita Parikh, Manasi Malik, Janna H. Neltner, Eseosa Ighodaro, Wang Xia Wang, Bernard R. Wilfred, Li San Wang, Walter A. Kukull, Kannabiran Nandakumar, Mark L. Farman, Wayne W. Poon, Maria M. Corrada, Claudia H. Kawas, David H. Cribbs, David A. Bennett, Julie A. Schneider, Eric B. LarsonPaul K. Crane, Otto Valladares, Frederick A. Schmitt, Richard J. Kryscio, Gregory A. Jicha, Charles D. Smith, Stephen W. Scheff, Joshua A. Sonnen, Jonathan L. Haines, Margaret A. Pericak-Vance, Richard Mayeux, Lindsay A. Farrer, Linda J. Van Eldik, Craig Horbinski, Robert C. Green, Marla Gearing, Leonard W. Poon, Patricia L. Kramer, Randall (Randy) Woltjer, Thomas J. Montine, Amanda B. Partch, Alexander J. Rajic, Katierose Richmire, Sarah E. Monsell, Gerard D. Schellenberg, David W. Fardo

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

Original languageEnglish (US)
Pages (from-to)825-843
Number of pages19
JournalActa Neuropathologica
Volume127
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Sclerosis
Adenosine Triphosphate
Pathology
Single Nucleotide Polymorphism
Genome-Wide Association Study
Genes
Odds Ratio
Alzheimer Disease
Alleles
Sulfonylurea Receptors
Pharmaceutical Preparations
Endophenotypes
Brain Diseases
Dementia
Meta-Analysis
Autopsy
History
Genome
Databases
Morbidity

Keywords

  • ADGC
  • CTAGE5
  • KATP
  • Neuropathology
  • Oldest old
  • Potassium channel

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Nelson, P. T., Estus, S., Abner, E. L., Parikh, I., Malik, M., Neltner, J. H., ... Fardo, D. W. (2014). ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathologica, 127(6), 825-843. https://doi.org/10.1007/s00401-014-1282-2

ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. / Nelson, Peter T.; Estus, Steven; Abner, Erin L.; Parikh, Ishita; Malik, Manasi; Neltner, Janna H.; Ighodaro, Eseosa; Wang, Wang Xia; Wilfred, Bernard R.; Wang, Li San; Kukull, Walter A.; Nandakumar, Kannabiran; Farman, Mark L.; Poon, Wayne W.; Corrada, Maria M.; Kawas, Claudia H.; Cribbs, David H.; Bennett, David A.; Schneider, Julie A.; Larson, Eric B.; Crane, Paul K.; Valladares, Otto; Schmitt, Frederick A.; Kryscio, Richard J.; Jicha, Gregory A.; Smith, Charles D.; Scheff, Stephen W.; Sonnen, Joshua A.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Mayeux, Richard; Farrer, Lindsay A.; Van Eldik, Linda J.; Horbinski, Craig; Green, Robert C.; Gearing, Marla; Poon, Leonard W.; Kramer, Patricia L.; Woltjer, Randall (Randy); Montine, Thomas J.; Partch, Amanda B.; Rajic, Alexander J.; Richmire, Katierose; Monsell, Sarah E.; Schellenberg, Gerard D.; Fardo, David W.

In: Acta Neuropathologica, Vol. 127, No. 6, 2014, p. 825-843.

Research output: Contribution to journalArticle

Nelson, PT, Estus, S, Abner, EL, Parikh, I, Malik, M, Neltner, JH, Ighodaro, E, Wang, WX, Wilfred, BR, Wang, LS, Kukull, WA, Nandakumar, K, Farman, ML, Poon, WW, Corrada, MM, Kawas, CH, Cribbs, DH, Bennett, DA, Schneider, JA, Larson, EB, Crane, PK, Valladares, O, Schmitt, FA, Kryscio, RJ, Jicha, GA, Smith, CD, Scheff, SW, Sonnen, JA, Haines, JL, Pericak-Vance, MA, Mayeux, R, Farrer, LA, Van Eldik, LJ, Horbinski, C, Green, RC, Gearing, M, Poon, LW, Kramer, PL, Woltjer, RR, Montine, TJ, Partch, AB, Rajic, AJ, Richmire, K, Monsell, SE, Schellenberg, GD & Fardo, DW 2014, 'ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology', Acta Neuropathologica, vol. 127, no. 6, pp. 825-843. https://doi.org/10.1007/s00401-014-1282-2
Nelson, Peter T. ; Estus, Steven ; Abner, Erin L. ; Parikh, Ishita ; Malik, Manasi ; Neltner, Janna H. ; Ighodaro, Eseosa ; Wang, Wang Xia ; Wilfred, Bernard R. ; Wang, Li San ; Kukull, Walter A. ; Nandakumar, Kannabiran ; Farman, Mark L. ; Poon, Wayne W. ; Corrada, Maria M. ; Kawas, Claudia H. ; Cribbs, David H. ; Bennett, David A. ; Schneider, Julie A. ; Larson, Eric B. ; Crane, Paul K. ; Valladares, Otto ; Schmitt, Frederick A. ; Kryscio, Richard J. ; Jicha, Gregory A. ; Smith, Charles D. ; Scheff, Stephen W. ; Sonnen, Joshua A. ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. ; Mayeux, Richard ; Farrer, Lindsay A. ; Van Eldik, Linda J. ; Horbinski, Craig ; Green, Robert C. ; Gearing, Marla ; Poon, Leonard W. ; Kramer, Patricia L. ; Woltjer, Randall (Randy) ; Montine, Thomas J. ; Partch, Amanda B. ; Rajic, Alexander J. ; Richmire, Katierose ; Monsell, Sarah E. ; Schellenberg, Gerard D. ; Fardo, David W. / ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. In: Acta Neuropathologica. 2014 ; Vol. 127, No. 6. pp. 825-843.
@article{ed234983706048ef91a877b9838b1448,
title = "ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology",
abstract = "Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.",
keywords = "ADGC, CTAGE5, KATP, Neuropathology, Oldest old, Potassium channel",
author = "Nelson, {Peter T.} and Steven Estus and Abner, {Erin L.} and Ishita Parikh and Manasi Malik and Neltner, {Janna H.} and Eseosa Ighodaro and Wang, {Wang Xia} and Wilfred, {Bernard R.} and Wang, {Li San} and Kukull, {Walter A.} and Kannabiran Nandakumar and Farman, {Mark L.} and Poon, {Wayne W.} and Corrada, {Maria M.} and Kawas, {Claudia H.} and Cribbs, {David H.} and Bennett, {David A.} and Schneider, {Julie A.} and Larson, {Eric B.} and Crane, {Paul K.} and Otto Valladares and Schmitt, {Frederick A.} and Kryscio, {Richard J.} and Jicha, {Gregory A.} and Smith, {Charles D.} and Scheff, {Stephen W.} and Sonnen, {Joshua A.} and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Richard Mayeux and Farrer, {Lindsay A.} and {Van Eldik}, {Linda J.} and Craig Horbinski and Green, {Robert C.} and Marla Gearing and Poon, {Leonard W.} and Kramer, {Patricia L.} and Woltjer, {Randall (Randy)} and Montine, {Thomas J.} and Partch, {Amanda B.} and Rajic, {Alexander J.} and Katierose Richmire and Monsell, {Sarah E.} and Schellenberg, {Gerard D.} and Fardo, {David W.}",
year = "2014",
doi = "10.1007/s00401-014-1282-2",
language = "English (US)",
volume = "127",
pages = "825--843",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

AU - Nelson, Peter T.

AU - Estus, Steven

AU - Abner, Erin L.

AU - Parikh, Ishita

AU - Malik, Manasi

AU - Neltner, Janna H.

AU - Ighodaro, Eseosa

AU - Wang, Wang Xia

AU - Wilfred, Bernard R.

AU - Wang, Li San

AU - Kukull, Walter A.

AU - Nandakumar, Kannabiran

AU - Farman, Mark L.

AU - Poon, Wayne W.

AU - Corrada, Maria M.

AU - Kawas, Claudia H.

AU - Cribbs, David H.

AU - Bennett, David A.

AU - Schneider, Julie A.

AU - Larson, Eric B.

AU - Crane, Paul K.

AU - Valladares, Otto

AU - Schmitt, Frederick A.

AU - Kryscio, Richard J.

AU - Jicha, Gregory A.

AU - Smith, Charles D.

AU - Scheff, Stephen W.

AU - Sonnen, Joshua A.

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A.

AU - Mayeux, Richard

AU - Farrer, Lindsay A.

AU - Van Eldik, Linda J.

AU - Horbinski, Craig

AU - Green, Robert C.

AU - Gearing, Marla

AU - Poon, Leonard W.

AU - Kramer, Patricia L.

AU - Woltjer, Randall (Randy)

AU - Montine, Thomas J.

AU - Partch, Amanda B.

AU - Rajic, Alexander J.

AU - Richmire, Katierose

AU - Monsell, Sarah E.

AU - Schellenberg, Gerard D.

AU - Fardo, David W.

PY - 2014

Y1 - 2014

N2 - Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

AB - Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

KW - ADGC

KW - CTAGE5

KW - KATP

KW - Neuropathology

KW - Oldest old

KW - Potassium channel

UR - http://www.scopus.com/inward/record.url?scp=84901614207&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901614207&partnerID=8YFLogxK

U2 - 10.1007/s00401-014-1282-2

DO - 10.1007/s00401-014-1282-2

M3 - Article

C2 - 24770881

AN - SCOPUS:84901614207

VL - 127

SP - 825

EP - 843

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -