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 Larson; Paul 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 L Woltjer; Thomas J Montine; Amanda B Partch; Alexander J Rajic; KatieRose Richmire; Sarah E Monsell; Gerard D Schellenberg; David W Fardo

doi:10.1007/s00401-014-1282-2

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ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Journal article

Open access

Peer reviewed

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, …

Acta neuropathologica, Vol.127(6), pp.825-843

2014-06

DOI: https://doi.org/10.1007/s00401-014-1282-2

PMCID: PMC4113197

PMID: 24770881

Abstract

KATP

ADGC

CTAGE5

Oldest old

Neuropathology

Potassium channel

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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 Amyotrophic Lateral Sclerosis
Web Of Science research areas: Clinical Neurology; Neurosciences; Pathology
ESI research areas: Neuroscience & Behavior

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Title: ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology
Creators: Peter T Nelson - Department of Pathology, Division of Neuropathology, Rm 311, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone Avenue, Lexington, KY 40536-0230, USA
Steven Estus - University of Kentucky, Lexington, KY, USA
Erin L Abner - University of Kentucky, Lexington, KY, USA
Ishita Parikh - University of Kentucky, Lexington, KY, USA
Manasi Malik - University of Kentucky, Lexington, KY, USA
Janna H Neltner - University of Kentucky, Lexington, KY, USA
Eseosa Ighodaro - University of Kentucky, Lexington, KY, USA
Wang-Xia Wang - University of Kentucky, Lexington, KY, USA
Bernard R Wilfred - University of Kentucky, Lexington, KY, USA
Li-San Wang - University of Pennsylvania, Philadelphia, PA, USA
Walter A Kukull - University of Washington, Seattle, WA, USA
Kannabiran Nandakumar - Mayo Clinic, Rochester, MN, USA
Mark L Farman - University of Kentucky, Lexington, KY, USA
Wayne W Poon - University of California, Irvine, Irvine, CA, USA
Maria M Corrada - University of California, Irvine, Irvine, CA, USA
Claudia H Kawas - University of California, Irvine, Irvine, CA, USA
David H Cribbs - University of California, Irvine, Irvine, CA, USA
David A Bennett - Rush University, Chicago, IL, USA
Julie A Schneider - Rush University, Chicago, IL, USA
Eric B Larson - Group Health Research Institute, Seattle, WA, USA
Paul K Crane - University of Washington, Seattle, WA, USA
Otto Valladares - University of Pennsylvania, Philadelphia, PA, USA
Frederick A Schmitt - University of Kentucky, Lexington, KY, USA
Richard J Kryscio - University of Kentucky, Lexington, KY, USA
Gregory A Jicha - University of Kentucky, Lexington, KY, USA
Charles D Smith - University of Kentucky, Lexington, KY, USA
Stephen W Scheff - University of Kentucky, Lexington, KY, USA
Joshua A Sonnen - University of Utah, Salt Lake City, UT, USA
Jonathan L Haines - Case Western Reserve University, Cleveland, OH, USA
Margaret A Pericak-Vance - University of Miami, Miami, FL, USA
Richard Mayeux - Columbia University, New York, NY, USA
Lindsay A Farrer - Boston University, Boston, MA, USA
Linda J Van Eldik - University of Kentucky, Lexington, KY, USA
Craig Horbinski - University of Kentucky, Lexington, KY, USA
Robert C Green - Harvard University, Boston, MA, USA
Marla Gearing - Emory University, Atlanta, GA, USA
Leonard W Poon - Institute of Gerontology, University of Georgia, Athens, GA, USA
Patricia L Kramer - Oregon Health and Sciences University, Portland, OR, USA
Randall L Woltjer - Oregon Health and Sciences University, Portland, OR, USA
Thomas J Montine - University of Washington, Seattle, WA, USA
Amanda B Partch - University of Pennsylvania, Philadelphia, PA, USA
Alexander J Rajic - University of California, Irvine, Irvine, CA, USA
KatieRose Richmire - Group Health Research Institute, Seattle, WA, USA
Sarah E Monsell - University of Washington, Seattle, WA, USA
Gerard D Schellenberg - University of Pennsylvania, Philadelphia, PA, USA
David W Fardo - Department of Biostatistics, University of Kentucky, 205E Multidisciplinary Science Building, 725 Rose Street, Lexington, KY 40536-0082, USA
Publication Details: Acta neuropathologica, Vol.127(6), pp.825-843
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 24770881
PMCID: PMC4113197
Record Identifier: 991031576638702976