Authors

Peter T. Nelson, University of KentuckyFollow
Steven Estus, University of KentuckyFollow
Erin L. Abner, University of KentuckyFollow
Ishita Parikh, University of KentuckyFollow
Manasi Malik, University of Kentucky
Janna H. Neltner, University of KentuckyFollow
Eseosa Ighodaro, University of KentuckyFollow
Wang-Xia Wang, University of Kentucky
Bernard R. Wilfred, University of KentuckyFollow
Li-San Wang, University of Pennsylvania
Walter A. Kukull, University of Washington
Kannabiran Nandakumar, Mayo Clinic
Mark L. Farman, University of KentuckyFollow
Wayne W. Poon, University of California, Irvine
Maria M. Corrada, University of California, Irvine
Claudia H. Kawas, University of California, Irvine
David H. Cribbs, University of California, Irvine
David A. Bennett, Rush University
Julie A. Schneider, Rush University
Eric B. Larson, Group Health Research Institute
Paul K. Crane, University of Washington
Otto Valladares, University of Pennsylvania
Frederick A. Schmitt, University of KentuckyFollow
Richard J. Kryscio, University of KentuckyFollow
Gregory A. Jicha, University of KentuckyFollow
Charles D. Smith, University of KentuckyFollow
Stephen W. Scheff, University of KentuckyFollow
Joshua A. Sonnen, University of Utah
Jonathan L. Haines, Case Western Reserve University
Margaret A. Pericak-Vance, University of Miami
Richard Mayeux, Columbia University
Lindsay A. Farrer, Boston University
Linda J. Van Eldik, University of KentuckyFollow
Craig Horbinski, University of KentuckyFollow
Robert C. Green, Harvard University
Marla Gearing, Emory University
Leonard W. Poon, University of Georgia
Patricia L. Kramer, Oregon Health and Sciences University
Randall L. Woltjer, Oregon Health and Sciences University
Thomas J. Montine, University of Washington
Amanda B. Partch, University of Pennsylvania
Alexander J. Rajic, University of California, Irvine
Katierose Richmire, Group Health Research Institute
Sarah E. Monsell, University of Washington
Gerard D. Schellenberg, University of Pennsylvania
David W. Fardo, University of KentuckyFollow

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.

Document Type

Article

Publication Date

6-2014

Notes/Citation Information

Published in Acta Neuropathologica, v. 127, issue 6, p. 825-843.

© Springer-Verlag Berlin Heidelberg 2014. The authors' final draft of the article is available for download 12 months after the official publication of the article. The final publication is available at link.springer.com.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1007/s00401-014-1282-2

Funding Information

Funding included National Institutes of Health (NIH) grants for ADGC (U01 AG032984), NACC (U01 AG016976), the National Cell Repository for AD (NCRAD; U24 AG21886), K25 AG043546, UL1TR000117, and the UK-ADC P30 AG028383 from the National Institute on Aging (NIA).

Rush Religious Order Study and Memory and Aging Project (D Bennett PI) is supported by NIH grants P30AG10161, R01AG15819, R01AG17917, R01AG42210, and the Translational Genomics Research Institute. University of California Irvine work was supported by NIH grants for the UCI ADC (P50AG16573) and 90+ Study (R01AG21055; C Kawas, PI). For additional acknowledgment and funding support, please see Supplemental material.

Related Content

ACT enrollment and clinical data are from NIA U01 AG 06781 (E Larson, PI). Genetic data for ACT are from Human Genome Research Institute U01 HG006375 (E Larson, PI).

Supplemental Figures 1-6.pptx (1431 kB)
Supplementary material 1

Supplemental Methods.docx (37 kB)
Supplementary material 2

Supplemental Tables 1-4.pdf (30 kB)
Supplementary material 3

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