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ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

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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.

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Acknowledgments

We are deeply grateful to all of the study participants and all the clinical workers, who make this research possible. We thank Ms. Sonya Anderson and Ms. Ela Patel for technical support. Thanks also to Drs. Julia Kofler and M. Ilyas Kamboh for collaborative assistance in this project. 1D3 antibody was a generous gift from Dr. Manuela Neumann. 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). 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). 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.

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Authors and Affiliations

  1. University of Kentucky, Lexington, KY, USA

    Steven Estus, Erin L. Abner, Ishita Parikh, Manasi Malik, Janna H. Neltner, Eseosa Ighodaro, Wang-Xia Wang, Bernard R. Wilfred, Mark L. Farman, Frederick A. Schmitt, Richard J. Kryscio, Gregory A. Jicha, Charles D. Smith, Stephen W. Scheff, Linda J. Van Eldik & Craig Horbinski

  2. University of Pennsylvania, Philadelphia, PA, USA

    Li-San Wang, Otto Valladares, Amanda B. Partch & Gerard D. Schellenberg

  3. University of Washington, Seattle, WA, USA

    Walter A. Kukull, Paul K. Crane, Thomas J. Montine & Sarah E. Monsell

  4. Mayo Clinic, Rochester, MN, USA

    Kannabiran Nandakumar

  5. University of California, Irvine, Irvine, CA, USA

    Wayne W. Poon, Maria M. Corrada, Claudia H. Kawas, David H. Cribbs & Alexander J. Rajic

  6. Rush University, Chicago, IL, USA

    David A. Bennett & Julie A. Schneider

  7. Group Health Research Institute, Seattle, WA, USA

    Eric B. Larson & KatieRose Richmire

  8. University of Utah, Salt Lake City, UT, USA

    Joshua A. Sonnen

  9. Case Western Reserve University, Cleveland, OH, USA

    Jonathan L. Haines

  10. University of Miami, Miami, FL, USA

    Margaret A. Pericak-Vance

  11. Columbia University, New York, NY, USA

    Richard Mayeux

  12. Boston University, Boston, MA, USA

    Lindsay A. Farrer

  13. Harvard University, Boston, MA, USA

    Robert C. Green

  14. Emory University, Atlanta, GA, USA

    Marla Gearing

  15. Oregon Health and Sciences University, Portland, OR, USA

    Patricia L. Kramer & Randall L. Woltjer

  16. Department of Biostatistics, University of Kentucky, 205E Multidisciplinary Science Building, 725 Rose Street, Lexington, KY, 40536-0082, USA

    David W. Fardo

  17. 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

    Peter T. Nelson

  18. Institute of Gerontology, University of Georgia, Athens, GA, USA

    Leonard W. Poon

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Alzheimer’ Disease Genetic Consortium

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Correspondence to Peter T. Nelson or David W. Fardo.

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Nelson, P.T., Estus, S., Abner, E.L. et al. ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol 127, 825–843 (2014). https://doi.org/10.1007/s00401-014-1282-2

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