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ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.

  • Author(s): 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 L;
  • Montine, Thomas J;
  • Partch, Amanda B;
  • Rajic, Alexander J;
  • Richmire, KatieRose;
  • Monsell, Sarah E;
  • Alzheimer’ Disease Genetic Consortium;
  • Schellenberg, Gerard D;
  • Fardo, David W
  • et al.

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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