학술논문
ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology
Document Type
article
Author
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
Source
Acta Neuropathologica. 127(6)
Subject
Language
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.