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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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.
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).
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.; Schellenberg, Gerard D.; and Fardo, David W., "ABCC9 Gene Polymorphism Is Associated with Hippocampal Sclerosis of Aging Pathology" (2014). Pathology and Laboratory Medicine Faculty Publications. 2.