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

TitleABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.
Publication TypeJournal Article
Year of Publication2014
AuthorsNelson PT, Estus S, Abner EL, Parikh I, Malik M, Neltner JH, Ighodaro E, Wang W-X, Wilfred BR, San Wang L-, Walter A Kukull, Nandakumar K, Farman ML, Poon WW, Corrada MM, Kawas CH, Cribbs DH, Bennett DA, Schneider JA, Larson EB, Crane PK, Otto Valladares, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, Scheff SW, Sonnen JA, Haines JL, Pericak-Vance MA, Mayeux R, Farrer LA, Van Eldik LJ, Horbinski C, Green RC, Gearing M, Poon LW, Kramer PL, Woltjer RL, Montine TJ, Partch AB, Rajic AJ, Richmire KR, Monsell SE, Gerard D Schellenberg, Fardo DW
Corporate AuthorsAlzheimer’ Disease Genetic Consortium
JournalActa Neuropathol
Volume127
Issue6
Pagination825-43
Date Published2014 Jun
ISSN1432-0533
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.

DOI10.1007/s00401-014-1282-2
Alternate JournalActa Neuropathol.
PubMed ID24770881
Grant ListK08 CA155764 / CA / NCI NIH HHS / United States
K25 AG043546 / AG / NIA NIH HHS / United States
K25 AG043546 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
P50AG16573 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
R01 AG021055 / AG / NIA NIH HHS / United States
R01 AG042210 / AG / NIA NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
R01AG21055 / AG / NIA NIH HHS / United States
R01AG42210 / AG / NIA NIH HHS / United States
U01 AG 06781 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
UL1 TR000117 / TR / NCATS NIH HHS / United States
UL1TR000117 / TR / NCATS NIH HHS / United States