Skip to main content
eScholarship
Open Access Publications from the University of California

ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

  • Author(s): Nelson, PT
  • Estus, S
  • Abner, EL
  • Parikh, I
  • Malik, M
  • Neltner, JH
  • Ighodaro, E
  • Wang, WX
  • Wilfred, BR
  • Wang, LS
  • Kukull, WA
  • Nandakumar, K
  • Farman, ML
  • Poon, WW
  • Corrada, MM
  • Kawas, CH
  • Cribbs, DH
  • Bennett, DA
  • Schneider, JA
  • Larson, EB
  • Crane, PK
  • Valladares, O
  • 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, K
  • Monsell, SE
  • Schellenberg, GD
  • Fardo, DW
  • et al.
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. © 2014 Springer-Verlag.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View