ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.
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.
Department of Pathology, Division of Neuropathology, Rm 311, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone Avenue, Lexington, KY, 40536-0230, USA, pnels2@email.uky.edu.
Peter T
PT
Nelson
Steven
S
Estus
Erin L
EL
Abner
Ishita
I
Parikh
Manasi
M
Malik
Janna H
JH
Neltner
Eseosa
E
Ighodaro
Wang-Xia
WX
Wang
Bernard R
BR
Wilfred
Li-San
LS
Wang
Walter A
WA
Kukull
Kannabiran
K
Nandakumar
Mark L
ML
Farman
Wayne W
WW
Poon
Maria M
MM
Corrada
Claudia H
CH
Kawas
David H
DH
Cribbs
David A
DA
Bennett
Julie A
JA
Schneider
Eric B
EB
Larson
Paul K
PK
Crane
Otto
O
Valladares
Frederick A
FA
Schmitt
Richard J
RJ
Kryscio
Gregory A
GA
Jicha
Charles D
CD
Smith
Stephen W
SW
Scheff
Joshua A
JA
Sonnen
Jonathan L
JL
Haines
Margaret A
MA
Pericak-Vance
Richard
R
Mayeux
Lindsay A
LA
Farrer
Linda J
LJ
Van Eldik
Craig
C
Horbinski
Robert C
RC
Green
Marla
M
Gearing
Leonard W
LW
Poon
Patricia L
PL
Kramer
Randall L
RL
Woltjer
Thomas J
TJ
Montine
Amanda B
AB
Partch
Alexander J
AJ
Rajic
KatieRose
K
Richmire
Sarah E
SE
Monsell
Gerard D
GD
Schellenberg
David W
DW
Fardo
D000369:Aged, 80 and over; D000375:Aging / Q000187:drug effects / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D019992:Databases as Topic; D058068:Endophenotypes; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012598:Sclerosis / Q000235:genetics / Q000473:pathology; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use; D064233:Sulfonylurea Receptors / Q000235:genetics*
C577510:ABCC9 protein, human; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors