title: Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2.
abstract: Hippocampal sclerosis of aging (HS-Aging) is a common neurodegenerative condition associated with dementia. To learn more about genetic risk of HS-Aging pathology, we tested gene-based associations of the GRN, TMEM106B, ABCC9, and KCNMB2 genes, which were reported to be associated with HS-Aging pathology in previous studies. Genetic data were obtained from the Alzheimer's Disease Genetics Consortium, linked to autopsy-derived neuropathological outcomes from the National Alzheimer's Coordinating Center. Of the 3251 subjects included in the study, 271 (8.3%) were identified as an HS-Aging case. The significant gene-based association between the ABCC9 gene and HS-Aging appeared to be driven by a region in which a significant haplotype-based association was found. We tested this haplotype as an expression quantitative trait locus using 2 different public-access brain gene expression databases. The HS-Aging pathology protective ABCC9 haplotype was associated with decreased ABCC9 expression, indicating a possible toxic gain of function.
authors.affiliation: Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Katsumata
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.affiliation: Division of Biomedical Informatics, University of Kentucky, Lexington, KY, USA.
authors.forename: Sally R
authors.initials: SR
authors.lastname: Ellingson
authors.affiliation: Department of Biostatistics, University of Kentucky, Lexington, KY, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. Electronic address: david.fardo@uky.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000473:pathology*; D003704:Dementia / Q000235:genetics / Q000473:pathology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D006239:Haplotypes; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D000077153:Progranulins; D012306:Risk; D012598:Sclerosis; D064233:Sulfonylurea Receptors / Q000235:genetics*
chemical_list: C577510:ABCC9 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C588418:KCNMB2 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D064233:Sulfonylurea Receptors; C556915:TMEM106B protein, human
keywords: CARTS; GWAS; KATP; PGRN; rs704180