title: Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology.
abstract: Hippocampal sclerosis of aging (HS-Aging) is a common high-morbidity neurodegenerative condition in elderly persons. To understand the risk factors for HS-Aging, we analyzed data from the Alzheimer's Disease Genetics Consortium and correlated the data with clinical and pathologic information from the National Alzheimer's Coordinating Center database. Overall, 268 research volunteers with HS-Aging and 2,957 controls were included; detailed neuropathologic data were available for all. The study focused on single-nucleotide polymorphisms previously associated with HS-Aging risk: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9). Analyses of a subsample that was not previously evaluated (51 HS-Aging cases and 561 controls) replicated the associations of previously identified HS-Aging risk alleles. To test for evidence of gene-gene interactions and genotype-phenotype relationships, pooled data were analyzed. The risk for HS-Aging diagnosis associated with these genetic polymorphisms was not secondary to an association with either Alzheimer disease or dementia with Lewy body neuropathologic changes. The presence of multiple risk genotypes was associated with a trend for additive risk for HS-Aging pathology. We conclude that multiple genes play important roles in HS-Aging, which is a distinctive neurodegenerative disease of aging.
authors.affiliation: From the Departments of Pathology (PTN) and Biostatistics (DWF), Sanders-Brown Center on Aging (PTN, W-XW, BRW, DWF), and Division of Biomedical Informatics, College of Public Health (SRE), University of Kentucky, Lexington, Kentucky; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (ABP, OV, L-SW); National Alzheimer's Coordinating Center (SEM) and Department of Epidemiology (WAK), University of Washington, Seattle, Washington; and Department of Biostatistics and Epidemiology, Perelman School of Medicine (ACN).
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.forename: Wang-Xia
authors.initials: WX
authors.lastname: Wang
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Partch
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Monsell
authors.forename: Otto
authors.initials: O
authors.lastname: Valladares
authors.forename: Sally R
authors.initials: SR
authors.lastname: Ellingson
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Wilfred
authors.forename: Adam C
authors.initials: AC
authors.lastname: Naj
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
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; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D023281:Genomics / Q000706:statistics & numerical data; D005838:Genotype; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000077153:Progranulins; D012307:Risk Factors; D012598:Sclerosis / Q000209:etiology / Q000473:pathology; D064233:Sulfonylurea Receptors / Q000235:genetics*
chemical_list: C577510:ABCC9 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D064233:Sulfonylurea Receptors; C556915:TMEM106B protein, human