title: Multiple loci influencing hippocampal degeneration identified by genome scan.
abstract: OBJECTIVE
  Large genome-wide association studies (GWASs) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a 2-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH).
  
  
  METHODS
  Brain magnetic resonance imaging measures of HV, TCV, and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer's Genetic Epidemiology) Study, and from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls in the Alzheimer's Disease Neuroimaging Initiative Study. A GWAS for each trait was conducted in the 2 Caucasian data sets in stage 1. Results from the 2 data sets were combined by meta-analysis. In stage 2, 1 single nucleotide polymorphism (SNP) from each region that was nominally significant in each data set (p < 0.05) and strongly associated in both data sets (p < 1.0 × 10(-5)) was evaluated in the African American data set.
  
  
  RESULTS
  Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p < 5.0 × 10(-8)) were attained for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set. Associations with different SNPs in the same gene (p < 1 × 10(-5) in Caucasians and p < 2.2 × 10(-4) in African Americans) were also observed for PICALM with HV, SYNPR with TCV, and TTC27 with WMH.
  
  
  CONCLUSIONS
  Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.
authors: Department of Medicine, Boston University School of Medicine, MA, USA.
authors: Scott A
authors: SA
authors: Melville
authors: Jacqueline
authors: J
authors: Buros
authors: Antonio R
authors: AR
authors: Parrado
authors: Badri
authors: B
authors: Vardarajan
authors: Mark W
authors: MW
authors: Logue
authors: Li
authors: L
authors: Shen
authors: Shannon L
authors: SL
authors: Risacher
authors: Sungeun
authors: S
authors: Kim
authors: Gyungah
authors: G
authors: Jun
authors: Charles
authors: C
authors: DeCarli
authors: Kathryn L
authors: KL
authors: Lunetta
authors: Clinton T
authors: CT
authors: Baldwin
authors: Andrew J
authors: AJ
authors: Saykin
authors: Lindsay A
authors: LA
authors: Farrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D059906:Neuroimaging; D020641:Polymorphism, Single Nucleotide