Multiple loci influencing hippocampal degeneration identified by genome scan

Scott A. Melville, Jacqueline Buros, Antonio R. Parrado, Badri Vardarajan, Mark W. Logue, Li Shen, Shannon L. Risacher, Sungeun Kim, Gyungah Jun, Charles Decarli, Kathryn L. Lunetta, Clinton T. Baldwin, Andrew Saykin, Lindsay A. Farrer

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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. Interpretation: Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.

Original languageEnglish
Pages (from-to)65-75
Number of pages11
JournalAnnals of Neurology
Volume72
Issue number1
DOIs
StatePublished - Jul 2012

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Alzheimer Disease
Genome
Genome-Wide Association Study
African Americans
Single Nucleotide Polymorphism
Genes
Endophenotypes
Molecular Epidemiology
Neuroimaging
Meta-Analysis
Datasets
Siblings
Magnetic Resonance Imaging
White Matter
Brain
Research

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Melville, S. A., Buros, J., Parrado, A. R., Vardarajan, B., Logue, M. W., Shen, L., ... Farrer, L. A. (2012). Multiple loci influencing hippocampal degeneration identified by genome scan. Annals of Neurology, 72(1), 65-75. https://doi.org/10.1002/ana.23644

Multiple loci influencing hippocampal degeneration identified by genome scan. / Melville, Scott A.; Buros, Jacqueline; Parrado, Antonio R.; Vardarajan, Badri; Logue, Mark W.; Shen, Li; Risacher, Shannon L.; Kim, Sungeun; Jun, Gyungah; Decarli, Charles; Lunetta, Kathryn L.; Baldwin, Clinton T.; Saykin, Andrew; Farrer, Lindsay A.

In: Annals of Neurology, Vol. 72, No. 1, 07.2012, p. 65-75.

Research output: Contribution to journalArticle

Melville, SA, Buros, J, Parrado, AR, Vardarajan, B, Logue, MW, Shen, L, Risacher, SL, Kim, S, Jun, G, Decarli, C, Lunetta, KL, Baldwin, CT, Saykin, A & Farrer, LA 2012, 'Multiple loci influencing hippocampal degeneration identified by genome scan', Annals of Neurology, vol. 72, no. 1, pp. 65-75. https://doi.org/10.1002/ana.23644
Melville, Scott A. ; Buros, Jacqueline ; Parrado, Antonio R. ; Vardarajan, Badri ; Logue, Mark W. ; Shen, Li ; Risacher, Shannon L. ; Kim, Sungeun ; Jun, Gyungah ; Decarli, Charles ; Lunetta, Kathryn L. ; Baldwin, Clinton T. ; Saykin, Andrew ; Farrer, Lindsay A. / Multiple loci influencing hippocampal degeneration identified by genome scan. In: Annals of Neurology. 2012 ; Vol. 72, No. 1. pp. 65-75.
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