Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's Disease

Steven G. Potkin, Guia Guffanti, Anita Lakatos, Jessica A. Turner, Frithjof Kruggel, James H. Fallon, Andrew Saykin, Alessandro Orro, Sara Lupoli, Erika Salvi, Michael Weiner, Fabio Macciardi

Research output: Contribution to journalArticle

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Abstract

Background: With the exception of APOE 4̇allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD) are unknown. Methods and Findings: We completed a genome-wide association study on 381 participants in the ADNI (Alzheimer's Disease Neuroimaging Initiative) study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs) were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/). Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40), at a genome-wide significance level of≤10-6 (10-11 for a haplotype). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value≤10-6, which can be considered potential "new" candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication. Conclusions: Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer's disease that merit further investigation.

Original languageEnglish
Article numbere6501
JournalPLoS One
Volume4
Issue number8
DOIs
StatePublished - Aug 7 2009

Fingerprint

Genome-Wide Association Study
Alzheimer disease
quantitative traits
atrophy
Atrophy
Alzheimer Disease
Genes
Association reactions
Neuroimaging
genes
single nucleotide polymorphism
Polymorphism
Single Nucleotide Polymorphism
Mitochondrial Membranes
Genome
Nucleotides
genome
Genotype
Phenotype
Molecular Sequence Annotation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Potkin, S. G., Guffanti, G., Lakatos, A., Turner, J. A., Kruggel, F., Fallon, J. H., ... Macciardi, F. (2009). Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's Disease. PLoS One, 4(8), [e6501]. https://doi.org/10.1371/journal.pone.0006501

Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's Disease. / Potkin, Steven G.; Guffanti, Guia; Lakatos, Anita; Turner, Jessica A.; Kruggel, Frithjof; Fallon, James H.; Saykin, Andrew; Orro, Alessandro; Lupoli, Sara; Salvi, Erika; Weiner, Michael; Macciardi, Fabio.

In: PLoS One, Vol. 4, No. 8, e6501, 07.08.2009.

Research output: Contribution to journalArticle

Potkin, SG, Guffanti, G, Lakatos, A, Turner, JA, Kruggel, F, Fallon, JH, Saykin, A, Orro, A, Lupoli, S, Salvi, E, Weiner, M & Macciardi, F 2009, 'Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's Disease', PLoS One, vol. 4, no. 8, e6501. https://doi.org/10.1371/journal.pone.0006501
Potkin, Steven G. ; Guffanti, Guia ; Lakatos, Anita ; Turner, Jessica A. ; Kruggel, Frithjof ; Fallon, James H. ; Saykin, Andrew ; Orro, Alessandro ; Lupoli, Sara ; Salvi, Erika ; Weiner, Michael ; Macciardi, Fabio. / Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's Disease. In: PLoS One. 2009 ; Vol. 4, No. 8.
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AU - Saykin, Andrew

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