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

Potkin SG, Guffanti G, Lakatos A, Turner JA, Kruggel F, Fallon JH, Saykin AJ, Orro A, Lupoli S, Salvi E, Weiner M, Macciardi F, Alzheimer's Disease Neuroimaging Initiati - PLoS ONE (2009)

Bottom Line: 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.Currently no available sample with both imaging and genetic data is available for replication.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA. sgpotkin@uci.edu

ABSTRACT

Background: With the exception of APOE epsilon4 allele, 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 < or =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 < or =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.

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Related in: MedlinePlus

Manhattan plot of the quantitative trait genome wide association analysis.Manhattan plot of the p-values (-Log10(Observed p-value)) from the QT (right hippocampus) genome-wide association analysis. The spacing between the SNPs does not reflect the actual distances between SNPs in the genome. Each color identifies an autosomal chromosome (from chromosome 1 to chromosome 22). The horizontal lines display the cutoffs for 3 significance levels: green line for mild significance (10−3<p<10−5), blue line for high significance (10−5<p<10−6) and red line for genome-wide significance level (p<10−6). Different symbols reflect the function of the SNPs as detailed here: “▴” intronic, “▪” 3′UTR or downstream region, “+” 5′UTR or upstream region, “⊠” synonymous coding, “░” non-synonymous coding, “•” intergenic.
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pone-0006501-g001: Manhattan plot of the quantitative trait genome wide association analysis.Manhattan plot of the p-values (-Log10(Observed p-value)) from the QT (right hippocampus) genome-wide association analysis. The spacing between the SNPs does not reflect the actual distances between SNPs in the genome. Each color identifies an autosomal chromosome (from chromosome 1 to chromosome 22). The horizontal lines display the cutoffs for 3 significance levels: green line for mild significance (10−3<p<10−5), blue line for high significance (10−5<p<10−6) and red line for genome-wide significance level (p<10−6). Different symbols reflect the function of the SNPs as detailed here: “▴” intronic, “▪” 3′UTR or downstream region, “+” 5′UTR or upstream region, “⊠” synonymous coding, “░” non-synonymous coding, “•” intergenic.

Mentions: The QT analysis identified 25 SNPs significant at the level of≤10−6 associated with either the left or right hippocampal grey matter volume (see Figure 1). A Q-Q plot of the association results is presented in Figure 2. P-values from the observed distribution of the test of interest (i.e., the SNPxDiagnosis interaction) are plotted for all SNPs against the distribution: p-values show a deviation in excess in the upper tail distribution, suggesting the presence of significant genetic association. Such deviation becomes evident at a p<1×10−6 supporting the hypothesis of a threshold for a claim of genetic association at this significance value. The significant SNPs (see Table 3) represent 15 loci and 6 desert regions. The QT analysis for all SNPs is provided in the supplementary materials (see Supplementary files). Of the 25 significant SNPs, thirteen map directly in genes and pseudogenes or are linked based on the LD structure of the region. Four SNPs map in regions characterized by a high level of genomic complexity given the overlap of several different genes and isoforms or pseudogenes in these areas. Eight SNPs map to 6 different “desert” regions where no specific gene annotation could be found including the LD block structure of the region. Details of these 25 significant SNPs follow. Supporting figures ( Figures S1 – Figure S20 ) and tables ( Table S1 – Table S20) are available for each of the 25 significant SNPs.


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

Potkin SG, Guffanti G, Lakatos A, Turner JA, Kruggel F, Fallon JH, Saykin AJ, Orro A, Lupoli S, Salvi E, Weiner M, Macciardi F, Alzheimer's Disease Neuroimaging Initiati - PLoS ONE (2009)

Manhattan plot of the quantitative trait genome wide association analysis.Manhattan plot of the p-values (-Log10(Observed p-value)) from the QT (right hippocampus) genome-wide association analysis. The spacing between the SNPs does not reflect the actual distances between SNPs in the genome. Each color identifies an autosomal chromosome (from chromosome 1 to chromosome 22). The horizontal lines display the cutoffs for 3 significance levels: green line for mild significance (10−3<p<10−5), blue line for high significance (10−5<p<10−6) and red line for genome-wide significance level (p<10−6). Different symbols reflect the function of the SNPs as detailed here: “▴” intronic, “▪” 3′UTR or downstream region, “+” 5′UTR or upstream region, “⊠” synonymous coding, “░” non-synonymous coding, “•” intergenic.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719581&req=5

pone-0006501-g001: Manhattan plot of the quantitative trait genome wide association analysis.Manhattan plot of the p-values (-Log10(Observed p-value)) from the QT (right hippocampus) genome-wide association analysis. The spacing between the SNPs does not reflect the actual distances between SNPs in the genome. Each color identifies an autosomal chromosome (from chromosome 1 to chromosome 22). The horizontal lines display the cutoffs for 3 significance levels: green line for mild significance (10−3<p<10−5), blue line for high significance (10−5<p<10−6) and red line for genome-wide significance level (p<10−6). Different symbols reflect the function of the SNPs as detailed here: “▴” intronic, “▪” 3′UTR or downstream region, “+” 5′UTR or upstream region, “⊠” synonymous coding, “░” non-synonymous coding, “•” intergenic.
Mentions: The QT analysis identified 25 SNPs significant at the level of≤10−6 associated with either the left or right hippocampal grey matter volume (see Figure 1). A Q-Q plot of the association results is presented in Figure 2. P-values from the observed distribution of the test of interest (i.e., the SNPxDiagnosis interaction) are plotted for all SNPs against the distribution: p-values show a deviation in excess in the upper tail distribution, suggesting the presence of significant genetic association. Such deviation becomes evident at a p<1×10−6 supporting the hypothesis of a threshold for a claim of genetic association at this significance value. The significant SNPs (see Table 3) represent 15 loci and 6 desert regions. The QT analysis for all SNPs is provided in the supplementary materials (see Supplementary files). Of the 25 significant SNPs, thirteen map directly in genes and pseudogenes or are linked based on the LD structure of the region. Four SNPs map in regions characterized by a high level of genomic complexity given the overlap of several different genes and isoforms or pseudogenes in these areas. Eight SNPs map to 6 different “desert” regions where no specific gene annotation could be found including the LD block structure of the region. Details of these 25 significant SNPs follow. Supporting figures ( Figures S1 – Figure S20 ) and tables ( Table S1 – Table S20) are available for each of the 25 significant SNPs.

Bottom Line: 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.Currently no available sample with both imaging and genetic data is available for replication.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA. sgpotkin@uci.edu

ABSTRACT

Background: With the exception of APOE epsilon4 allele, 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 < or =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 < or =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.

Show MeSH
Related in: MedlinePlus