Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study
<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive...
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| Format: | Article |
| Language: | English |
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BMC
2010-10-01
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| Series: | BMC Neurology |
| Online Access: | http://www.biomedcentral.com/1471-2377/10/90 |
| _version_ | 1811251026009784320 |
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| author | Schellenberg Gerard D Han Mi-Ryung Wang Li-San |
| author_facet | Schellenberg Gerard D Han Mi-Ryung Wang Li-San |
| author_sort | Schellenberg Gerard D |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ<sub>1-42</sub>, T-tau, and P-tau<sub>181P</sub>, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels.</p> <p>Methods</p> <p>Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ<sub>1-42</sub>, T-tau, and P-tau<sub>181P </sub>Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software.</p> <p>Results</p> <p>We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ<sub>1-42 </sub>levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. <it>CYP19A1 </it>'aromatase' (rs2899472), <it>NCAM2</it>, and multiple SNPs located on chromosome 10 near the <it>ARL5B </it>gene demonstrated the strongest associations with Aβ<sub>1-42 </sub>in normal subjects. Two genes found to be near the top SNPs, <it>CYP19A1 </it>(rs2899472, p = 1.90 × 10<sup>-7</sup>) and <it>NCAM2 </it>(rs1022442, p = 2.75 × 10<sup>-7</sup>) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau<sub>181P </sub>levels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ<sub>1-42</sub>).</p> <p>Conclusions</p> <p>Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.</p> |
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| spelling | doaj.art-3d70bcd1b50849e7b99e73abaf805e442022-12-22T03:25:49ZengBMCBMC Neurology1471-23772010-10-011019010.1186/1471-2377-10-90Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control studySchellenberg Gerard DHan Mi-RyungWang Li-San<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ<sub>1-42</sub>, T-tau, and P-tau<sub>181P</sub>, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels.</p> <p>Methods</p> <p>Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ<sub>1-42</sub>, T-tau, and P-tau<sub>181P </sub>Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software.</p> <p>Results</p> <p>We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ<sub>1-42 </sub>levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. <it>CYP19A1 </it>'aromatase' (rs2899472), <it>NCAM2</it>, and multiple SNPs located on chromosome 10 near the <it>ARL5B </it>gene demonstrated the strongest associations with Aβ<sub>1-42 </sub>in normal subjects. Two genes found to be near the top SNPs, <it>CYP19A1 </it>(rs2899472, p = 1.90 × 10<sup>-7</sup>) and <it>NCAM2 </it>(rs1022442, p = 2.75 × 10<sup>-7</sup>) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau<sub>181P </sub>levels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ<sub>1-42</sub>).</p> <p>Conclusions</p> <p>Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.</p>http://www.biomedcentral.com/1471-2377/10/90 |
| spellingShingle | Schellenberg Gerard D Han Mi-Ryung Wang Li-San Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study BMC Neurology |
| title | Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study |
| title_full | Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study |
| title_fullStr | Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study |
| title_full_unstemmed | Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study |
| title_short | Genome-wide association reveals genetic effects on human Aβ<sub>42 </sub>and τ protein levels in cerebrospinal fluids: a case control study |
| title_sort | genome wide association reveals genetic effects on human aβ sub 42 sub and τ protein levels in cerebrospinal fluids a case control study |
| url | http://www.biomedcentral.com/1471-2377/10/90 |
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