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• W2493923192 abstract "The cerebrospinal fluid (CSF) level of total tau (t-tau) is one of potential diagnostic biomarkers for Alzheimer's disease (AD). The influence of genetic variation on this marker has been investigated in candidate or genome-wide association studies (GWAS) [1]. We perform a protein-interaction-network-based pathway analysis (PINBPA) on the t-tau GWAS findings, in order to gain further biological insights via integrating statistical gene associations with physical protein interactions. Baseline CSF t-tau and genome-wide array data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) GO/2 cohort were downloaded. 843 subjects with CSF and genotyping data were included. PLINK was used to perform GWAS on t-tau using quality controlled genotype data including 578,227 single nucleotide polymorphisms (SNPs), with age and sex as covariates. A gene-wise p-value was calculated using VEGAS [2]. Genes with p-value ≤ 0.01 were mapped on to a PPI network (9617 nodes, 39240 edges, from HPRD Database), and sub-networks significantly enriched by these genes were discovered by PINBPA [3]. These sub-networks were compared with the KEGG pathway on AD. Shown in Table 1 are the 10 most significant genes identified by the t-tau GWAS and VEGAS analysis. A subsequent PINBPA analysis on genes with p-value ≤ 0.01 identified 61 enriched sub-networks. Figure 1 shows an example sub-network on the left and the KEGG AD pathway on the right. Genes appearing in both the enriched sub-network and the KEGG AD pathway include GAPDH, FAS, ITPR1, ITPR3, MAPT, ATP2A2, PLCB2, PLCB3, PPP3CA, MAPK1, BID, SNCA, and CACNA1C. Left: Example sub-network identified by PINBPA. Right: KEGG Pathway on Alzheimer᾿s disease. Red nodes are genes occurring in both sub-network and AD pathway. A combined GWAS and VEGAS analysis on CSF t-tau identified a few previously reported genes (e.g., those in the APOE region) as well as several novel ones (e.g., TSC22D1, FOXN3, and NAV2). A PINBPA analysis revealed some enriched sub-networks that share multiple genes with KEGG AD pathway. These findings may offer valuable biological insights and suggest high confidence candidates for subsequent analyses. Work is in progress to systematically compare all the identified sub-networks with relevant KEGG pathways. References: [1] Kim et al., Neurology, 2011, 76(1):69-79. [2] Am J Hum Genet. 2010 Jul 9;87(1):139-45. [3] Wang et al., Bioinformatics, 2015, (31)2: 262–264." @default.
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• W2493923192 date "2015-07-01" @default.
• W2493923192 modified "2023-09-27" @default.
• W2493923192 title "P4-002: Genome-wide network-based pathway analysis of CSF biomarker t-tau in the ADNI cohort" @default.
• W2493923192 doi "https://doi.org/10.1016/j.jalz.2015.06.1706" @default.
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