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Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.

ABSTRACT: CSF levels of A?1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (A?1-42, t-tau, p-tau181p, p-tau181p/A?1-42, and t-tau/A?1-42).A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p<0.01 (uncorrected p<3.10×10(-8)) and secondarily examined SNPs with uncorrected p values less than 10(-5) to identify potential candidates.Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.

SUBMITTER: Kim S

PROVIDER: S-EPMC3030225 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.

Kim S S Swaminathan S S Shen L L Risacher S L SL Nho K K Foroud T T Shaw L M LM Trojanowski J Q JQ Potkin S G SG Huentelman M J MJ Craig D W DW DeChairo B M BM Aisen P S PS Petersen R C RC Weiner M W MW Saykin A J AJ

Neurology 20101201 1

<h4>Objectives</h4>CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).<h4>Methods</h4>A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging ...[more]

PMID: 21123754

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Project description:BackgroundThe cerebrospinal fluid (CSF) levels of total tau (t-tau) and Aβ1-42 are potential early diagnostic markers for probable Alzheimer's disease (AD). The influence of genetic variation on these CSF biomarkers has been investigated in candidate or genome-wide association studies (GWAS). However, the investigation of statistically modest associations in GWAS in the context of biological networks is still an under-explored topic in AD studies. The main objective of this study is to gain further biological insights via the integration of statistical gene associations in AD with physical protein interaction networks.ResultsThe CSF and genotyping data of 843 study subjects (199 CN, 85 SMC, 239 EMCI, 207 LMCI, 113 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed. PLINK was used to perform GWAS on the t-tau/Aβ1-42 ratio using quality controlled genotype data, including 563,980 single nucleotide polymorphisms (SNPs), with age, sex and diagnosis as covariates. Gene-level p-values were obtained by VEGAS2. Genes with p-value ≤ 0.05 were mapped on to a protein-protein interaction (PPI) network (9,617 nodes, 39,240 edges, from the HPRD Database). We integrated a consensus model strategy into the iPINBPA network analysis framework, and named it as CM-iPINBPA. Four consensus modules (CMs) were discovered by CM-iPINBPA, and were functionally annotated using the pathway analysis tool Enrichr. The intersection of four CMs forms a common subnetwork of 29 genes, including those related to tau phosphorylation (GSK3B, SUMO1, AKAP5, CALM1 and DLG4), amyloid beta production (CASP8, PIK3R1, PPA1, PARP1, CSNK2A1, NGFR, and RHOA), and AD (BCL3, CFLAR, SMAD1, and HIF1A).ConclusionsThis study coupled a consensus module (CM) strategy with the iPINBPA network analysis framework, and applied it to the GWAS of CSF t-tau/Aβ1-42 ratio in an AD study. The genome-wide network analysis yielded 4 enriched CMs that share not only genes related to tau phosphorylation or amyloid beta production but also multiple genes enriching several KEGG pathways such as Alzheimer's disease, colorectal cancer, gliomas, renal cell carcinoma, Huntington's disease, and others. This study demonstrated that integration of gene-level associations with CMs could yield statistically significant findings to offer valuable biological insights (e.g., functional interaction among the protein products of these genes) and suggest high confidence candidates for subsequent analyses.

Project description:Alzheimer's disease (AD) is the main cause of dementia worldwide, and the genetic mechanism of which is not yet fully understood. Much evidence has accumulated over the past decade to suggest that after the first large-scale genome-wide association studies (GWAS) were conducted, the problem of "missing heritability" in AD is still a great challenge. Epistasis has been considered as one of the main causes of "missing heritability" in AD, which has been largely ignored in human genetics. The focus of current genome-wide epistasis studies is usually on single nucleotide polymorphisms (SNPs) that have significant individual effects, and the amount of heritability explained by which was very low. Moreover, AD is characterized by progressive cognitive decline and neuronal damage, and some studies have suggested that hyperphosphorylated tau (P-tau) mediates neuronal death by inducing necroptosis and inflammation in AD. Therefore, this study focused on identifying epistasis between two-marker interactions at marginal main effects across the whole genome using cerebrospinal fluid (CSF) P-tau as quantitative trait (QT). We sought to detect interactions between SNPs in a multi-GPU based linear regression method by using age, gender, and clinical diagnostic status (cds) as covariates. We then used the STRING online tool to perform the PPI network and identify two-marker epistasis at the level of gene-gene interaction. A total of 758 SNP pairs were found to be statistically significant. Particularly, between the marginal main effect SNP pairs, highly significant SNP-SNP interactions were identified, which explained a relatively high variance at the P-tau level. In addition, 331 AD-related genes were identified, 10 gene-gene interaction pairs were replicated in the PPI network. The identified gene-gene interactions and genes showed associations with AD in terms of neuroinflammation and neurodegeneration, neuronal cells activation and brain development, thereby leading to cognitive decline in AD, which is indirectly associated with the P-tau pathological feature of AD and in turn supports the results of this study. Thus, the results of our study might be beneficial for explaining part of the "missing heritability" of AD.

Project description:BackgroundA relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus. Relationship quantitative trait loci (rQTL) are often involved in gene-by-gene (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G.MethodsWe performed genome-wide association studies to identify rQTL between tau and Aβ42 and ptau and Aβ42 with over 3000 individuals using age, gender, series, APOE ε2, APOE ε4, and two principal components for population structure as covariates. Each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model. Parametric bootstrapping was used to assess significance.ResultsWe found four significant tau/Aβ42 rQTL from three unique locations and six ptau/Aβ42 rQTL from five unique locations. G×G screens with these rQTL produced four significant G×G interactions (one Aβ42, two ptau, and one tau) with four rQTL where each second locus was from a unique location. On follow-up, rs1036819 and rs74025622 were associated with Alzheimer's disease (AD) case/control status; rs15205 and rs79099429 were associated with rate of decline.ConclusionsThe two most significant rQTL (rs8027714 and rs1036819) for ptau/Aβ42 are on different chromosomes and both are strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/Aβ42 relationship but may suggest that these two loci share a pathway. In addition to a ptau/Aβ42 rQTL and association with AD case/control status, rs1036819 is a strong rQTL for case/control status/Aβ42 and for tau/Aβ42. It resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/Aβ42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a β-secretase enzyme that initiates production of the β-amyloid peptide involved in AD and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important AD endophenotypes and some are due to interactions with other loci. Some affect the risk of AD and/or rate of progression.

Dataset Information

Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.

Publications

Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.

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