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SUCLG2 identified as both a determinator of CSF A?1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

ABSTRACT: Cerebrospinal fluid amyloid-beta 1-42 (A?1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on A?1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between A?1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-?4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of A?1-42.

SUBMITTER: Ramirez A

PROVIDER: S-EPMC4240204 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

Ramirez Alfredo A van der Flier Wiesje M WM Herold Christine C Ramonet David D Heilmann Stefanie S Lewczuk Piotr P Popp Julius J Lacour André A Drichel Dmitriy D Louwersheimer Eva E Kummer Markus P MP Cruchaga Carlos C Hoffmann Per P Teunissen Charlotte C Holstege Henne H Kornhuber Johannes J Peters Oliver O Naj Adam C AC Chouraki Vincent V Bellenguez Céline C Gerrish Amy A Heun Reiner R Frölich Lutz L Hüll Michael M Buscemi Lara L Herms Stefan S Kölsch Heike H Scheltens Philip P Breteler Monique M MM Rüther Eckart E Wiltfang Jens J Goate Alison A Jessen Frank F Maier Wolfgang W Heneka Michael T MT Becker Tim T Nöthen Markus M MM

Human molecular genetics 20140715 24

Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9 ...[more]

PMID: 25027320

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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.

Dataset Information

SUCLG2 identified as both a determinator of CSF A?1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

Publications

SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

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