Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation
Year: 2012
Type: review
Study design: Observational Study
Abstract: Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathological hallmark of PD. We generated and analyzed expression data from the prefrontal cortex Brodmann Area 9 (BA9) of 27 PD and 26 control samples using the 44K One-Color Agilent 60-mer Whole Human Genome Microarray. All samples were male, without significant Alzheimer disease pathology and with extensive pathological annotation available. 507 of the 39,122 analyzed expression probes were different between PD and control samples at false discovery rate (FDR) of 5%. One of the genes with significantly increased expression in PD was the forkhead box O1 (FOXO1) transcription factor. Notably, genes carrying the FoxO1 binding site were significantly enriched in the FDR-significant group of genes (177 genes covered by 189 probes), suggesting a role for FoxO1 upstream of the observed expression changes. Single-nucleotide polymorphisms (SNPs) selected from a recent meta-analysis of PD genome-wide association studies (GWAS) were successfully genotyped in 50 out of the 53 microarray brains, allowing a targeted expression-SNP (eSNP) analysis for 52 SNPs associated with PD affection at genome-wide significance and the 189 probes from FoxO1 regulated genes. A significant association was observed between a SNP in the cyclin G associated kinase (GAK) gene and a probe in the spermine oxidase (SMOX) gene. Further examination of the FOXO1 region in a meta-analysis of six available GWAS showed two SNPs significantly associated with age at onset of PD. These results implicate FOXO1 as a PD-relevant gene and warrant further functional analyses of its transcriptional regulatory mechanisms.
Source: PLoS Genetics
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Michael J. Fox Foundation for Parkinson's Research, School of Medicine, Boston University, Arizona Department of Health Services, Johns Hopkins University, Multiple Sclerosis Society, Arizona Biomedical Research Commission, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Human Genome Research Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: G1052080286, G1315589061, Parkinson Disease Collaborative Study of Genetic Linkage, G1591652791, G1606131442, G1783170366, G2146332128, G2161113364, G2263991784, G250893170, G2898431357, A National Resource for Postmortem Brain Research, G3228411741, G3250808129, G3521153818, G3540482749, G3903239027, Parkinson Disease Collaborative Study of Genetic Linkage, G4750584109, G4791902628, Genetic Linkage Study in Parkinson's Disease, G5541772598, G58661875, G6030318873, G6125194395, PD GWAS Consortium, Characterization of the role of cyclin G-associated kinase in Parkinson disease, Arizona Alzheimer's Disease Core Center, G7093047072, G7161884846, G7747731141, G7887587830, G7924111682, G8004032478, G8267674335, Genetics of Parkonsonism, G8450332877, G8508790466, The Genetics of Parkinsonism, G866630070, G890115980, G9000159448, G961669115
OpenAlex ID: W2058006779