title: Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation.
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.
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America. adumitri@bu.edu
authors: Alexandra
authors: A
authors: Dumitriu
authors: Jeanne C
authors: JC
authors: Latourelle
authors: Tiffany C
authors: TC
authors: Hadzi
authors: Nathan
authors: N
authors: Pankratz
authors: Dan
authors: D
authors: Garza
authors: John P
authors: JP
authors: Miller
authors: Jeffery M
authors: JM
authors: Vance
authors: Tatiana
authors: T
authors: Foroud
authors: Thomas G
authors: TG
authors: Beach
authors: Richard H
authors: RH
authors: Myers
mesh_terms: D017668:Age of Onset; D000369:Aged, 80 and over; D001665:Binding Sites; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000097667:Polyamine Oxidase
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D017346:Protein Serine-Threonine Kinases; D000097667:Polyamine Oxidase; C085126:FOXO1 protein, human; C486325:GAK protein, human