Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation

Alexandra Dumitriu, Jeanne C. Latourelle, Tiffany C. Hadzi, Nathan Pankratz, Dan Garza, John P. Miller, Jeffery M. Vance, Tatiana Foroud, Thomas G. Beach, Richard H. Myers

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere1002794
JournalPLoS Genetics
Volume8
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Parkinson disease
Prefrontal Cortex
Transcriptome
gene expression
Parkinson Disease
gene
Single Nucleotide Polymorphism
single nucleotide polymorphism
Genes
genes
polymorphism
Genome-Wide Association Study
genome
probe
Meta-Analysis
Cyclin G
meta-analysis
Forkhead Transcription Factors
Lewy Bodies
brain

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Dumitriu, A., Latourelle, J. C., Hadzi, T. C., Pankratz, N., Garza, D., Miller, J. P., ... Myers, R. H. (2012). Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation. PLoS Genetics, 8(6), [e1002794]. https://doi.org/10.1371/journal.pgen.1002794

Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation. / Dumitriu, Alexandra; Latourelle, Jeanne C.; Hadzi, Tiffany C.; Pankratz, Nathan; Garza, Dan; Miller, John P.; Vance, Jeffery M.; Foroud, Tatiana; Beach, Thomas G.; Myers, Richard H.

In: PLoS Genetics, Vol. 8, No. 6, e1002794, 06.2012.

Research output: Contribution to journalArticle

Dumitriu, A, Latourelle, JC, Hadzi, TC, Pankratz, N, Garza, D, Miller, JP, Vance, JM, Foroud, T, Beach, TG & Myers, RH 2012, 'Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation', PLoS Genetics, vol. 8, no. 6, e1002794. https://doi.org/10.1371/journal.pgen.1002794
Dumitriu, Alexandra ; Latourelle, Jeanne C. ; Hadzi, Tiffany C. ; Pankratz, Nathan ; Garza, Dan ; Miller, John P. ; Vance, Jeffery M. ; Foroud, Tatiana ; Beach, Thomas G. ; Myers, Richard H. / Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation. In: PLoS Genetics. 2012 ; Vol. 8, No. 6.
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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.",
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