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.

Highlights

  • Parkinson disease (PD, OMIM #168600) is a neurodegenerative disorder, which affects primarily motor function, and secondarily cognitive capabilities of affected individuals

  • One common investigation approach for PD has been the comparison of gene expression levels in brain tissue from PD cases with those from neurologically healthy controls

  • Analyses of DNA sequence variants known as singlenucleotide polymorphisms (SNPs) in the forkhead box O1 (FOXO1) region, as well as of PD–relevant Single-nucleotide polymorphisms (SNPs) across the genome, suggest functional connections between this gene and 1) the age at onset in PD, and 2) the spermine oxidase (SMOX) gene

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Summary

Introduction

Parkinson disease (PD, OMIM #168600) is a neurodegenerative disorder, which affects primarily motor function (difficulty in movement initiation, tremor, slowness of movement), and secondarily cognitive capabilities of affected individuals. The lifetime risk for the disease is 1.5%, with a median age at onset of 60 and 1.5 increased risk in men compared to women. While a minority of PD cases has been attributed to rare monogenic forms, most cases are likely to be attributed to both genetic and environmental influences [1]. PD has an established pathology, with depletion of up to 60% of dopaminergic neurons in the substantia nigra pars compacta (SN) brain region prior to the onset of motor symptoms, and with protein inclusion aggregates known as Lewy bodies. A common strategy for studying neurodegenerative diseases has been the analysis of gene expression differences between diseased and neurologically healthy control brain samples using microarray

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