Top age at onset (AAO) meta-analysis results for the <i>FOXO1</i> region.

1<p>Position for genome build 36.3 (hg18).</p>2<p>Required p-value level for significance p-values = 8.68E-5; <b>bold</b> indicates significant p-value.</p>3<p>Direction of effects are listed in the following order: PROGENI/GenePD, NIA Phase I, NIA Phase II, LEAPS, HIHG, NGRC; a question mark (?) indicates that the marker failed imputation (Rsq<0.30).</p>4<p>Values for imputed (I) or genotyped (G) status.</p>5<p>The meta-analysis included the PROGENI/GenePD, NIA Phase I, NIA Phase II, HIHG, and NGRC studies.</p>6<p>The SNPExpress database <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002794#pgen.1002794-Heinzen1" target="_blank">[29]</a> was used to look up eSNP relationships between the expression of <i>FOXO1</i> transcripts or exons and the SNPs of interest. The best <i>FOXO1</i> eSNP result is displayed if a p-value<0.05 was observed. The presented eSNP results were obtained in brain tissue. N/A values are used when the SNPs were not available in the database.</p

Description of retained brain samples for the Agilent microarray study.

1<p>PMI: post-mortem interval.</p>2<p>RIN: RNA Integrity Number.</p>3<p>The pH was measured following a previously established protocol <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002794#pgen.1002794-Harrison1" target="_blank">[58]</a>.</p

Expression by genotype relationship between the <i>SMOX</i> probe, A_23_P102731, and the <i>GAK</i> SNP, rs11731387.

<p>The box whiskers extend to the most extreme data point, which is at most 1.5 times the interquartile range from the box. The result for the 2-degree of freedom test was p = 8.1E-6, and the eSNP relationship was stronger in PD (p = 7.47E-5, beta = −0.727) than in controls (p = 0.037, beta = −0.494). The minor allele frequency for rs11731387 in the used brain sample was 0.15, and the odds ratio for this SNP in the additive model affection study of the meta-GWAS was 1.35.</p

FoxO1 TFBS genes with evidence of partial mediation for the relationship between <i>FOXO1</i> and PD.

1<p>The direct effect represents the effect of <i>FOXO1</i> expression on PD directly, while the indirect effect represents the effect that is mediated through each FoxO1 TFBS gene.</p

The top ten over-represented pathways from (a) the GWAS PD study and (b) the gene expression PD study.

<p>The pathways are presented in the decreasing order of significance.</p

Top microarray probes.

<p>Probes with FDR-adjusted p-values smaller than 0.05 and with expression differences between PD and control prefrontal cortex BA9 samples greater than 1.5 fold changes. Twenty-one probes (42%) were in genes with FoxO1 transcription factor binding sites. The GENE-E software (<a href="http://www.broadinstitute.org/cancer/software/GENE-E/" target="_blank">http://www.broadinstitute.org/cancer/software/GENE-E/</a>) was used to generate the heatmap.</p

KEGG pathway for melanogenesis.

<p>Similar to a gene expression array, those significant genes in the GWAS study are green, those in the expression study are pink and those that are significant in both are yellow.</p

The Venn diagram shows 25 and 42 over-represented pathways in the GWAS (green) and the expression PD (pink) studies respectively.

<p>Twelve over-represented pathways common to both PD studies are also shown (yellow). The pathway's rank in the meta-analysis is provided in parenthesis.</p

Conversion of Gene Expression and GWAS Pathways.

<p>For gene expression analysis, differentially expressed genes between adjacent tissues affected in PD were identified in each individual and adjusted using average control expression profiles. Three subtractions were used to identify genes of interest in PD. The first subtraction between two adjacent tissues relates to a given PD patient (eg CASE N). The second subtraction is in controls, where a similar subtraction as above is performed, and then averaged over the four controls for the two given adjacent tissues. This is denoted as CONTROLAVG. To establish if gene X is of interest in PD between two adjacent tissues, the CONTROLAVG was subtracted from the first subtraction for each patient. An overview of the GWAS PD study is shown. Pathway analysis was performed on each of the GWAS and gene expression PD gene sets derived. Two types of convergence were performed. First, significantly over represented pathways common in both studies were identified (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016917#pone-0016917-g001" target="_blank">Figure 1</a>). Second, a meta-analysis was carried out to combine the results obtained from the gene expression and the GWAS PD pathway analyses (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016917#pone-0016917-t002" target="_blank">Table 2</a>). DMV = dorsal motor nucleus, LCER =  locus ceruleus, SNGRA =  substantia nigra, PTMN =  putamen, INSLA =  insula.</p

The top twenty over-represented pathways determined by the meta-analysis combining the GWAS and the gene expression PD studies.

<p>The over-represented pathways are presented in rank order.</p