<i>Trans</i>-Acting SNP effects on gene expression.

<p><i>Trans</i>-Acting SNP effects on gene expression.</p

Evaluation of Parkinson Disease Risk Variants as Expression-QTLs

<div><p>The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci <em>SNCA</em>, <em>MAPT</em>, <em>GAK/DGKQ</em>, and <em>HLA</em> and identified a novel risk locus at <em>RIT2</em>. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for <em>cis</em>-acting effects on all probes within 250 kb of each locus. <em>Trans</em>-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of <em>cis</em>-acting SNP effects, several SNPs in the <em>MAPT</em> region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene <em>LOC644246</em> and the duplicated genes <em>LRRC37A</em> and <em>LRRC37A2</em>, and a third uncorrelated probe targeting the gene <em>DCAKD</em>. Significant <em>cis</em>-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine <em>trans</em> effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8×10⁻⁸) including SNPs from the <em>SNCA, MAPT</em> and <em>RIT2</em> regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations.</p> </div

<i>Cis</i>-Acting SNP effects on gene expression for probes within 250 kb of the PD associated risk loci.

<p><i>Cis</i>-Acting SNP effects on gene expression for probes within 250 kb of the PD associated risk loci.</p

Brain Sample Characteristics.

*<p> <i>significantly different between cases and controls (p = 0.02).</i></p

<i>MAPT</i> region probes and SNPs involved in significant <i>cis</i> eSNP relationships.

<p>Three probes in the <i>MAPT</i> region on chromosme 17 showing significant association with PD risk SNPs are displayed. Significant SNP associations with A_24_P110521 located in the duplicated genes <i>LRRC37A</i> and <i>LRRC37A2</i> are shown in blue, while SNPs associated with A_24_P221327 located in <i>LOC644246</i> are shown in green and SNPs associated with A_24_P58331 (in <i>DCAKD</i>) are shown in red.</p

HLA region probes and SNPs involved in significant <i>cis</i> eSNP relationships.

<p>Two probes in the HLA region on chromosme 6 showing significant association with PD risk SNPs are shown on the alternative sequence haplotype chr6_ssto_hap7. Six PD risk SNPs (shown in green) showed significant association to A_24_P326084 located in <i>HLA-DQA1</i>, while four SNPs (shown in red) had significant association to A_24P852756, located in <i>HLA-DQA2</i>.</p

Antibodies used in western blots.

Antibodies used in western blots.</p

Protein expression of proteolyic degradation enzymes, IDE, CatD and neprilysin in the liver of non-demented controls (NDC) and Alzheimer’s disease (AD) subjects.

Liver protein expression of the proteolytic degradation enzyme insulin degrading enzyme (IDE) was lower in AD subjects (A); while cathepsin (CatD) levels (B) were higher. Neprilysin was not statistically significantly between the two groups (C). GAPDH was used as a total protein loading control.</p

Representative western blot showing faster Aβ degradation in the liver of non-demented controls subjects when compared to the AD group.

Lyophilized fluorescein-labeled Aβ40 (A) or Aβ42 (B) peptides were added to liver homogenates to quantify its degradation. Sucrose lysis buffer containing complete protease inhibitor cocktail was added to stop the reaction and Western blot performed to visualized Aβ degradation (molecular weight ~7kDA).</p

Additional file 2 of Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels

Additional file 2: Figure S2. Immunostaining against Ckid. Image in (A and B) show pictures of Cornu Ammonus 1 (CA1) and entorhinal cortex (EC) of and AD patients captured with 20 × magnification. The number of Ckid positive clusters and vesicle within each cluster (indicated with arrows) are several times higher in CA1 (A) compared to EC (B). Scalebar = 20 µ