Linkage disequilibrium between SNPs in controls as measured by pairwise r² values.

<p>Values are given as percentages out of a maximum of 100. Solid black boxes indicate an r² value of 100.</p

Single SNP associations with PD.

<p>PD = Parkinson's disease. SNP = single nucleotide polymorphism. MA = minor allele. OR = odds ratio. CI = confidence interval. *Chromosomal positions based on the February 2009 (GRCH37/hg19) genome assembly [<i>SNCA</i> is located at Chr4;90,645,251–90,759,447]. ORs, 95% CIs, and p-values result from logistic regression models adjusted for age and gender. ORs correspond to presence vs. absence of the minor allele.</p

Analysis of Nuclear Export Sequence Regions of FUS-Related RNA-Binding Proteins in Essential Tremor

<div><p>Background and Objective</p><p>Genes encoding RNA-binding proteins, including FUS and TDP43, play a central role in different neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Recently, a mutation located in the nuclear export signal (NES) of the <i>FUS</i> gene has been reported to cause an autosomal dominant form of familial Essential tremor.</p><p>Material and Methods</p><p>We sequenced the exons coding the NES domains of five RNA-binding proteins (<i>TARDBP</i>, <i>hnRNPA2B1</i>, <i>hnRNPA1</i>, <i>TAF15</i> and <i>EWSR1</i>) that have been previously implicated in neurodegeneration in a series of 257 essential tremor (ET) cases and 376 healthy controls. We genotyped 404 additional ET subjects and 510 healthy controls to assess the frequency of the EWSR1 p.R471C substitution.</p><p>Results</p><p>We identified a rare EWSR1 p.R471C substitution, which is highly conserved, in a single subject with familial ET. The pathogenicity of this substitution remains equivocal, as DNA samples from relatives were not available and the genotyping of 404 additional ET subjects did not reveal any further carriers. No other variants were observed with significant allele frequency differences compared to controls in the NES coding regions.</p><p>Conclusions</p><p>The present study demonstrates that the NES domains of RNA-binding proteins are highly conserved. The role of the EWSR1 p.R471C substitution needs to be further evaluated in future studies.</p></div

Demographic data of Discovery and Replication Samples.

<p>Fam ET = familial essential tremor; Spo ET = sporadic essential tremor; Cont = Healthy controls; y = years; AAO = age at onset; SD = standard deviation; NA = data not applicable.</p><p>*Age was not available for 57 subjects (6 familial, 17 sporadic cases and 34 controls) from Replication Sample 1 and for 11 subjects (1 familial, 3 sporadic cases and 7 controls) from Replication Sample 2.</p>§<p>AAO was not available for 22 subjects (10 familial and 12 sporadic cases) from the Discovery Sample, for 27 subjects (14 familial and 13 sporadic cases) from the Replication Sample 1 and for 6 subjects (4 familial and 2 sporadic cases) from Replication Sample 2.</p><p>Demographic data of Discovery and Replication Samples.</p

Nuclear export signal (NES) prediction of candidate proteins based on the NetNES 1.1 prediction tool [16].

<p>NN = neural network algorithm; HMM = hidden Markov Model algorithm; NES score = combination of NN and HMM algorithms; QGSY-rich = glutamine, glycine, serine, tyrosine rich region; G-rich = glycine rich region; RRM = RNA recognition motif; RGG = Arg-Gly-Gly rich domain; Zn = zinc finger domain; The ? denotes that the NES predicted location does not surpass the NetNES established threshold. The thin black line denotes the prion-like domain location and the thick black line represents the highest score core region according to the Alberti algorithm <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111989#pone.0111989-Alberti1" target="_blank">[20]</a>.</p

Exonic Re-Sequencing of the Chromosome 2q24.3 Parkinson’s Disease Locus

<div><p>Genome-wide association studies (GWAS) in Parkinson’s disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: <i>B3GALT1</i>, <i>STK39</i>, and <i>CERS6</i>. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a <i>STK39</i> exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11–1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.</p></div

Bilateral small chronic infarcts and patchy and confluent areas of leukoaraiosis seen on fluid attenuated inversion recovery (FLAIR) MRI on patient with NOTCH3 p.R558C mutation.

<p>Bilateral small chronic infarcts and patchy and confluent areas of leukoaraiosis seen on fluid attenuated inversion recovery (FLAIR) MRI on patient with NOTCH3 p.R558C mutation.</p

Exonic variants detected by sequencing of 187 PD patients and validation in 376 controls.

<p>*Exon 1 of <i>B3GALT1</i> is non-coding, AA = amino acid, MAF = minor allele frequency, OR = Odds ratio, CI = confidence interval, P = P-value. Only non-synonymous and indel coding variants were genotyped in controls.</p><p>Exonic variants detected by sequencing of 187 PD patients and validation in 376 controls.</p

Single variant associations with PD.

<p>MAF = minor allele frequency, OR = Odds ratio, CI = confidence interval, P = p-value, P corr = p-value with Bonferroni correction. ORs, 95% CIs, and P-values result from logistic regression models adjusted for age, gender, and series (combined series only).</p><p>*Numbers of samples with complete clinical information included in model.</p><p>Single variant associations with PD.</p

Haplotypic associations with PD.

<p>Haplotypes are encoded as 1 for major allele and 2 for minor allele see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128586#pone.0128586.t002" target="_blank">Table 2</a> for specific alleles, MAF = minor allele frequency, OR = Odds ratio, CI = confidence interval, P = p-value, P corr = P-value with Bonferroni correction. ORs, 95% CIs, and P-values result from haplotype-based logistic regression analysis.</p><p>*Numbers of samples with complete clinical information included in model.</p><p>Haplotypic associations with PD.</p