Results of association testing at published loci. OR published is based on replication phase odds ratio previously published for these SNPs [6], [7].

<p>Note gene is the best proximal candidate or closest gene to the locus and may not be the true pathologically important species. Notably the power to detect association at these loci, based on previously published effect sizes, p<5E-8, and an additive model is effectively 0 (based on methodology of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041859#pone.0041859-Skol1" target="_blank">[17]</a>). MAF, Minor Allele Frequency; OR, odds ratio; CI, confidence interval; IQ, Imputation quality from MACH (RSQR metric).</p

Logistic models for proportion and rate of rare ROHs.

a)<p>Logistic model 4 (adjusted for <i>f</i>, chronological age, and MDS covariates) with phenotype (EOPD case or control, 1 or 0) as dependent variable and proportion of samples with at least one rare ROH of a given minimum size as independent variable.</p>b)<p>Logistic model 4 (adjusted for <i>f</i>, chronological age, and MDS covariates) with phenotype (EOPD case or control, 1 or 0) as dependent variable and rate of rare ROHs per person of a given minimum size as independent variable. (Models 1–3 in supplementary material).</p

Samples and SNPs.

<p>Samples and SNPs.</p

Top 10 associated consensus regions.

<p>P = uncorrected p value.</p><p>P* = p value corrected for multiple testing using 100,000 case/control status permutations.</p

Number of rare ROHs at different size thresholds in EOPD and control groups.

<p>In this bar plot the average number of rare ROHs per person (rate) in either EOPD (red) or control (blue) groups is shown for different minimum size thresholds. The black line represents the ratio of average rate in cases vs. average rate in controls. Differences were statistically significant from a threshold of 2 Mb (0.91 vs. 0.82, ratio: 1.09, p = 0.01) and remained strongly significant throughout, peaking at 9 Mb (0.04 vs. 0.01, ratio: 3.17, p<1.00×10⁻⁸.</p

Proportion of cases and controls with rare ROH of a given minimum size.

<p>This bar plot displays the proportion of individuals presenting with at least one ROH of a given size threshold in EOPD (red) and control groups (blue). The ratio of the case/control proportions is represented by the black line. The difference between ROH-positive proportions in cases and controls became statistically significant at 4 Mb (0.12 vs. 0.08, ratio: 1.45, p = 4.30×10⁻⁶), and remained highly significant throughout higher size thresholds.</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>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

Top 10 associated gene groups.

<p>P = uncorrected p value.</p><p>P* = p value corrected for multiple testing using 100,000 case/control status permutations.</p

Manhattan plots for eQTL p-values +/− 250Kb of the previously AD associated regions near <i>CLU</i>.

<p>For this plot the x-axis represents the physical region of the chromosome and the y-axis is the –log₁₀ of the asymptotic p-values from the eQTL analyses. The horizontal black dashed line represent the statistically significant threshold based on a Bonferonni correction for the number of SNPs and mRNA transcripts tested, while the black dotted represent the suggestive threshold based on the average number of SNPs tested per transcript. The relative positions of previously disease associated SNPs are denoted by vertical black lines. The individual p-values points for the SNP/Transcript tests are indicated by color and number so that the most significant values are the dark red ‘5’s for SCARA3 and the blue ‘6’s for CCDC25. In the plots the transcripts depicted are not all mRNA transcripts within the region but are instead the transcripts within the region with a probe present on the expression array and was well detected within the sample series.</p

Changes (synonymous and non-synonymous) found in <i>CLU</i> and observed in only one subject (AD case or control) in both series.

<p>Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequences (CLU: NM_001831.2). The initiation codon is codon 1. Genomic numbering refers to reference sequence NC_000008.9. Protein numbering refers to sequence NP_001822.2. AAO: age at onset; Fam hist: Family history; N.A.: not applicable; -: information not available. Prediction of pathogenicity was performed in silico using the PolyPhen software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009510#pone.0009510-Sunyaev1" target="_blank">[27]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009510#pone.0009510-Ramensky1" target="_blank">[28]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009510#pone.0009510-Sunyaev2" target="_blank">[29]</a>.</p