Frailty analysis.

<p>We obtained effect estimates from two sources: (1) analysis of the causal influence of BMI on PD using real data and (2) simulations where BMI had no effect on PD, and any apparent effect was due to survival bias alone. This figure shows the comparison of the estimates from these two sources using three different approaches—MR IVW analysis, MR–Egger regression, and observational associations. For the true effect estimates, the horizontal lines denote the 95% confidence intervals; for the results from simulations, the horizontal lines denote 95% confidence intervals obtained from 1,000 simulations. BMI, body mass index; IVW, inverse-variance weighted; MR, Mendelian randomisation; PD, Parkinson disease.</p

Directed acyclic graph of instrumental variable analysis using genetic variants as proxies for environmental exposures (adapted from Lawlor et al. [14]).

<p>Genetic variants (<i>Z</i>) associated with an exposure such as BMI (<i>X</i>) can be used as proxies to determine the effect of the exposure (<i>X</i>) on the outcome (<i>Y</i>). The three IV assumptions are indicated by arrows or the absence of arrows: (1) the IV in this schematic (<i>FTO</i> gene variant) is robustly associated with the exposure; (2) the IV is not associated with confounding factors (<i>C</i>); and (3) there is no alternative way that the IV affects the outcome other than via the exposure. BMI, body mass index; IV, instrumental variable; PD, Parkinson disease.</p

Examples of previous observational studies of body mass index and Parkinson disease.

<p>Examples of previous observational studies of body mass index and Parkinson disease.</p

Forest plot of Wald ratios and 95% CIs generated from clumped SNPs associated with BMI.

<p>Odds ratios for individual SNPs are listed according to magnitude of effect in the instrumental variable analysis and are presented with pooled effects using the IVW method and MR–Egger regression. The most recent meta-analysis of observational studies is also plotted (Wang et al. [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002314#pmed.1002314.ref013" target="_blank">13</a>]). Squares represent the point estimate, and the bars are the 95% confidence intervals. There was weak evidence of heterogeneity (<i>Q</i> statistic = 95.5; <i>I</i>² = 20.4%; <i>p</i> = 0.065). IVW, inverse-variance weighted; MR, Mendelian randomisation.</p

Variants and effect alleles with frequencies and magnitude of effect on BMI and strength of association with PD.

<p>Variants and effect alleles with frequencies and magnitude of effect on BMI and strength of association with PD.</p

Evidence for association of A allele of rs660599 (chromosome 11; Base position 102,234,967) with large artery atherosclerotic stroke and all ischaemic stroke.

<p>LAA, large artery stroke; IS, all ischaemic stroke; SNP, single nucleotide polymorphism; RAF, risk allele frequency; OR, odds ratio; 95% CI, 95% confidence interval; EUR, meta-analysis in individuals of European ancestry alone; ALL, trans-ethnic meta-analysis of all individuals. Forest plots of effect sizes and standard errors for each replication centre are given in Figures S3, S4.</p

Sample size of replication populations.

<p>LAA, large artery stroke; IS, all ischaemic stroke; ARIC, the Atherosclerosis Risk in communities study; ASGC, the Australian Stroke Genetics collaboration; deCODE, deCODE genetics; GEOS, the Genetics of early onset stroke study; HVH, the heart and vascular health study; ISGS/SWISS, the Ischaemic stroke genetics study/Siblings with Ischaemic stroke study; MGH-GASROS, Massachusetts General Hospital – Genetics affecting stroke risk and outcome; PROMISe, Prognostic modeling in ischaemic stroke study <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004469#pgen.1004469-Achterberg1" target="_blank">[55]</a>; RACE, Risk Assessment of Cerebrovascular Events study. For further details of these populations please see the original METASTROKE publication <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004469#pgen.1004469-Traylor2" target="_blank">[16]</a>.</p

LocusZoom plot of <i>MMP12</i> association using age-at-onset informed approach.

<p>SNPs are colored based on their correlation (r²) with the labeled top SNP, which has the smallest P value in the region. The fine-scale recombination rates estimated from 1000 Genomes (EUR) data are marked in light blue, with genes marked below by horizontal blue lines. Arrows on the horizontal blue lines show the direction of transcription, and rectangles are exons. SNP p-values are from the discovery meta-analysis only with the exception of rs660599, for which the given p-value indicates the overall evidence for association from the discovery and replication cohorts.</p

Sample size of discovery populations.

<p>IS, all ischaemic stroke; CE, cardioembolic stroke; LAA, large artery stroke; SVD, small vessel disease.</p

Evaluation of evidence genome-wide for SNPs exhibiting greater significance using the age-at-onset informed approach compared to permutations.

<p>-log10(p value) from permutations for evidence of age-at-onset effect at given SNP p-value selection threshold shown in red; median proportion of SNPs (with IQR) more significant in observed age-at-onset informed meta-analysis compared to permutations shown in blue; horizontal line at p = 0.05 in red; horizontal line at median proportion of SNP = 0.5 in blue; IS, all ischaemic stroke; CE, cardioembolic stroke; LAA, large artery atherosclerotic stroke; SVD, small vessel disease. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004469#pgen.1004469.s009" target="_blank">Table S5</a> for number of SNPs included at each p-value selection threshold.</p