Demographic characteristics of participants.

<p>Demographic characteristics of participants.</p

Lead SNPs for each independent locus associated with residual cognition.

<p>Lead SNPs for each independent locus associated with residual cognition.</p

Quantile–quantile plots for the association of residual cognition and DNA methylation pattern in <i>UNC5C</i>, <i>ENC1</i>, and <i>TMEM106B</i> regions.

<p>Each panel presents the results of the DNA methylation analysis of one of the three tested regions: (A) <i>UNC5C</i>, (B) <i>ENC1</i>, and (C) <i>TMEM106B</i>. The omnibus analysis assesses the level of evidence of association for the entire region; here, we illustrate the results by plotting the association statistic for each CpG (dots) comparing the observed <i>p-</i>value to the value expected from a null distribution. The dark gray area in each plot denotes the 90% confidence interval, and the light gray area denotes the 95% confidence interval. The functional unit of methylation is not a single CpG but rather a methylated region, and we see that the <i>ENC1</i> and <i>UNC5C</i> regions demonstrate a level of association that is globally different from what one would expect by chance.</p

Regional genetic association plots for <i>UNC5C</i>, <i>ENC1</i>, and <i>TMEM106B</i> regions.

<p>In these regional plots, we present the association results for all SNPs (dots) within each region of interest. In each region, the lead SNP is colored in purple, and other SNPs are colored based on their extent of linkage disequilibrium with the lead SNP, following the color key included at the top right of each panel. The <i>x</i>-axis denotes the physical position of the SNP, and the <i>y</i>-axis reports −log(<i>p-</i>value) for each SNP. The blue line denotes the recombination rate in this region in EUR participants from the 1000 Genomes Project. The location of the gene is presented at the bottom of the figure. (A) <i>UNC5C</i> region where rs3836455 (hg19 chr4:96363012) is the lead SNP associated with residual cognition. (B) <i>ENC1</i> region where rs76662990 (hg19 chr5:73847916) is the lead SNP. (C) <i>TMEM106B</i> region where rs11509153 (hg19 chr7:12263800) is the lead SNP. Regional genetic association plots were plotted with LocusZoom [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002287#pmed.1002287.ref049" target="_blank">49</a>].</p

The slope of global cognitive decline by genotype.

<p>The average slope of global cognitive decline of individuals with a certain genotype is shown, after adjusting for pathology and demographics. In both panels, the <i>x</i>-axis reports years before the participant’s death, and the <i>y</i>-axis presents pathology-adjusted global cognition (<i>z-</i>score, derived from baseline mean and standard deviation). The slope is the pathology-adjusted residual slope of global cognitive decline, and the intercept represents mean residual cognition. (A) All Religious Orders Study and Rush Memory and Aging Project participants are partitioned by their genotype at rs3846455 in the <i>UNC5C</i> locus. Cognition is declining faster for participants with one or two copies of the minor allele (blue line) than for individuals who are homozygous for the major allele (red line). (B) The results for participants partitioned by rs76662990 genotype, near the <i>ENC1</i> locus. Here, the presence of the minor allele is protective against pathology-adjusted cognitive decline. Of note, we grouped participants who were homozygotes for the minor allele together with the heterozygotes in this plot, as homozygotes were rare for both SNPs.</p

Manhattan plot from the genome-wide association study for residual cognition.

<p>In this plot, we present the results for each SNP tested in the genome-wide association study that included 979 participants from the Religious Orders Study and the Rush Memory and Aging Project. Each point is one SNP. The <i>x</i>-axis denotes the physical position of the SNP, and the <i>y</i>-axis reports −log(<i>p-</i>value) for each SNP. The threshold for a suggestive association (<i>p <</i> 10⁻⁵) is denoted by the black dotted line and identifies those loci that were considered in step 2 of our analysis. The red dotted line denotes the threshold of genome-wide significance. The three loci considered in step 2 are highlighted: <i>UNC5C</i>, <i>ENC1</i>, and <i>TMEM106B</i>.</p