<i>Cis-</i> Signals of SNP−Gene Associations in the Human Genome

<p>(A) The relationship between statistical significance and distance from gene. Each data point represents the maximum −log₁₀<i>p</i> for a single gene and SNPs located <i>cis-</i> to its coding locus. The −log₁₀<i>p</i>-values from the additive model are plotted as a function of distance between the center of the genomic span of the gene and <i>cis-</i> located SNPs (<i>cis-</i> < 4 Mb). Only those gene-SNP associations that have −log₁₀<i>p</i> > 4 are shown. SNPs are from the 5-kb HapMap. This plot includes data for 101 genes (129 probes). (B) <i>Cis-</i> SNPs with −log₁₀<i>p</i> ≥ 4 from the 688 probes analyzed are plotted against their chromosomal location on NCBI34 coordinates of the human genome.</p

Continued

<p>(B) Genomic location of associated SNPs close to the <i>TMEM8</i> and <i>MRPL28</i> genes. Note the correlation between the <i>p</i>-values for the two genes. Custom tracks in the UCSC genome browser show the location of the Illumina probe and proximal SNPs in the context of genome annotation. The lower horizontal black line indicates the −log₁₀<i>p</i> threshold where the corresponding <i>q-</i>value is 0.05 (i.e., any SNPs with values −log₁₀<i>p</i> that meet or exceed this threshold are significant at the <i>q</i> = 0.05 level), and the upper line is the Bonferroni genome-wide threshold. Additional tracks describe known genes, first-exon and promoter predictions, conserved transcription factor binding sites, Gencode genes, RNA polymerase 2, and Transcription factor 2 binding sites, identified by Affymetrix ChIP/chip experiments, and Sp1 and Sp3 binding sites identified by Stanford's ChIP/chip experiments. Consensus conserved elements are shown in the final track. HapMap LD information below is for the CEU individuals (<a href="http://genome.ucsc.edu" target="_blank">http://genome.ucsc.edu</a>) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0010078#pgen-0010078-b039" target="_blank">39</a>].</p

QQ Plot of <i>cis</i> versus <i>trans</i> HSA20 −log₁₀<i>p</i>-Values

<p>The figure shows the contrast of −log₁₀<i>p</i>-values deriving from associations of SNPs and genes within the 10-Mb region of HSA20 with −log₁₀<i>p</i>-values deriving from associations between genes on the 10-Mb region HSA20 with SNPs in one of ten ENCODE regions. Note that the distribution falls off the diagonal around −log₁₀<i>p</i> = 4, which we consider the borderline for the high enrichment of <i>cis</i> significant effects. A similar pattern is observed with any set of <i>trans</i> −log₁₀<i>p</i>-values on HSA20 or any other <i>cis</i> vs. <i>trans</i> contrast in any region we tested.</p

Examples of <i>cis-</i> Associations from the Genome-Wide and High-Density SNP Maps

<p>(A) Genomic location of associated SNPs close to the <i>SERPINB10</i> gene. Custom tracks in the UCSC genome browser (<a href="http://genome.ucsc.edu" target="_blank">http://genome.ucsc.edu</a>) show the location of the Illumina probe and proximal SNPs in the context of genome annotation. The lower horizontal black line indicates the −log₁₀<i>p</i> threshold where the corresponding <i>q-</i>value is 0.05 (i.e., any SNPs with values −log₁₀<i>p</i> that meet or exceed this threshold are significant at the <i>q</i> = 0.05 level), and the upper line is the Bonferroni genome-wide threshold. Additional tracks describe known genes, first-exon and promoter predictions, conserved transcription factor binding sites, Gencode genes, RNA polymerase 2, and Transcription factor 2 binding sites, identified by Affymetrix ChIP/chip experiments, and Sp1 and Sp3 binding sites identified by Stanford's ChIP/chip experiments. Consensus conserved elements are shown in the final track. HapMap LD information below is for the CEU individuals and suggests that there are two conserved haplotype clusters in this region.</p

Distribution of individuals in every genotype score group and cumulative effects of the risk alleles from the 36 SNPs for glucose levels.

<p>The bar plots show the average and standard error of glucose in mmol/L for each genotype score group distribution of the genetic risk score.</p

Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies ^a.

<p>Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186669#t001fn001" target="_blank">^a</a>.</p

Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies ^b.

<p>Associations of the unweighted Genetic Risk Score (GRS) and the weighted Genetic Risk Score (wGRS) with glucose levels for the meta-analysis of the GOMAP and THISEAS studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186669#t002fn001" target="_blank">^b</a>.</p

Additional file 2: of Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases

Supplementary Figures S1-S5, Supplementary Methods. (DOCX 8021 kb

DataSheet1_The 10th Santorini conference: Systems medicine, personalised health and therapy. “The odyssey from hope to practice: Patient first. Keep Ithaca always in your mind”, Santorini, Greece, 23–26 May 2022.DOCX

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