2q33.1 and 5q23.2 loci cohort-wise ADVANCED model effect estimates and meta-analysis results with systolic blood pressure (SBP).^$

<p>Genomic positions are based on the human genome build 36. Alleles are reported on the forward strand of the reference genome. The effects are reported for the alleles increasing risk for IA in the Yasuno et al. studies <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002563#pgen.1002563-Yasuno1" target="_blank">[12]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002563#pgen.1002563-Yasuno2" target="_blank">[13]</a>. Risk alleles are aligned according to the forward strand of the reference genome. Minor allele frequencies (MAF) are based on from the HapMap Phase II CEU population data.</p>$<p>Diastolic blood pressure (DBP) and mean arterial pressure (MAP) association results from 2q33.1 and 5q23.2 SNP are in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002563#pgen.1002563.s005" target="_blank">Table S2</a>.</p>*<p>Meta SBP: meta-analysis of discovery and replication cohort p-values and beta for systolic blood pressure (SBP) with the ADVANCED model. Association analyses were corrected for gender, age, BMI, smoking habits and alcohol consumption.</p><p>SE: standard error.</p

Meta-analysis results of 5q23.2 SNPs with systolic blood pressure from all four Finnish cohorts and ICBP-GWAS combined.

<p>Genomic positions are based on the human genome build 36. Risk alleles are aligned according to the forward strand of the reference genome. SE: standard error.</p

Summary of cohort characteristics.

<p>WG: whole-genome, QC: quality control, BP: blood pressure, SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial pressure, PP: pulse pressure, BMI: body-mass index, SD: 1 standard deviation.</p

Summary of leading SNPs from the 19 loci showing strong or suggestive association with IA in a multinational GWAS containing Finnish patients [12].

<p>Association results with intracranial aneurysm (IA) by Yasuno and colleagues are followed by our meta-analysis association results with systolic blood pressure (SBP), with the ROBUST and the ADVANCED models, respectively.</p><p>Table first shows association p-values with IA for the Finnish sub-group from the multinational GWAS (IA GWAS), followed by results from our meta-analysis of association with systolic blood pressure (SBP) with the ROBUST and ADVANCED models. In the ROBUST model of association we corrected for gender and age and in the ADVANCED model we further corrected for BMI, smoking habits and alcohol consumption.</p><p>Genomic positions are based on the human genome build 36. Alleles are reported on the forward strand of the reference genome. The effects are reported for the alleles increasing risk for IA in the Yasuno et al. studies <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002563#pgen.1002563-Yasuno1" target="_blank">[12]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002563#pgen.1002563-Yasuno2" target="_blank">[13]</a>. If SNP is intergenic, Gene represents the nearest gene. SNPs are directly genotyped unless otherwise marked (* HM2 imputed SNP, ** 1000G+HM3 imputed SNP). Yasuno et al (2011) at 8q24.23 followed-up with rs1554349 instead of the lead SNP, rs6577930.</p><p><b>In bold:</b> locus showing strongest association with SBP in meta-analysis.</p>#<p>‘IA GWAS’ triplet column shows the Finnish sub-group (n_{FINN-IA-CASES} = 912, n_{FINN-CONTROLS} = 8180) association results on IA of the GWAS by Yasuno and colleagues, except for the PPA results, which is not Finnish sub-group specific, but counted for the whole multinational cohort.</p>##<p>PPA: posterior probability of association with IA as calculated by Yasuno and colleagues for the multinational IA GWAS.</p>$<p>‘SBP meta-analysis with ROBUST model’ and ‘with ADVANCED model’ twin-columns show results of our candidate locus meta-analysis with SBP as the outcome variable. SBP meta-analysis beta values are given for IA risk alleles.</p><p>OR: odds ratio, CI: confidence interval, SE: standard error.</p

Cohort-wise effects of risk allele count on SBP.

<p>The higher median age in HBCS is reflected as higher systolic blood pressure (SBP) and less consistent association. Error bars show standard error.</p

Characteristics of Stage1 and Stage2 studies.

a<p>See <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008.s005" target="_blank">Table S1</a></b> for more information on genotyping, imputation and software used. ^b The characteristics of the studies in the AAGC are presented in Ferreira et al., 2011 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-Ferreira1" target="_blank">[8]</a>. ^c EPIC = European Prospective Investigation into Cancer and Nutrition.</p

Results in APCAT for SNPs at loci with strong previously published evidence of association with asthma.

a<p>Gene shown is nearest gene to associated SNP. SNPs from the same locus are grouped together. ^bReferences: 1 = Moffatt et al. (2010) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-Moffatt2" target="_blank">[17]</a>; 2 = Moffatt et al. (2007) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-Moffatt1" target="_blank">[7]</a>; 3 = Gudbjartsson et al. (2009) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-Gudbjartsson1" target="_blank">[16]</a>; 4 = Sleiman et al (2010) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-Sleiman1" target="_blank">[13]</a>; 5 = Himes et al (2009) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-Himes1" target="_blank">[12]</a>; 6 = Li et al. (2010) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044008#pone.0044008-LangoAllen1" target="_blank">[22]</a>.^cAlleles are indexed to the forward strand of NCBI build36. ^dAPCAT <i>P</i> values are one-tailed with respect to the direction of the original association.^e<i>P</i> values are from fixed-effect inverse-variance model of meta analysis. ^fResults shown are from Moffatt et al (2010), which is the larger and more recent study. ^g SNP rs9273349 is present in NFBC1966 data set only. ^hResults exclude the Framingham Heart Study, which contributed to the original report in Himes et al (2009) ^IShown here are the random effects <i>P</i> value in Gabriel data, the <i>P</i> value for fixed effects model had a genome wide significance <i>P</i> value of 1.4E-08 with no evidence of heterogeneity.</p

Replication results for top signals from APCAT (Stage1 <i>N</i> = 18,604) in additional studies (Stage 2 <i>N</i> = 15,576) and in GABRIEL.

a<p>Positions/alleles are relative to the forward strand of NCBI build36. ^b,cResults from GABRIEL are from a re-analysis using fixed-effects meta-analysis, excluding the B58C and ECRHS2 cohorts which are included in Stage2 or with occupational asthma (see Methods), and are for the APCAT SNP or the best available proxy. All p values are two-tailed.</p

Effects of disrupted <i>GRB10</i> through knock-down on islet function.

<p>(A) Disrupted <i>GRB10</i> in INS-1 rat β-cells markedly reduced glucose-stimulated insulin secretion. (B) <i>GRB10</i> knock-down showed reduced glucose-stimulated insulin secretion at 20 mM glucose and glucagon secretion at 1 mM glucose in human pancreatic islets (N_insulin = 7, N_glucagon = 6 donors of human pancreatic islets; 3–6 measurements in each experiment for each donor). (C) <i>GRB10</i> knock-down resulted in a reduction of insulin and glucagon mRNA expression (N = 3 donors of human pancreatic islets; 3 measurements in each experiment for each donor). * <i>p</i><0.05; ** <i>p</i><0.01, *** <i>p</i><0.001. Error bars denote SEM.</p

Meta-analysis of genome wide association studies for morning plasma cortisol.

<p>A) Manhattan plot of −lop₁₀<i>P</i> values by chromosome. The red horizontal line indicates genome-wide significance (<i>P</i><5×10⁻⁸) and the blue horizontal line indicates moderate significance (<i>P</i><5×10⁻⁵). The lead SNP rs12589136 (chr14:94,793,686; b37) in red is genome-wide significant. SNPs within ±50 kb of cortisol-related candidate genes (listed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004474#pgen.1004474.s006" target="_blank">Table S6</a>) are highlighted in colours. B) Quantile-quantile plot of −log₁₀<i>P</i>, comparing the distribution of observed −log₁₀<i>P</i>-values and that expected by chance.</p