Genome-wide association study identifies eight loci associated with blood pressure

Christopher Newton-Cheh and colleagues report a genome-wide association study for blood pressure traits as part of the Global BPgen consortium. They report eight loci with replicated association to systolic and/or diastolic blood pressure, with each also showing association to hypertension

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldTo understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD

Common variants at ten loci modulate the QT interval duration in the QTSCD Study.

The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 x 10(-8). Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD

A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P <= 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis

Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p &lt; 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p &lt; 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time

Genome-wide association study identifies eight loci associated with blood pressure.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease