Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation

Hoffmann, Thomas J.; Ehret, Georg; Nandakumar, Priyanka; Ranatunga, Dilrini K.; Schaefer, Catherine; Kwok, Pui‐Yan; Iribarren, Carlos; Chakravarti, Aravinda; Risch, Neil

doi:10.1038/ng.3715

Cited by 300 publications

(328 citation statements)

References 60 publications

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“…rs6749447, rs10474346, rs11564022), or from a gene-age interaction analysis (rs16833934). In addition, we confirmed a further 92 previously reported, but not replicated, loci (Supplementary Table 5)9; together with 274 previously reported loci confirmed, and 535 novel loci identified here, there are 901 BP-associated loci in total.…”

Section: Resultssupporting

confidence: 90%

“…All of the following criteria had to be satisfied for a signal to be reported as a novel signal of association with BP using our one-stage criteria: the sentinel SNP has P < 5 × 10 -9 in the discovery (UKB+ICBP) meta-analysis;the sentinel SNP shows support ( P < 0.01) in the UKB GWAS alone;the sentinel SNP shows support ( P < 0.01) in the ICBP GWAS alone;the sentinel SNP has concordant direction of effect between UKB and ICBP datasets;The sentinel SNP must not be located within any of the 274 previously reported loci described above (Supplementary Table 4) or the recently reported non-replicated loci from Hoffman et al9 (Supplementary Table 23). …”

Section: Methodsmentioning

confidence: 80%

“…The sentinel SNP must not be located within any of the 274 previously reported loci described above (Supplementary Table 4) or the recently reported non-replicated loci from Hoffman et al9 (Supplementary Table 23). …”

Section: Methodsmentioning

confidence: 99%

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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Εvangelou¹,

Warren²,

et al. 2018

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High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic, pulse pressure) to date in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

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Section: Resultssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 80%

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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Εvangelou¹,

Warren²,

et al. 2018

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“…By integrating GTEx data with summary statistics from diverse GWAS, we observed that half of complex trait- associated loci co-localize with a GTEx eQTL. GTEx data have already served as a valuable community resource for the identification of the tissue-specific regulatory effects underlying variants associated with human disease phenotypes 58–61 .…”

Section: Discussionmentioning

confidence: 99%

Genetic effects on gene expression across human tissues

groups

Fund

Nhgri³

et al. 2017

Nature

3,681

2,412

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Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

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“…[3][4][5][6][7] It is now evident that hypertension is a polygenic trait, wherein rare syndromes of hypertension Regulation of Aldosterone Synthesis by Csk…”

mentioning

confidence: 99%

Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone

Kim

Kang

Lim

et al. 2018

Circ J

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represent extreme cases, because most hypertensive cases are not explained by a mutation in a single gene. 3 Further, the finding of genes that cause monogenic syndromes highlights the significant functions of the kidney and adrenal gland in regulating blood pressure. 2,3 Specifically, 10% of all monogenic forms of hypertension are estimated to have primary aldosteronism, suggesting that the homeostatic maintenance of aldosterone levels and the effect of aldosterone on kidney function are pivotal in keeping blood pressure within the normal range. 3 Despite the increase in the discoveries of SNPs that are associated with blood pressure, few cases have revealed an association between a genetic variation and the causal pathway that leads to hypertension. The most notable studies have reported a variant (rs13333226) in the promoter region of the uromodulin gene (UMOD), 8 a SNP in the promoter (rs3918226) near the endothelial nitric oxide synthase (eNOS) gene, 9,10 a SNP (rs5068) in the 3' untranslated region of NPPA, the gene that encodes for atrial natriuretic peptide (ANP), 11,12 and a SNP (rs17249754) B lood pressure is a complex trait that is regulated by a network of physiological pathways that involve the modulation of heart rate, vascular tone, and blood volume. 1 Short-term regulation of blood pressure is attained via the effects of sympathetic/parasympathetic activation on vascular tone and cardiac contractility through the sensing of baroreceptors in large arteries, whereas longterm regulation occurs through the effects of the reninangiotensin-aldosterone system (RAAS) on the kidney in controlling blood volume. 2 Despite their classical definition, short-term regulatory mechanisms are not easily dissected from long-term mechanisms, because the autonomic nervous system and RAAS permeate common target tissues and often relay signals through shared signaling pathways.Genetic research, including genome-wide association studies (GWASs), has identified approximately 116 singlenucleotide polymorphisms (SNPs) and rare mutations that contribute to the genetic architecture of blood pressure and hypertension. 3-7 It is now evident that hypertension is a polygenic trait, wherein rare syndromes of hypertension Background: Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported that Csk insufficiency increases blood pressure through Src. The mechanisms of hypertension in Csk +/− mice are examined further in this study.

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Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation

Cited by 300 publications

References 60 publications

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Genetic effects on gene expression across human tissues

Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone

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