Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Liu, Chunyu; Kraja, Aldi T.; Smith, Jennifer A.; Brody, Jennifer A.; Franceschini, Nora; Bis, Joshua C.; Rice, Kenneth; Morrison, Alanna C.; Lu, Yingchang; Weiß, Stefan; Guo, Xiuqing; Palmas, Walter; Martin, Lisa W.; Chen, Yii‐Der Ida; Surendran, Praveen; Drenos, Fotios; Cook, James P.; Auer, Paul L.; Chu, Audrey Y.; Giri, Ayush; Zhao, Wei; Jakobsdóttir, Jóhanna; Lin, Lian Yu; Stafford, Jeanette M.; Amin, Najaf; Mei, Hao; Yao, Jie; Voorman, Arend; Larson, Martin G.; Grove, Megan L.; Smith, Albert V.; Hwang, Shih‐Jen; Chen, Han; Huan, Tianxiao; Kosova, Gülüm; Stitziel, Nathan O.; Kathiresan, Sekar; Samani, Nilesh J.; Schunkert, Heribert; Deloukas, Panos; Li, Man; Fuchsberger, Christian; Pattaro, Cristian; Kronenberg, Florian; Kooperberg, Charles; Papanicolaou, George; Rossouw, Jacques E.; Faul, Jessica D.; Kardia, Sharon L.R.; Bouchard, Claude; Raffel, Leslie J.; Uitterlinden, André G.; Franco, Oscar H.; Vasan, Ramachandran S.; O’Donnell, Christopher J.; Taylor, Kent D.; Liu, Kiang; Böttinger, Erwin P.; Gottesman, Omri; Daw, E. Warwick; Giulianini, Franco; Ganesh, Santhi K.; Salfati, Elias; Harris, Tamara B.; Launer, Lenore J.; Dörr, Marcus; Felix, Stephan B.; Rettig, Rainer; Völzke, Henry; Kim, Eric; Lee, Wen‐Jane; Lee, I-Te; Sheu, Wayne H‐H; Tsosie, Krystal S.; Edwards, Digna R. Velez; Liu, Yongmei; Correa, Adolfo; Weir, David R.; Völker, Uwe; Ridker, Paul M.; Boerwinkle, Eric; Gudnason, Vilmundur; Reiner, Alexander P.; Duijn, Cornelia M. van; Borecki, Ingrid B.; Edwards, Todd L.; Chakravarti, Aravinda; Rotter, Jerome I.; Psaty, Bruce M.; Loos, Ruth J.F.; Fornage, Myriam; Ehret, Georg; Newton‐Cheh, Christopher; Levy, Daniel; Chasman, Daniel I.

doi:10.1038/ng.3660

Cited by 240 publications

(203 citation statements)

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“…Realizing that large and inclusive international collaborative efforts are essential in providing new biological leads in complex disease pathogenesis [15][16][17][18][19][20] , we report here a world-wide collaborative XFS study aimed at further understanding the genetic basis of the disorder. Firstly, due to the allele reversals seen at LOXL1 common polymorphisms led by rs3825942 G>A (p.153Gly>Asp) and to a lesser extent, rs1048661 T>G (p.141Leu>Arg) 12,[21][22][23][24][25][26][27][28] (Supplementary Figure 1), we aimed to refine the LOXL1 genetic landscape by performing deep sequencing of the entire gene in 5,570 XFS and XFG cases and 6,279 controls from 9 countries (Supplementary Table 1).…”

Section: Introductionmentioning

confidence: 99%

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

et al. 2017

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Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

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Section: Introductionmentioning

confidence: 99%

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

et al. 2017

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“…These analyses consisted of a meta-analysis of results from three independent publications, the CHARGE Exome BP consortium 8 , European-led Exome consortia (contributory consortia, CHD Exome+, ExomeBP, and GoT2D:T2DGenes) 9 and the BP analyses from the UK Biobank Cardiometabolic consortium 11 .…”

Section: Methodsmentioning

confidence: 99%

“…Two recent reports independently performed discovery analyses, in sample sizes of up to ~146k (CHARGE Exome BP consortium) and ~192k individuals (the European-led Exome consortia [contributory consortia, CHD Exome+, ExomeBP, and GoT2D:T2DGenes]) 8, 9 . All samples were genotyped on the Illumina Exome array that was designed to interrogate rare and low frequency non-synonymous and other putative functional variants, as well as non-coding variants for association with biomedical traits.…”

mentioning

confidence: 99%

“…All samples were genotyped on the Illumina Exome array that was designed to interrogate rare and low frequency non-synonymous and other putative functional variants, as well as non-coding variants for association with biomedical traits. They each identified ~80 promising single nucleotide variant (SNV) associations with systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) or hypertension and took them forward for replication in the reciprocal consortium 8, 9 resulting in the identification of 56 novel BP-associated loci across the two reports, including associations with coding and rare SNVs. A total of 100 SNVs remained of interest, but did not achieve genome-wide significance.…”

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confidence: 99%

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New Blood Pressure–Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Kraja¹,

Cook²,

Warren³

et al. 2017

Circ Cardiovasc Genet

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Background Genome-wide association studies have recently identified over 400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier work identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of Exome Chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results Here, we augment the sample with 140,886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic or diastolic blood pressure (SBP, DBP) or pulse pressure (PP). We performed two meta-analyses, one in individuals of European, South Asian, African and Hispanic descent (pan-ancestry, ~475,000), and the other in the subset of individuals of European descent (~423,000). Twenty-one SNVs were genome-wide significant (P < 5×10−8) for BP, of which four are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1) and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV (rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at three loci are associated with other traits. One SNV with a minor allele frequency < 0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions We report four novel loci associated with BP regulation, and one independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

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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…”

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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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Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Cited by 240 publications

References 81 publications

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

New Blood Pressure–Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone

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