Dataset Information

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

ABSTRACT: Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

SUBMITTER: Tragante V

PROVIDER: S-EPMC3951943 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

Tragante Vinicius V Barnes Michael R MR Ganesh Santhi K SK Lanktree Matthew B MB Guo Wei W Franceschini Nora N Smith Erin N EN Johnson Toby T Holmes Michael V MV Padmanabhan Sandosh S Karczewski Konrad J KJ Karczewski Konrad J KJ Almoguera Berta B Barnard John J Baumert Jens J Chang Yen-Pei Christy YP Elbers Clara C CC Farrall Martin M Fischer Mary E ME Gaunt Tom R TR Gho Johannes M I H JM Gieger Christian C Goel Anuj A Gong Yan Y Isaacs Aaron A Kleber Marcus E ME Mateo Leach Irene I McDonough Caitrin W CW Meijs Matthijs F L MF Melander Olle O Nelson Christopher P CP Nolte Ilja M IM Pankratz Nathan N Price Tom S TS Shaffer Jonathan J Shah Sonia S Tomaszewski Maciej M van der Most Peter J PJ Van Iperen Erik P A EP Vonk Judith M JM Witkowska Kate K Wong Caroline O L CO Zhang Li L Beitelshees Amber L AL Berenson Gerald S GS Bhatt Deepak L DL Brown Morris M Burt Amber A Cooper-DeHoff Rhonda M RM Connell John M JM Cruickshanks Karen J KJ Curtis Sean P SP Davey-Smith George G Delles Christian C Gansevoort Ron T RT Guo Xiuqing X Haiqing Shen S Hastie Claire E CE Hofker Marten H MH Hovingh G Kees GK Kim Daniel S DS Kirkland Susan A SA Klein Barbara E BE Klein Ronald R Li Yun R YR Maiwald Steffi S Newton-Cheh Christopher C O'Brien Eoin T ET Onland-Moret N Charlotte NC Palmas Walter W Parsa Afshin A Penninx Brenda W BW Pettinger Mary M Vasan Ramachandran S RS Ranchalis Jane E JE M Ridker Paul P Rose Lynda M LM Sever Peter P Shimbo Daichi D Steele Laura L Stolk Ronald P RP Thorand Barbara B Trip Mieke D MD van Duijn Cornelia M CM Verschuren W Monique WM Wijmenga Cisca C Wyatt Sharon S Young J Hunter JH Zwinderman Aeilko H AH Bezzina Connie R CR Boerwinkle Eric E Casas Juan P JP Caulfield Mark J MJ Chakravarti Aravinda A Chasman Daniel I DI Davidson Karina W KW Doevendans Pieter A PA Dominiczak Anna F AF FitzGerald Garret A GA Gums John G JG Fornage Myriam M Hakonarson Hakon H Halder Indrani I Hillege Hans L HL Illig Thomas T Jarvik Gail P GP Johnson Julie A JA Kastelein John J P JJ Koenig Wolfgang W Kumari Meena M März Winfried W Murray Sarah S SS O'Connell Jeffery R JR Oldehinkel Albertine J AJ Pankow James S JS Rader Daniel J DJ Redline Susan S Reilly Muredach P MP Schadt Eric E EE Kottke-Marchant Kandice K Snieder Harold H Snyder Michael M Stanton Alice V AV Tobin Martin D MD Uitterlinden André G AG van der Harst Pim P van der Schouw Yvonne T YT Samani Nilesh J NJ Watkins Hugh H Johnson Andrew D AD Reiner Alex P AP Zhu Xiaofeng X de Bakker Paul I W PI Levy Daniel D Asselbergs Folkert W FW Munroe Patricia B PB Keating Brendan J BJ

American journal of human genetics 20140220 3

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci cont ...[more]

PMID: 24560520

Similar Datasets

Project description:Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Dataset Information

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

Publications

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets