Sequence Analysis of Six Blood Pressure Candidate Regions in 4,178 Individuals: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pre...

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Published in:PloS one Vol. 9; no. 10; p. e109155
Main Authors: Morrison, Alanna C., Bis, Joshua C., Hwang, Shih-Jen, Ehret, Georg B., Lumley, Thomas, Rice, Kenneth, Muzny, Donna, Gibbs, Richard A., Boerwinkle, Eric, Psaty, Bruce M., Chakravarti, Aravinda, Levy, Daniel
Format: Journal Article
Language:English
Published: United States Public Library of Science 02.10.2014
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ISSN:1932-6203, 1932-6203
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Abstract Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
AbstractList BackgroundGenome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).Methods and resultsTargeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.ConclusionSix targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes - ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3 - were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants ([greater than or equal to]50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF[less than or equal to]1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r.sup.2 = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r.sup.2 = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Background Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3 – were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Methods and Results Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r2 = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r2 = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. Conclusion Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).BACKGROUNDGenome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.METHODS AND RESULTSTargeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.CONCLUSIONSix targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Background Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes - ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3 - were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Methods and Results Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants ([greater than or equal to]50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF[less than or equal to]1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r.sup.2 = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r.sup.2 = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. Conclusion Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Background Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1 , CACNB2 , CYP17A1 , JAG1 , PLEKHA7 , and SH2B3 – were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Methods and Results Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r 2  = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r 2  = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7 ) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. Conclusion Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
Audience Academic
Author Boerwinkle, Eric
Rice, Kenneth
Gibbs, Richard A.
Morrison, Alanna C.
Hwang, Shih-Jen
Levy, Daniel
Bis, Joshua C.
Psaty, Bruce M.
Ehret, Georg B.
Chakravarti, Aravinda
Muzny, Donna
Lumley, Thomas
AuthorAffiliation 4 Department of Health Services, University of Washington, Seattle, Washington, United States of America
9 Center for Complex Disease Genomics, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
6 The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America
11 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America
2 Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America
5 The Framingham Heart Study, Framingham, Massachusetts, United States of America
1 University of Texas Health Science Center at Houston, Houston, Texas, United States of America
7 Department of Specialties of Medicine, Geneva University Hospitals, Geneva, Switzerland
3 Department of Epidemiology, University of Washington, Seattle, Washington,
AuthorAffiliation_xml – name: 11 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America
– name: 1 University of Texas Health Science Center at Houston, Houston, Texas, United States of America
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– name: 3 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America
– name: Sapienza University of Rome, Italy
– name: 5 The Framingham Heart Study, Framingham, Massachusetts, United States of America
– name: 7 Department of Specialties of Medicine, Geneva University Hospitals, Geneva, Switzerland
– name: 10 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America
– name: 8 Department of Statistics, University of Auckland, Auckland, New Zealand
– name: 9 Center for Complex Disease Genomics, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
– name: 4 Department of Health Services, University of Washington, Seattle, Washington, United States of America
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/25275628$$D View this record in MEDLINE/PubMed
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– notice: 2014. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Competing Interests: The authors have read the journal's policy and an author of this manuscript has the following competing interests: Dr. Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor), and on the Steering Committee for the Yale Open-Data Access Project funded by Medtronic. Dr. Psaty, co-author, has indicated a potential competing interest for the purpose of transparency, but this disclosure does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
Conceived and designed the experiments: RAG EB BMP AC DL. Performed the experiments: DM RAG. Analyzed the data: ACM JCB SJH. Contributed reagents/materials/analysis tools: TL KR. Wrote the paper: ACM JCB SJH GBE. Determined the regions for targeted sequencing: GBE.
ACM, JB, and SJH are joint first authors on this work.
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Snippet Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7,...
Background Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes - ATP2B1, CACNB2, CYP17A1, JAG1,...
Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes - ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7,...
Background Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1, CACNB2, CYP17A1, JAG1,...
BackgroundGenome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1,...
Background Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1 , CACNB2 , CYP17A1 ,...
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SubjectTerms Aging
Aging - genetics
Alleles
Atherosclerosis
Biology and Life Sciences
Blood
Blood pressure
Blood Pressure - genetics
Cardiovascular disease
Cohort Studies
Consortia
Cytochrome
Epidemiology
Gene frequency
Gene sequencing
Genes
Genetic research
Genome-wide association studies
Genomes
Genomics
Heart
Heart - physiology
Humans
Hydroxylases
Hypertension
Loci
Medical research
Medicine
Medicine and Health Sciences
Polymorphism
Pressure effects
Sequence Analysis
Single-nucleotide polymorphism
Studies
Variation
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Title Sequence Analysis of Six Blood Pressure Candidate Regions in 4,178 Individuals: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study
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