A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

The CHARGE Neurology Working Group, The COGENT-Kidney Consortium, The GIANT consortium, Lifelines Cohort Study, Yun J. Sung, Thomas W. Winkler, Lisa de las Fuentes, Amy R. Bentley, Michael R. Brown, Aldi T. Kraja, Karen Schwander, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Yingchang Lu, Ching Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K. Musani & 34 others Changwei Li, Mary F. Feitosa, Tuomas O. Kilpeläinen, Melissa A. Richard, Raymond Noordam, Stella Aslibekyan, Hugues Aschard, Traci M. Bartz, Rajkumar Dorajoo, Yongmei Liu, Alisa K. Manning, Tuomo Rankinen, Albert Vernon Smith, Salman M. Tajuddin, Bamidele O. Tayo, Helen R. Warren, Wei Zhao, Yanhua Zhou, Nana Matoba, Tamar Sofer, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Ilaria Gandin, Chuan Gao, Franco Giulianini, Anuj Goel, Sarah E. Harris, Fernando Pires Hartwig, Andrea R.V.R. Horimoto, Sudha Seshadri

Research output: Contribution to journalArticle

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Abstract

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10−8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10−8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

LanguageEnglish (US)
Pages375-400
Number of pages26
JournalAmerican Journal of Human Genetics
Volume102
Issue number3
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Fingerprint

Smoking
Genome
Blood Pressure
Genome-Wide Association Study
Blood Vessels
Meta-Analysis
Telomere
Hispanic Americans
Single Nucleotide Polymorphism
Coronary Disease
Stroke
Maintenance
Population
Genes

Keywords

  • blood pressure
  • GWAS
  • GxE interactions
  • lifestyle
  • multi-ancestry
  • smoking

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

The CHARGE Neurology Working Group, The COGENT-Kidney Consortium, The GIANT consortium, & Lifelines Cohort Study (2018). A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. American Journal of Human Genetics, 102(3), 375-400. https://doi.org/10.1016/j.ajhg.2018.01.015

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. / The CHARGE Neurology Working Group; The COGENT-Kidney Consortium; The GIANT consortium; Lifelines Cohort Study.

In: American Journal of Human Genetics, Vol. 102, No. 3, 01.03.2018, p. 375-400.

Research output: Contribution to journalArticle

The CHARGE Neurology Working Group, The COGENT-Kidney Consortium, The GIANT consortium & Lifelines Cohort Study 2018, 'A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure' American Journal of Human Genetics, vol. 102, no. 3, pp. 375-400. https://doi.org/10.1016/j.ajhg.2018.01.015
The CHARGE Neurology Working Group, The COGENT-Kidney Consortium, The GIANT consortium, Lifelines Cohort Study. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. American Journal of Human Genetics. 2018 Mar 1;102(3):375-400. https://doi.org/10.1016/j.ajhg.2018.01.015
The CHARGE Neurology Working Group ; The COGENT-Kidney Consortium ; The GIANT consortium ; Lifelines Cohort Study. / A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 3. pp. 375-400.
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AU - Chen, Xu

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