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

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, Changwei Li, Mary F Feitosa, Tuomas O Kilpeläinen, Melissa A Richard & 31 others 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, Alison D Murray, CHARGE Neurology Working Group

Research output: Contribution to journalArticle

10 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)375-400
Number of pages6
JournalAmerican Journal of Human Genetics
Volume102
Issue number3
Early online date15 Feb 2018
DOIs
Publication statusPublished - 31 Mar 2018

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

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

Cite this

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

In: American Journal of Human Genetics, Vol. 102, No. 3, 31.03.2018, p. 375-400.

Research output: Contribution to journalArticle

Sung, YJ, Winkler, TW, de Las Fuentes, L, Bentley, AR, Brown, MR, Kraja, AT, Schwander, K, Ntalla, I, Guo, X, Franceschini, N, Lu, Y, Cheng, C-Y, Sim, X, Vojinovic, D, Marten, J, Musani, SK, Li, C, Feitosa, MF, Kilpeläinen, TO, Richard, MA, Noordam, R, Aslibekyan, S, Aschard, H, Bartz, TM, Dorajoo, R, Liu, Y, Manning, AK, Rankinen, T, Smith, AV, Tajuddin, SM, Tayo, BO, Warren, HR, Zhao, W, Zhou, Y, Matoba, N, Sofer, T, Alver, M, Amini, M, Boissel, M, Chai, JF, Chen, X, Divers, J, Gandin, I, Gao, C, Giulianini, F, Goel, A, Harris, SE, Hartwig, FP, Horimoto, ARVR, Murray, AD & CHARGE Neurology Working Group 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
Sung, Yun J ; Winkler, Thomas W ; de Las Fuentes, Lisa ; Bentley, Amy R ; Brown, Michael R ; Kraja, Aldi T ; Schwander, Karen ; Ntalla, Ioanna ; Guo, Xiuqing ; Franceschini, Nora ; Lu, Yingchang ; Cheng, Ching-Yu ; Sim, Xueling ; Vojinovic, Dina ; Marten, Jonathan ; Musani, Solomon K ; Li, Changwei ; Feitosa, Mary F ; Kilpeläinen, Tuomas O ; Richard, Melissa A ; Noordam, Raymond ; Aslibekyan, Stella ; Aschard, Hugues ; Bartz, Traci M ; Dorajoo, Rajkumar ; Liu, Yongmei ; Manning, Alisa K ; Rankinen, Tuomo ; Smith, Albert Vernon ; Tajuddin, Salman M ; Tayo, Bamidele O ; Warren, Helen R ; Zhao, Wei ; Zhou, Yanhua ; Matoba, Nana ; Sofer, Tamar ; Alver, Maris ; Amini, Marzyeh ; Boissel, Mathilde ; Chai, Jin Fang ; Chen, Xu ; Divers, Jasmin ; Gandin, Ilaria ; Gao, Chuan ; Giulianini, Franco ; Goel, Anuj ; Harris, Sarah E ; Hartwig, Fernando Pires ; Horimoto, Andrea R V R ; Murray, Alison D ; CHARGE Neurology Working Group. / 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 - Sung, Yun J

AU - Winkler, Thomas W

AU - de Las Fuentes, Lisa

AU - Bentley, Amy R

AU - Brown, Michael R

AU - Kraja, Aldi T

AU - Schwander, Karen

AU - Ntalla, Ioanna

AU - Guo, Xiuqing

AU - Franceschini, Nora

AU - Lu, Yingchang

AU - Cheng, Ching-Yu

AU - Sim, Xueling

AU - Vojinovic, Dina

AU - Marten, Jonathan

AU - Musani, Solomon K

AU - Li, Changwei

AU - Feitosa, Mary F

AU - Kilpeläinen, Tuomas O

AU - Richard, Melissa A

AU - Noordam, Raymond

AU - Aslibekyan, Stella

AU - Aschard, Hugues

AU - Bartz, Traci M

AU - Dorajoo, Rajkumar

AU - Liu, Yongmei

AU - Manning, Alisa K

AU - Rankinen, Tuomo

AU - Smith, Albert Vernon

AU - Tajuddin, Salman M

AU - Tayo, Bamidele O

AU - Warren, Helen R

AU - Zhao, Wei

AU - Zhou, Yanhua

AU - Matoba, Nana

AU - Sofer, Tamar

AU - Alver, Maris

AU - Amini, Marzyeh

AU - Boissel, Mathilde

AU - Chai, Jin Fang

AU - Chen, Xu

AU - Divers, Jasmin

AU - Gandin, Ilaria

AU - Gao, Chuan

AU - Giulianini, Franco

AU - Goel, Anuj

AU - Harris, Sarah E

AU - Hartwig, Fernando Pires

AU - Horimoto, Andrea R V R

AU - Murray, Alison D

AU - CHARGE Neurology Working Group

N1 - Copyright © 2018 American Society of Human Genetics. All rights reserved.

PY - 2018/3/31

Y1 - 2018/3/31

N2 - 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).

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KW - Journal Article

KW - GWAS

KW - GxE interactions

KW - lifestyle

KW - blood pressure

KW - multi-ancestry

KW - smoking

U2 - 10.1016/j.ajhg.2018.01.015

DO - 10.1016/j.ajhg.2018.01.015

M3 - Article

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SP - 375

EP - 400

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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