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; 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; Kaare Christensen; Ruth J F Loos

doi: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

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 RichardRaymond 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, Kaare Christensen, Ruth J F Loos

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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).

Original language	English
Journal	American Journal of Human Genetics
Volume	102
Issue number	3
Pages (from-to)	375-400
Number of pages	26
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2018.01.015
Publication status	Published - 2018

Keywords

blood pressure
GWAS
GxE interactions
lifestyle
multi-ancestry
smoking

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Sung, Y. J., Winkler, T. W., de Las Fuentes, L., Bentley, A. R., Brown, M. R., Kraja, A. T., Schwander, K., Ntalla, I., Guo, X., Franceschini, N., Lu, Y., Cheng, C-Y., Sim, X., Vojinovic, D., Marten, J., Musani, S. K., Li, C., Feitosa, M. F., Kilpeläinen, T. O., ... Loos, R. J. F. (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

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, Christensen, K & Loos, RJF 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

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

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).",

keywords = "blood pressure, GWAS, GxE interactions, lifestyle, multi-ancestry, smoking",

author = "Sung, {Yun J} and Winkler, {Thomas W} and {de Las Fuentes}, Lisa and Bentley, {Amy R} and Brown, {Michael R} and Kraja, {Aldi T} and Karen Schwander and Ioanna Ntalla and Xiuqing Guo and Nora Franceschini and Yingchang Lu and Ching-Yu Cheng and Xueling Sim and Dina Vojinovic and Jonathan Marten and Musani, {Solomon K} and Changwei Li and Feitosa, {Mary F} and Kilpel{\"a}inen, {Tuomas O} and Richard, {Melissa A} and Raymond Noordam and Stella Aslibekyan and Hugues Aschard and Bartz, {Traci M} and Rajkumar Dorajoo and Yongmei Liu and Manning, {Alisa K} and Tuomo Rankinen and Smith, {Albert Vernon} and Tajuddin, {Salman M} and Tayo, {Bamidele O} and Warren, {Helen R} and Wei Zhao and Yanhua Zhou and Nana Matoba and Tamar Sofer and Maris Alver and Marzyeh Amini and Mathilde Boissel and Chai, {Jin Fang} and Xu Chen and Jasmin Divers and Ilaria Gandin and Chuan Gao and Franco Giulianini and Anuj Goel and Harris, {Sarah E} and Hartwig, {Fernando Pires} and Kaare Christensen and Loos, {Ruth J F}",

year = "2018",

doi = "10.1016/j.ajhg.2018.01.015",

language = "English",

volume = "102",

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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 - Christensen, Kaare

AU - Loos, Ruth J F

PY - 2018

Y1 - 2018

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).

AB - 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).

KW - blood pressure

KW - GWAS

KW - GxE interactions

KW - lifestyle

KW - multi-ancestry

KW - smoking

U2 - 10.1016/j.ajhg.2018.01.015

DO - 10.1016/j.ajhg.2018.01.015

M3 - Journal article

C2 - 29455858

SN - 0002-9297

VL - 102

SP - 375

EP - 400

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

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

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Keywords

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