A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

LifeLines Cohort Study, Yun Ju Sung (Lead / Corresponding author), Lisa de Las Fuentes (Lead / Corresponding author), Thomas W. Winkler (Lead / Corresponding author), Daniel I. Chasman (Lead / Corresponding author), Amy R. Bentley, Aldi T. Kraja (Lead / Corresponding author), Ioanna Ntalla (Lead / Corresponding author), Helen R. Warren (Lead / Corresponding author), Xiuqing Guo (Lead / Corresponding author), Karen Schwander, Alisa K. Manning, Michael R. Brown, Hugues Aschard, Mary F. Feitosa, Nora Franceschini, Yingchang Lu, Ching-Yu Cheng, Xueling Sim, Dina VojinovicJonathan Marten, Solomon K. Musani, Tuomas O. Kilpeläinen, Melissa A. Richard, Stella Aslibekyan, Traci M. Bartz, Rajkumar Dorajoo, Changwei Li, Yongmei Liu, Tuomo Rankinen, Albert Vernon Smith, Salman M. Tajuddin, Bamidele O. Tayo, 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 P. Hartwig, John M. Connell, Blair H. Smith, Jerome I. Rotter, Paul W. Franks, Kenneth Rice, Paul Elliott, Mark J. Caulfield, W. James Gauderman, Patricia B. Munroe, Dabeeru C. Rao, Alanna C. Morrison

Research output: Contribution to journalArticle

Abstract

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

Original languageEnglish
Pages (from-to)2615-2633
Number of pages19
JournalHuman Molecular Genetics
Volume28
Issue number15
Early online date10 Apr 2019
DOIs
Publication statusPublished - 1 Aug 2019

Fingerprint

Arterial Pressure
Smoking
Genome
Blood Pressure
Genes
Life Style
Cardiac Myocytes
Chloride-Bicarbonate Antiporters
Long Noncoding RNA
Kidney
Inbred SHR Rats
Vascular Smooth Muscle
Smooth Muscle Myocytes
Insulin Resistance
Myocardium
Heart Failure
Apoptosis
Morbidity
Mortality
Brain

Keywords

  • smoking
  • hypertension
  • genes
  • genome
  • life style
  • genetics
  • kidney
  • mean arterial pressure
  • blood pressure regulation
  • pulse pressure
  • genome-wide association study

Cite this

LifeLines Cohort Study, Sung, Y. J., de Las Fuentes, L., Winkler, T. W., Chasman, D. I., Bentley, A. R., ... Morrison, A. C. (2019). A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. Human Molecular Genetics, 28(15), 2615-2633. https://doi.org/10.1093/hmg/ddz070
LifeLines Cohort Study ; Sung, Yun Ju ; de Las Fuentes, Lisa ; Winkler, Thomas W. ; Chasman, Daniel I. ; Bentley, Amy R. ; Kraja, Aldi T. ; Ntalla, Ioanna ; Warren, Helen R. ; Guo, Xiuqing ; Schwander, Karen ; Manning, Alisa K. ; Brown, Michael R. ; Aschard, Hugues ; Feitosa, Mary F. ; Franceschini, Nora ; Lu, Yingchang ; Cheng, Ching-Yu ; Sim, Xueling ; Vojinovic, Dina ; Marten, Jonathan ; Musani, Solomon K. ; Kilpeläinen, Tuomas O. ; Richard, Melissa A. ; Aslibekyan, Stella ; Bartz, Traci M. ; Dorajoo, Rajkumar ; Li, Changwei ; Liu, Yongmei ; Rankinen, Tuomo ; Smith, Albert Vernon ; Tajuddin, Salman M. ; Tayo, Bamidele O. ; 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 P. ; Connell, John M. ; Smith, Blair H. ; Rotter, Jerome I. ; Franks, Paul W. ; Rice, Kenneth ; Elliott, Paul ; Caulfield, Mark J. ; Gauderman, W. James ; Munroe, Patricia B. ; Rao, Dabeeru C. ; Morrison, Alanna C. / A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. In: Human Molecular Genetics. 2019 ; Vol. 28, No. 15. pp. 2615-2633.
@article{caeedce1ef44471c969e57a8782cd259,
title = "A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure",
abstract = "Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.",
keywords = "smoking, hypertension, genes, genome, life style, genetics, kidney, mean arterial pressure, blood pressure regulation, pulse pressure, genome-wide association study",
author = "{LifeLines Cohort Study} and Sung, {Yun Ju} and {de Las Fuentes}, Lisa and Winkler, {Thomas W.} and Chasman, {Daniel I.} and Bentley, {Amy R.} and Kraja, {Aldi T.} and Ioanna Ntalla and Warren, {Helen R.} and Xiuqing Guo and Karen Schwander and Manning, {Alisa K.} and Brown, {Michael R.} and Hugues Aschard and Feitosa, {Mary F.} and Nora Franceschini and Yingchang Lu and Ching-Yu Cheng and Xueling Sim and Dina Vojinovic and Jonathan Marten and Musani, {Solomon K.} and Kilpel{\"a}inen, {Tuomas O.} and Richard, {Melissa A.} and Stella Aslibekyan and Bartz, {Traci M.} and Rajkumar Dorajoo and Changwei Li and Yongmei Liu and Tuomo Rankinen and Smith, {Albert Vernon} and Tajuddin, {Salman M.} and Tayo, {Bamidele O.} 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 P.} and Connell, {John M.} and Smith, {Blair H.} and Rotter, {Jerome I.} and Franks, {Paul W.} and Kenneth Rice and Paul Elliott and Caulfield, {Mark J.} and Gauderman, {W. James} and Munroe, {Patricia B.} and Rao, {Dabeeru C.} and Morrison, {Alanna C.}",
note = "U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.); National Institutes of Health (R01HL118305).",
year = "2019",
month = "8",
day = "1",
doi = "10.1093/hmg/ddz070",
language = "English",
volume = "28",
pages = "2615--2633",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "15",

}

LifeLines Cohort Study, Sung, YJ, de Las Fuentes, L, Winkler, TW, Chasman, DI, Bentley, AR, Kraja, AT, Ntalla, I, Warren, HR, Guo, X, Schwander, K, Manning, AK, Brown, MR, Aschard, H, Feitosa, MF, Franceschini, N, Lu, Y, Cheng, C-Y, Sim, X, Vojinovic, D, Marten, J, Musani, SK, Kilpeläinen, TO, Richard, MA, Aslibekyan, S, Bartz, TM, Dorajoo, R, Li, C, Liu, Y, Rankinen, T, Smith, AV, Tajuddin, SM, Tayo, BO, 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, Connell, JM, Smith, BH, Rotter, JI, Franks, PW, Rice, K, Elliott, P, Caulfield, MJ, Gauderman, WJ, Munroe, PB, Rao, DC & Morrison, AC 2019, 'A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure', Human Molecular Genetics, vol. 28, no. 15, pp. 2615-2633. https://doi.org/10.1093/hmg/ddz070

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. / LifeLines Cohort Study; Sung, Yun Ju (Lead / Corresponding author); de Las Fuentes, Lisa (Lead / Corresponding author); Winkler, Thomas W. (Lead / Corresponding author); Chasman, Daniel I. (Lead / Corresponding author); Bentley, Amy R.; Kraja, Aldi T. (Lead / Corresponding author); Ntalla, Ioanna (Lead / Corresponding author); Warren, Helen R. (Lead / Corresponding author); Guo, Xiuqing (Lead / Corresponding author); Schwander, Karen; Manning, Alisa K.; Brown, Michael R.; Aschard, Hugues; Feitosa, Mary F.; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K.; Kilpeläinen, Tuomas O.; Richard, Melissa A.; Aslibekyan, Stella; Bartz, Traci M.; Dorajoo, Rajkumar; Li, Changwei; Liu, Yongmei; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M.; Tayo, Bamidele O.; 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 P.; Connell, John M.; Smith, Blair H.; Rotter, Jerome I. (Lead / Corresponding author); Franks, Paul W. (Lead / Corresponding author); Rice, Kenneth (Lead / Corresponding author); Elliott, Paul (Lead / Corresponding author); Caulfield, Mark J. (Lead / Corresponding author); Gauderman, W. James; Munroe, Patricia B. (Lead / Corresponding author); Rao, Dabeeru C. (Lead / Corresponding author); Morrison, Alanna C. (Lead / Corresponding author).

In: Human Molecular Genetics, Vol. 28, No. 15, 01.08.2019, p. 2615-2633.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

AU - LifeLines Cohort Study

AU - Sung, Yun Ju

AU - de Las Fuentes, Lisa

AU - Winkler, Thomas W.

AU - Chasman, Daniel I.

AU - Bentley, Amy R.

AU - Kraja, Aldi T.

AU - Ntalla, Ioanna

AU - Warren, Helen R.

AU - Guo, Xiuqing

AU - Schwander, Karen

AU - Manning, Alisa K.

AU - Brown, Michael R.

AU - Aschard, Hugues

AU - Feitosa, Mary F.

AU - Franceschini, Nora

AU - Lu, Yingchang

AU - Cheng, Ching-Yu

AU - Sim, Xueling

AU - Vojinovic, Dina

AU - Marten, Jonathan

AU - Musani, Solomon K.

AU - Kilpeläinen, Tuomas O.

AU - Richard, Melissa A.

AU - Aslibekyan, Stella

AU - Bartz, Traci M.

AU - Dorajoo, Rajkumar

AU - Li, Changwei

AU - Liu, Yongmei

AU - Rankinen, Tuomo

AU - Smith, Albert Vernon

AU - Tajuddin, Salman M.

AU - Tayo, Bamidele O.

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 P.

AU - Connell, John M.

AU - Smith, Blair H.

AU - Rotter, Jerome I.

AU - Franks, Paul W.

AU - Rice, Kenneth

AU - Elliott, Paul

AU - Caulfield, Mark J.

AU - Gauderman, W. James

AU - Munroe, Patricia B.

AU - Rao, Dabeeru C.

AU - Morrison, Alanna C.

N1 - U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.); National Institutes of Health (R01HL118305).

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

AB - Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

KW - smoking

KW - hypertension

KW - genes

KW - genome

KW - life style

KW - genetics

KW - kidney

KW - mean arterial pressure

KW - blood pressure regulation

KW - pulse pressure

KW - genome-wide association study

U2 - 10.1093/hmg/ddz070

DO - 10.1093/hmg/ddz070

M3 - Article

C2 - 31127295

VL - 28

SP - 2615

EP - 2633

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 15

ER -