Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

Tanika N. Kelly; Xiao Sun; Karen Y. He; Michael R. Brown; Sarah A.Gagliano Taliun; Jacklyn N. Hellwege; Marguerite R. Irvin; Xuenan Mi; Jennifer A. Brody; Nora Franceschini; Xiuqing Guo; Shih Jen Hwang; Paul S. De Vries; Yan Gao; Arden Moscati; Girish N. Nadkarni; Lisa R. Yanek; Tali Elfassy; Jennifer A. Smith; Ren Hua Chung; Amber L. Beitelshees; Amit Patki; Stella Aslibekyan; Brandon M. Blobner; Juan M. Peralta; Themistocles L. Assimes; Walter R. Palmas; Chunyu Liu; Adam P. Bress; Zhijie Huang; Lewis C. Becker; Chii Min Hwa; Jeffrey R. O'connell; Jenna C. Carlson; Helen R. Warren; Sayantan Das; Ayush Giri; Lisa W. Martin; W. Craig Johnson; Ervin R. Fox; Erwin P. Bottinger; Alexander C. Razavi; Dhananjay Vaidya; Lee Ming Chuang; Yen Pei C. Chang; Take Naseri; Deepti Jain; Hyun Min Kang; Adriana M. Hung; Vinodh Srinivasasainagendra; Beverly M. Snively; Dongfeng Gu; May E. Montasser; Muagututi'a Sefuiva Reupena; Benjamin D. Heavner; Jonathon Lefaive; James E. Hixson; Kenneth M. Rice; Fei Fei Wang; Jonas B. Nielsen; Jianfeng Huang; Alyna T. Khan; Wei Zhou; Jovia L. Nierenberg; Cathy C. Laurie; Nicole D. Armstrong; Mengyao Shi; Yang Pan; Adrienne M. Stilp; Leslie Emery; Quenna Wong; Nicola L. Hawley; Ryan L. Minster; Joanne E. Curran; Patricia B. Munroe; Daniel E. Weeks; Kari E. North; Russell P. Tracy; Eimear E. Kenny; Daichi Shimbo; Aravinda Chakravarti; Stephen S. Rich; Alex P. Reiner; John Blangero; Susan Redline; Braxton D. Mitchell; Dabeeru C. Rao; Yii Der Ida Chen; Sharon L.R. Kardia; Robert C. Kaplan; Rasika A. Mathias; Jiang He; Bruce M. Psaty; Myriam Fornage; Ruth J.F. Loos; Adolfo Correa; Eric Boerwinkle; Jerome I. Rotter; Charles Kooperberg; Todd L. Edwards; Gonçalo R. Abecasis; Xiaofeng Zhu; Daniel Levy; Donna K. Arnett; Alanna C. Morrison

doi:10.1161/HYPERTENSIONAHA.122.19324

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

Tanika N. Kelly, Xiao Sun, Karen Y. He, Michael R. Brown, Sarah A.Gagliano Taliun, Jacklyn N. Hellwege, Marguerite R. Irvin, Xuenan Mi, Jennifer A. Brody, Nora Franceschini, Xiuqing Guo, Shih Jen Hwang, Paul S. De Vries, Yan Gao, Arden Moscati, Girish N. Nadkarni, Lisa R. Yanek, Tali Elfassy, Jennifer A. Smith, Ren Hua ChungAmber L. Beitelshees, Amit Patki, Stella Aslibekyan, Brandon M. Blobner, Juan M. Peralta, Themistocles L. Assimes, Walter R. Palmas, Chunyu Liu, Adam P. Bress, Zhijie Huang, Lewis C. Becker, Chii Min Hwa, Jeffrey R. O'connell, Jenna C. Carlson, Helen R. Warren, Sayantan Das, Ayush Giri, Lisa W. Martin, W. Craig Johnson, Ervin R. Fox, Erwin P. Bottinger, Alexander C. Razavi, Dhananjay Vaidya, Lee Ming Chuang, Yen Pei C. Chang, Take Naseri, Deepti Jain, Hyun Min Kang, Adriana M. Hung, Vinodh Srinivasasainagendra, Beverly M. Snively, Dongfeng Gu, May E. Montasser, Muagututi'a Sefuiva Reupena, Benjamin D. Heavner, Jonathon Lefaive, James E. Hixson, Kenneth M. Rice, Fei Fei Wang, Jonas B. Nielsen, Jianfeng Huang, Alyna T. Khan, Wei Zhou, Jovia L. Nierenberg, Cathy C. Laurie, Nicole D. Armstrong, Mengyao Shi, Yang Pan, Adrienne M. Stilp, Leslie Emery, Quenna Wong, Nicola L. Hawley, Ryan L. Minster, Joanne E. Curran, Patricia B. Munroe, Daniel E. Weeks, Kari E. North, Russell P. Tracy, Eimear E. Kenny, Daichi Shimbo, Aravinda Chakravarti, Stephen S. Rich, Alex P. Reiner, John Blangero, Susan Redline, Braxton D. Mitchell, Dabeeru C. Rao, Yii Der Ida Chen, Sharon L.R. Kardia, Robert C. Kaplan, Rasika A. Mathias, Jiang He, Bruce M. Psaty, Myriam Fornage, Ruth J.F. Loos, Adolfo Correa, Eric Boerwinkle, Jerome I. Rotter, Charles Kooperberg, Todd L. Edwards, Gonçalo R. Abecasis, Xiaofeng Zhu, Daniel Levy, Donna K. Arnett, Alanna C. Morrison

Epidemiology & Population Health

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10^-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10^-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10^-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10^-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10^-6and P<1×10^-4, respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

Original language	English (US)
Pages (from-to)	1656-1667
Number of pages	12
Journal	Hypertension
Volume	79
Issue number	8
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.122.19324
State	Published - Aug 1 2022

Keywords

allele
blood pressure
genome
hypertension
whole genome sequencing

ASJC Scopus subject areas

Internal Medicine

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10.1161/HYPERTENSIONAHA.122.19324

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Kelly, T. N., Sun, X., He, K. Y., Brown, M. R., Taliun, S. A. G., Hellwege, J. N., Irvin, M. R., Mi, X., Brody, J. A., Franceschini, N., Guo, X., Hwang, S. J., De Vries, P. S., Gao, Y., Moscati, A., Nadkarni, G. N., Yanek, L. R., Elfassy, T., Smith, J. A., ... Morrison, A. C. (2022). Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. Hypertension, 79(8), 1656-1667. https://doi.org/10.1161/HYPERTENSIONAHA.122.19324

Kelly, TN, Sun, X, He, KY, Brown, MR, Taliun, SAG, Hellwege, JN, Irvin, MR, Mi, X, Brody, JA, Franceschini, N, Guo, X, Hwang, SJ, De Vries, PS, Gao, Y, Moscati, A, Nadkarni, GN, Yanek, LR, Elfassy, T, Smith, JA, Chung, RH, Beitelshees, AL, Patki, A, Aslibekyan, S, Blobner, BM, Peralta, JM, Assimes, TL, Palmas, WR, Liu, C, Bress, AP, Huang, Z, Becker, LC, Hwa, CM, O'connell, JR, Carlson, JC, Warren, HR, Das, S, Giri, A, Martin, LW, Craig Johnson, W, Fox, ER, Bottinger, EP, Razavi, AC, Vaidya, D, Chuang, LM, Chang, YPC, Naseri, T, Jain, D, Kang, HM, Hung, AM, Srinivasasainagendra, V, Snively, BM, Gu, D, Montasser, ME, Reupena, MS, Heavner, BD, Lefaive, J, Hixson, JE, Rice, KM, Wang, FF, Nielsen, JB, Huang, J, Khan, AT, Zhou, W, Nierenberg, JL, Laurie, CC, Armstrong, ND, Shi, M, Pan, Y, Stilp, AM, Emery, L, Wong, Q, Hawley, NL, Minster, RL, Curran, JE, Munroe, PB, Weeks, DE, North, KE, Tracy, RP, Kenny, EE, Shimbo, D, Chakravarti, A, Rich, SS, Reiner, AP, Blangero, J, Redline, S, Mitchell, BD, Rao, DC, Ida Chen, YD, Kardia, SLR, Kaplan, RC, Mathias, RA, He, J, Psaty, BM, Fornage, M, Loos, RJF, Correa, A, Boerwinkle, E, Rotter, JI, Kooperberg, C, Edwards, TL, Abecasis, GR, Zhu, X, Levy, D, Arnett, DK & Morrison, AC 2022, 'Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension', Hypertension, vol. 79, no. 8, pp. 1656-1667. https://doi.org/10.1161/HYPERTENSIONAHA.122.19324

@article{3d32b2f5b0ad49d5ae0d09d45f810dc5,

title = "Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension",

abstract = "Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10-6and P<1×10-4, respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.",

keywords = "allele, blood pressure, genome, hypertension, whole genome sequencing",

author = "Kelly, {Tanika N.} and Xiao Sun and He, {Karen Y.} and Brown, {Michael R.} and Taliun, {Sarah A.Gagliano} and Hellwege, {Jacklyn N.} and Irvin, {Marguerite R.} and Xuenan Mi and Brody, {Jennifer A.} and Nora Franceschini and Xiuqing Guo and Hwang, {Shih Jen} and {De Vries}, {Paul S.} and Yan Gao and Arden Moscati and Nadkarni, {Girish N.} and Yanek, {Lisa R.} and Tali Elfassy and Smith, {Jennifer A.} and Chung, {Ren Hua} and Beitelshees, {Amber L.} and Amit Patki and Stella Aslibekyan and Blobner, {Brandon M.} and Peralta, {Juan M.} and Assimes, {Themistocles L.} and Palmas, {Walter R.} and Chunyu Liu and Bress, {Adam P.} and Zhijie Huang and Becker, {Lewis C.} and Hwa, {Chii Min} and O'connell, {Jeffrey R.} and Carlson, {Jenna C.} and Warren, {Helen R.} and Sayantan Das and Ayush Giri and Martin, {Lisa W.} and {Craig Johnson}, W. and Fox, {Ervin R.} and Bottinger, {Erwin P.} and Razavi, {Alexander C.} and Dhananjay Vaidya and Chuang, {Lee Ming} and Chang, {Yen Pei C.} and Take Naseri and Deepti Jain and Kang, {Hyun Min} and Hung, {Adriana M.} and Vinodh Srinivasasainagendra and Snively, {Beverly M.} and Dongfeng Gu and Montasser, {May E.} and Reupena, {Muagututi'a Sefuiva} and Heavner, {Benjamin D.} and Jonathon Lefaive and Hixson, {James E.} and Rice, {Kenneth M.} and Wang, {Fei Fei} and Nielsen, {Jonas B.} and Jianfeng Huang and Khan, {Alyna T.} and Wei Zhou and Nierenberg, {Jovia L.} and Laurie, {Cathy C.} and Armstrong, {Nicole D.} and Mengyao Shi and Yang Pan and Stilp, {Adrienne M.} and Leslie Emery and Quenna Wong and Hawley, {Nicola L.} and Minster, {Ryan L.} and Curran, {Joanne E.} and Munroe, {Patricia B.} and Weeks, {Daniel E.} and North, {Kari E.} and Tracy, {Russell P.} and Kenny, {Eimear E.} and Daichi Shimbo and Aravinda Chakravarti and Rich, {Stephen S.} and Reiner, {Alex P.} and John Blangero and Susan Redline and Mitchell, {Braxton D.} and Rao, {Dabeeru C.} and {Ida Chen}, {Yii Der} and Kardia, {Sharon L.R.} and Kaplan, {Robert C.} and Mathias, {Rasika A.} and Jiang He and Psaty, {Bruce M.} and Myriam Fornage and Loos, {Ruth J.F.} and Adolfo Correa and Eric Boerwinkle and Rotter, {Jerome I.} and Charles Kooperberg and Edwards, {Todd L.} and Abecasis, {Gon{\c c}alo R.} and Xiaofeng Zhu and Daniel Levy and Arnett, {Donna K.} and Morrison, {Alanna C.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), 2022.",

year = "2022",

month = aug,

day = "1",

doi = "10.1161/HYPERTENSIONAHA.122.19324",

language = "English (US)",

volume = "79",

pages = "1656--1667",

journal = "Hypertension",

issn = "0194-911X",

publisher = "Lippincott Williams and Wilkins",

number = "8",

}

TY - JOUR

T1 - Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

AU - Kelly, Tanika N.

AU - Sun, Xiao

AU - He, Karen Y.

AU - Brown, Michael R.

AU - Taliun, Sarah A.Gagliano

AU - Hellwege, Jacklyn N.

AU - Irvin, Marguerite R.

AU - Mi, Xuenan

AU - Brody, Jennifer A.

AU - Franceschini, Nora

AU - Guo, Xiuqing

AU - Hwang, Shih Jen

AU - De Vries, Paul S.

AU - Gao, Yan

AU - Moscati, Arden

AU - Nadkarni, Girish N.

AU - Yanek, Lisa R.

AU - Elfassy, Tali

AU - Smith, Jennifer A.

AU - Chung, Ren Hua

AU - Beitelshees, Amber L.

AU - Patki, Amit

AU - Aslibekyan, Stella

AU - Blobner, Brandon M.

AU - Peralta, Juan M.

AU - Assimes, Themistocles L.

AU - Palmas, Walter R.

AU - Liu, Chunyu

AU - Bress, Adam P.

AU - Huang, Zhijie

AU - Becker, Lewis C.

AU - Hwa, Chii Min

AU - O'connell, Jeffrey R.

AU - Carlson, Jenna C.

AU - Warren, Helen R.

AU - Das, Sayantan

AU - Giri, Ayush

AU - Martin, Lisa W.

AU - Craig Johnson, W.

AU - Fox, Ervin R.

AU - Bottinger, Erwin P.

AU - Razavi, Alexander C.

AU - Vaidya, Dhananjay

AU - Chuang, Lee Ming

AU - Chang, Yen Pei C.

AU - Naseri, Take

AU - Jain, Deepti

AU - Kang, Hyun Min

AU - Hung, Adriana M.

AU - Srinivasasainagendra, Vinodh

AU - Snively, Beverly M.

AU - Gu, Dongfeng

AU - Montasser, May E.

AU - Reupena, Muagututi'a Sefuiva

AU - Heavner, Benjamin D.

AU - Lefaive, Jonathon

AU - Hixson, James E.

AU - Rice, Kenneth M.

AU - Wang, Fei Fei

AU - Nielsen, Jonas B.

AU - Huang, Jianfeng

AU - Khan, Alyna T.

AU - Zhou, Wei

AU - Nierenberg, Jovia L.

AU - Laurie, Cathy C.

AU - Armstrong, Nicole D.

AU - Shi, Mengyao

AU - Pan, Yang

AU - Stilp, Adrienne M.

AU - Emery, Leslie

AU - Wong, Quenna

AU - Hawley, Nicola L.

AU - Minster, Ryan L.

AU - Curran, Joanne E.

AU - Munroe, Patricia B.

AU - Weeks, Daniel E.

AU - North, Kari E.

AU - Tracy, Russell P.

AU - Kenny, Eimear E.

AU - Shimbo, Daichi

AU - Chakravarti, Aravinda

AU - Rich, Stephen S.

AU - Reiner, Alex P.

AU - Blangero, John

AU - Redline, Susan

AU - Mitchell, Braxton D.

AU - Rao, Dabeeru C.

AU - Ida Chen, Yii Der

AU - Kardia, Sharon L.R.

AU - Kaplan, Robert C.

AU - Mathias, Rasika A.

AU - He, Jiang

AU - Psaty, Bruce M.

AU - Fornage, Myriam

AU - Loos, Ruth J.F.

AU - Correa, Adolfo

AU - Boerwinkle, Eric

AU - Rotter, Jerome I.

AU - Kooperberg, Charles

AU - Edwards, Todd L.

AU - Abecasis, Gonçalo R.

AU - Zhu, Xiaofeng

AU - Levy, Daniel

AU - Arnett, Donna K.

AU - Morrison, Alanna C.

PY - 2022/8/1

Y1 - 2022/8/1

N2 - Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10-6and P<1×10-4, respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

AB - Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10-6and P<1×10-4, respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

KW - allele

KW - blood pressure

KW - genome

KW - hypertension

KW - whole genome sequencing

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Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

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