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Human Genetics

, Volume 138, Issue 2, pp 199–210 | Cite as

Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data

  • Karen Y. He
  • Xiaoyin Li
  • Tanika N. Kelly
  • Jingjing Liang
  • Brian E. Cade
  • Themistocles L. Assimes
  • Lewis C. Becker
  • Amber L. Beitelshees
  • Adam P. Bress
  • Yen-Pei Christy Chang
  • Yii-Der Ida Chen
  • Paul S. de Vries
  • Ervin R. Fox
  • Nora Franceschini
  • Anna Furniss
  • Yan Gao
  • Xiuqing Guo
  • Jeffrey Haessler
  • Shih-Jen Hwang
  • Marguerite Ryan Irvin
  • Rita R. Kalyani
  • Ching-Ti Liu
  • Chunyu Liu
  • Lisa Warsinger Martin
  • May E. Montasser
  • Paul M. Muntner
  • Stanford Mwasongwe
  • Walter Palmas
  • Alex P. Reiner
  • Daichi Shimbo
  • Jennifer A. Smith
  • Beverly M. Snively
  • Lisa R. Yanek
  • Eric Boerwinkle
  • Adolfo Correa
  • L. Adrienne Cupples
  • Jiang He
  • Sharon L. R. Kardia
  • Charles Kooperberg
  • Rasika A. Mathias
  • Braxton D. Mitchell
  • Bruce M. Psaty
  • Ramachandran S. Vasan
  • D. C. Rao
  • Stephen S. Rich
  • Jerome I. Rotter
  • James G. Wilson
  • NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Blood Pressure Working Group
  • Aravinda Chakravarti
  • Alanna C. Morrison
  • Daniel Levy
  • Donna K. Arnett
  • Susan Redline
  • Xiaofeng ZhuEmail author
Original Investigation

Abstract

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10−4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.

Notes

Acknowledgements

This work was supported by Grants T32 HL007567, HL113338 and HL086694 from the National Heart, Lung, and Blood Institute (NHLBI) and HG003054 from the National Human Genome Research Institute (NHGRI). Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Atherosclerosis Risk in Communities” (phs001211.v1.p1) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C, 3U54HG003273-12S2). WGS for “NHLBI TOPMed: The Framingham Heart Study” (phs000974.v2.p2) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). WGS for “NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish” (phs000956.v2.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964.v2.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: The Cleveland Family Study” (phs000954.v1.p1) was performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1). WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). WGS for “NHLBI TOPMed: Hypertension Genetic Epidemiology Network and Genetic Epidemiology Network of Arteriopathy” (phs001293.v1.p1) was performed at the University of Washington Northwest Genomics Center (3R01HL055673-18S1). WGS for “NHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy” (phs001345.v1.p1) was performed at the University of Washington Northwest Genomics Center (3R01HL055673-18S1). WGS for “NHLBI TOPMed: Genetic Studies of Atherosclerosis Risk” (phs001218.v1.p1) was performed at the Macrogen and the Broad Institute of MIT and Harvard (HHSN268201500014C). WGS for “NHLBI TOPMed: Genetic Epidemiology Network of Salt Sensitivity” (phs001217.v1.p1) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C). WGS for “NHLBI TOPMed: Women’s Health Initiative” (phs001237.v1.p1) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. The Amish studies upon which these data are based were supported by NIH Grants R01 AG18728, U01 HL072515, R01 HL088119, R01 HL121007, and P30 DK072488. See publication: PMID: 18440328. Support for the Cleveland Family Study was provided by NIH Grants HL 046389, HL113338, and 1R35HL135818. The Framingham Heart Study has been supported by contracts N01-HC-25195 and HHSN268201500001I and Grant R01 HL092577. The Framingham Heart Study thanks the study participants and the multitude of investigators who over its 70-year history continue to contribute so much to further our knowledge of heart, lung, blood, and sleep disorders and associated traits. GeneSTAR was supported by Grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (U01 HL72518, HL087698, HL49762, HL58625, HL071025, HL112064), the National Institutes of Health/National Institute of Nursing Research (NR0224103), and by a Grant from the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL054457, HL054464, HL054481, and HL087660) of the National Institutes of Health. The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) was supported by research Grants (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of the JHS. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Dr. Bress is supported by K01HL133468 from the National Heart, Lung, and Blood Institute, Bethesda, MD. Dr. Franceschini is supported by DK117445 from the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) and MD012765 from the National Institute on Minority Health and Health Disparities (NIMHD). The authors would like to acknowledge contributions from the investigators of the NHLBI TOPMed Consortium (https://www.nhlbiwgs.org/topmed-banner-authorship).

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Data availability

The datasets analyzed during the current study are available in the dbGaP repository. Instructions for accessing TOPMed data can be found on: https://www.nhlbiwgs.org/topmed-data-access-scientific-community.

Supplementary material

439_2019_1975_MOESM1_ESM.pdf (804 kb)
Supplementary material 1 (PDF 804 KB)
439_2019_1975_MOESM2_ESM.xlsx (104 kb)
Supplementary material 2 (XLSX 105 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Karen Y. He
    • 1
  • Xiaoyin Li
    • 1
  • Tanika N. Kelly
    • 2
  • Jingjing Liang
    • 1
  • Brian E. Cade
    • 3
    • 4
  • Themistocles L. Assimes
    • 5
  • Lewis C. Becker
    • 6
  • Amber L. Beitelshees
    • 7
  • Adam P. Bress
    • 8
  • Yen-Pei Christy Chang
    • 7
  • Yii-Der Ida Chen
    • 9
  • Paul S. de Vries
    • 10
  • Ervin R. Fox
    • 11
  • Nora Franceschini
    • 12
  • Anna Furniss
    • 13
  • Yan Gao
    • 14
  • Xiuqing Guo
    • 9
  • Jeffrey Haessler
    • 15
  • Shih-Jen Hwang
    • 16
  • Marguerite Ryan Irvin
    • 17
  • Rita R. Kalyani
    • 18
  • Ching-Ti Liu
    • 16
  • Chunyu Liu
    • 16
  • Lisa Warsinger Martin
    • 19
  • May E. Montasser
    • 7
  • Paul M. Muntner
    • 17
  • Stanford Mwasongwe
    • 20
  • Walter Palmas
    • 21
  • Alex P. Reiner
    • 22
  • Daichi Shimbo
    • 21
  • Jennifer A. Smith
    • 23
  • Beverly M. Snively
    • 24
  • Lisa R. Yanek
    • 25
  • Eric Boerwinkle
    • 10
    • 26
  • Adolfo Correa
    • 13
  • L. Adrienne Cupples
    • 16
  • Jiang He
    • 2
  • Sharon L. R. Kardia
    • 23
  • Charles Kooperberg
    • 15
  • Rasika A. Mathias
    • 27
  • Braxton D. Mitchell
    • 7
    • 28
  • Bruce M. Psaty
    • 29
    • 30
  • Ramachandran S. Vasan
    • 16
  • D. C. Rao
    • 31
  • Stephen S. Rich
    • 32
  • Jerome I. Rotter
    • 9
  • James G. Wilson
    • 14
  • NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Blood Pressure Working Group
  • Aravinda Chakravarti
    • 33
  • Alanna C. Morrison
    • 10
  • Daniel Levy
    • 16
    • 34
  • Donna K. Arnett
    • 35
  • Susan Redline
    • 3
    • 4
    • 36
  • Xiaofeng Zhu
    • 1
    Email author
  1. 1.Department of Population and Quantitative Health SciencesCase Western Reserve UniversityClevelandUSA
  2. 2.Department of EpidemiologyTulane University School of Public Health and Tropical MedicineNew OrleansUSA
  3. 3.Division of Sleep and Circadian DisordersBrigham and Women’s HospitalBostonUSA
  4. 4.Division of Sleep MedicineHarvard Medical SchoolBostonUSA
  5. 5.Department of MedicineStanford UniversityPalo AltoUSA
  6. 6.GeneSTAR Research Program, Divisions of Cardiology and General Internal Medicine, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  7. 7.Program for Personalized and Genomic Medicine, Division of Endocrinology Diabetes and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreUSA
  8. 8.Department of Population Health SciencesUniversity of Utah School of MedicineSalt Lake CityUSA
  9. 9.Departments of Pediatrics and Medicine, Institute for Translational Genomics and Population SciencesLABioMed at Harbor-UCLA Medical CenterTorranceUSA
  10. 10.Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, Human Genetics CenterThe University of Texas Health Science Center at HoustonHoustonUSA
  11. 11.Division of Cardiovascular Diseases, Department of MedicineUniversity of Mississippi Medical CenterJacksonUSA
  12. 12.Department of EpidemiologyUNC Gillings School of Global Public HealthChapel HillUSA
  13. 13.Jackson Heart StudyUniversity of Mississippi Medical CenterJacksonUSA
  14. 14.Department of Physiology and BiophysicsUniversity of Mississippi Medical CenterJacksonUSA
  15. 15.Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA
  16. 16.Boston University’s and National Heart, Lung, and Blood Institute’s Framingham Heart StudyFraminghamUSA
  17. 17.Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamUSA
  18. 18.GeneSTAR Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  19. 19.Division of Cardiology, Department of MedicineGeorge Washington UniversityWashingtonUSA
  20. 20.Jackson Heart StudyJackson State UniversityJacksonUSA
  21. 21.Division of General MedicineColumbia University Medical CenterNew YorkUSA
  22. 22.Department of EpidemiologyUniversity of WashingtonSeattleUSA
  23. 23.Department of Epidemiology, School of Public HealthUniversity of MichiganAnn ArborUSA
  24. 24.Department of Biostatistical SciencesWake Forest University School of MedicineWinston-SalemUSA
  25. 25.GeneSTAR Research Program, Division of General Internal Medicine, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  26. 26.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  27. 27.GeneSTAR Research Program, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  28. 28.Geriatrics Research and Education Clinical CenterVeterans Affairs Medical CenterBaltimoreUSA
  29. 29.Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health ServicesUniversity of WashingtonSeattleUSA
  30. 30.Kaiser Permanente Washington Health Research InstituteSeattleUSA
  31. 31.Division of BiostatisticsWashington University School of MedicineSt. LouisUSA
  32. 32.Center for Public Health GenomicsUniversity of VirginiaCharlottesvilleUSA
  33. 33.Department of Medicine, Center for Human Genetics and GenomicsNew York University Langone HealthNew YorkUSA
  34. 34.Population Sciences BranchNational Heart, Lung, and Blood Institute, National Institutes of HealthBethesdaUSA
  35. 35.University of Kentucky College of Public HealthLexingtonUSA
  36. 36.Division of Pulmonary, Critical Care, and Sleep MedicineBeth Israel Deaconess Medical CenterBostonUSA

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