Rare coding variants in RCN3 are associated with blood pressure

Karen Y He¹, Tanika N Kelly², Heming Wang^{3

4

5}, Jingjing Liang¹, Luke Zhu⁶, Brian E Cade^{3

4

5}, Themistocles L Assimes⁷, Lewis C Becker⁸, Amber L Beitelshees⁹, Lawrence F Bielak¹⁰, Adam P Bress¹¹, Jennifer A Brody¹², Yen-Pei Christy Chang⁹, Yi-Cheng Chang^{13

14

15}, Paul S de Vries¹⁶, Ravindranath Duggirala¹⁷, Ervin R Fox¹⁸, Nora Franceschini¹⁹, Anna L Furniss²⁰, Yan Gao²¹, Xiuqing Guo²², Jeffrey Haessler²³, Yi-Jen Hung²⁴, Shih-Jen Hwang^{25

26}, Marguerite Ryan Irvin²⁷, Rita R Kalyani²⁸, Ching-Ti Liu^{25

26}, Chunyu Liu^{25

26}, Lisa Warsinger Martin²⁹, May E Montasser⁹, Paul M Muntner²⁷, Stanford Mwasongwe³⁰, Take Naseri³¹, Walter Palmas³², Muagututi'a Sefuiva Reupena³³, Kenneth M Rice³⁴, Wayne H-H Sheu³⁵, Daichi Shimbo³², Jennifer A Smith^{10

36}, Beverly M Snively³⁷, Lisa R Yanek³⁸, Wei Zhao¹⁰, John Blangero¹⁷, Eric Boerwinkle^{16

39}, Yii-Der Ida Chen^{22

40}, Adolfo Correa²⁰, L Adrienne Cupples^{25

26}, Joanne E Curran¹⁷, Myriam Fornage^{16

41}, Jiang He², Lifang Hou⁴², Robert C Kaplan⁴³, Sharon L R Kardia¹⁰, Eimear E Kenny⁴⁴, Charles Kooperberg²³, Donald Lloyd-Jones⁴³, Ruth J F Loos⁴⁵, Rasika A Mathias⁴⁶, Stephen T McGarvey^{47

48}, Braxton D Mitchell^{9

49}, Kari E North^{19

50}, Patricia A Peyser¹⁰, Bruce M Psaty⁵¹, Laura M Raffield⁵⁰, D C Rao⁵², Susan Redline^{3

5}, Alex P Reiner⁵³, Stephen S Rich⁵⁴, Jerome I Rotter²², Kent D Taylor²², Russell Tracy^{55

56}, Ramachandran S Vasan^{26

57}; Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Alanna C Morrison¹⁶, Daniel Levy^{26

58}, Aravinda Chakravarti⁶, Donna K Arnett⁵⁹, Xiaofeng Zhu⁶⁰

Affiliations

¹ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH, 44106, USA.
² Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁶ Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY, USA.
⁷ Department of Medicine (Division of Cardiovascular Medicine), Stanford University, Palo Alto, CA, USA.
⁸ GeneSTAR Research Program, Department of Medicine, Divisions of Cardiology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹³ Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei City, Taiwan.
¹⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan.
¹⁵ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁷ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁸ Division of Cardiovascular Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁹ Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
²⁰ Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
²¹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
²² The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁴ Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan.
²⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
²⁶ Framingham Heart Study, National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
²⁷ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AB, USA.
²⁸ GeneSTAR Research Program, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁹ Division of Cardiology, Department of Medicine, George Washington University, Washington, DC, USA.
³⁰ Jackson Heart Study, Jackson State University, Jackson, MS, USA.
³¹ Ministry of Health, Government of Samoa, Apia, Samoa.
³² Division of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
³³ Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa.
³⁴ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
³⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan.
³⁶ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
³⁷ Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁸ GeneSTAR Research Program, Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁴⁰ Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center Professor of Pediatrics, UCLA, Torrance, CA, USA.
⁴¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴² Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, USA.
⁴³ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA.
⁴⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁵ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁶ GeneSTAR Research Program, Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁷ International Health Institute and Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA.
⁴⁸ Department of Anthropology, Brown University, Providence, RI, USA.
⁴⁹ Geriatrics Research and Education Clinical Center, Veterans Affairs Medical Center, Baltimore, MD, USA.
⁵⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵¹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁵² Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
⁵³ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁵⁵ Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁵⁶ Department of Biochemistry, University of Vermont, Burlington, VT, USA.
⁵⁷ Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
⁵⁸ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁵⁹ University of Kentucky College of Public Health, Lexington, KY, USA.
⁶⁰ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH, 44106, USA. xxz10@case.edu.

PMID: 35183128
PMCID: PMC8858539
DOI: 10.1186/s12864-022-08356-4

Rare coding variants in RCN3 are associated with blood pressure

Karen Y He et al. BMC Genomics. 2022.

. 2022 Feb 19;23(1):148.

doi: 10.1186/s12864-022-08356-4.

Authors

Affiliations

¹ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH, 44106, USA.
² Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁶ Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY, USA.
⁷ Department of Medicine (Division of Cardiovascular Medicine), Stanford University, Palo Alto, CA, USA.
⁸ GeneSTAR Research Program, Department of Medicine, Divisions of Cardiology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹³ Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei City, Taiwan.
¹⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan.
¹⁵ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁷ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁸ Division of Cardiovascular Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁹ Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
²⁰ Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
²¹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
²² The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁴ Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan.
²⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
²⁶ Framingham Heart Study, National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
²⁷ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AB, USA.
²⁸ GeneSTAR Research Program, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁹ Division of Cardiology, Department of Medicine, George Washington University, Washington, DC, USA.
³⁰ Jackson Heart Study, Jackson State University, Jackson, MS, USA.
³¹ Ministry of Health, Government of Samoa, Apia, Samoa.
³² Division of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
³³ Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa.
³⁴ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
³⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan.
³⁶ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
³⁷ Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁸ GeneSTAR Research Program, Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁴⁰ Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center Professor of Pediatrics, UCLA, Torrance, CA, USA.
⁴¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴² Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, USA.
⁴³ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA.
⁴⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁵ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁶ GeneSTAR Research Program, Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁷ International Health Institute and Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA.
⁴⁸ Department of Anthropology, Brown University, Providence, RI, USA.
⁴⁹ Geriatrics Research and Education Clinical Center, Veterans Affairs Medical Center, Baltimore, MD, USA.
⁵⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵¹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁵² Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
⁵³ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁵⁵ Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁵⁶ Department of Biochemistry, University of Vermont, Burlington, VT, USA.
⁵⁷ Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
⁵⁸ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁵⁹ University of Kentucky College of Public Health, Lexington, KY, USA.
⁶⁰ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH, 44106, USA. xxz10@case.edu.

PMID: 35183128
PMCID: PMC8858539
DOI: 10.1186/s12864-022-08356-4

Abstract

Background: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries.

Results: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10^{- 7}).

Conclusions: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Keywords: Blood pressure; Rare variant analysis; Whole genome sequencing.

PubMed Disclaimer

Conflict of interest statement

Karen Y. He is currently an employee of The Janssen Pharmaceutical Companies of Johnson & Johnson. This publication does not represent the views of her employer. Adam P. Bress receives research support to his institution from Novartis, Amgen, and Amarin. Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

Figures

**Fig. 1**
Overview of analysis workflow. Abbreviations: MLOD (maximum LOD score), LOD_j (family-specific LOD score for family j), QC (quality control), PCs (principal components), R-INT (rescaled inverse normal transformation), AA (African American), EA (European American), EAS (Eastern Asian/Asian American), HA (Hispanic American)

**Fig. 2**
Linkage analysis with HyperGEN and GENOA subjects in TOPMed Freeze 6a release. Abbreviations: SBP (systolic blood pressure); DBP (diastolic blood pressure); PP (pulse pressure); cM (centimorgan); LOD (logarithm of the odds); MLOD (maximum LOD score)

**Fig. 3**
Heat map of p-values from GTEx tissue-specific gene expression association analysis. Gene expression-association analyses were conducted in EPACTS using variable threshold burden test (BurdenVT) and Sequence Kernel Association Test (SKAT)

See this image and copyright information in PMC

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Rare coding variants in RCN3 are associated with blood pressure

Affiliations

Rare coding variants in RCN3 are associated with blood pressure

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources