Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure

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  • He, Karen Y.
    • ORCID: 0000-0002-8686-7697
    • Other Affiliation: Department of Epidemiology and Biostatistics; Case Western Reserve University
  • Wang, Heming
    • Other Affiliation: Department of Epidemiology and Biostatistics; Case Western Reserve University
  • Cade, Brian E.
    • Other Affiliation: Division of Sleep Medicine; Harvard Medical School
  • Nandakumar, Priyanka
    • ORCID: 0000-0002-2332-6746
    • Other Affiliation: McKusick-Nathans Institute of Genetic Medicine; Johns Hopkins University School of Medicine
  • Giri, Ayush
    • ORCID: 0000-0002-7786-4670
    • Other Affiliation: Division of Epidemiology; Department of Medicine; Institute for Medicine and Public Health; Vanderbilt Genetics Institute; Vanderbilt University
  • Ware, Erin B.
    • Other Affiliation: Biosocial Methods Collaborative; Institute for Social Research; University of Michigan
  • Haessler, Jeffrey
    • Other Affiliation: Division of Public Health Sciences; Fred Hutchinson Cancer Research Center
  • Liang, Jingjing
    • Other Affiliation: Department of Epidemiology and Biostatistics; Case Western Reserve University
  • Smith, Jennifer A.
    • ORCID: 0000-0002-3575-5468
    • Other Affiliation: Department of Epidemiology; School of Public Health; University of Michigan
  • Franceschini, Nora
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Le, Thu H.
    • Other Affiliation: Department of Medicine; Division of Nephrology; University of Virginia
  • Kooperberg, Charles
    • Other Affiliation: Division of Public Health Sciences; Fred Hutchinson Cancer Research Center
  • Edwards, Todd L.
    • Other Affiliation: Division of Epidemiology; Department of Medicine; Institute for Medicine and Public Health; Vanderbilt Genetics Institute; Vanderbilt University
  • Kardia, Sharon L. R.
    • Other Affiliation: Department of Epidemiology; School of Public Health; University of Michigan
  • Lin, Xihong
    • Other Affiliation: Department of Biostatistics; Harvard T.H. Chan School of Public Health
  • Chakravarti, Aravinda
    • Other Affiliation: McKusick-Nathans Institute of Genetic Medicine; Johns Hopkins University School of Medicine
  • Redline, Susan
    • Other Affiliation: Division of Pulmonary; Critical Care; and Sleep Medicine; Beth Israel Deaconess Medical Center
  • Zhu, Xiaofeng
    • Other Affiliation: Department of Epidemiology and Biostatistics; Case Western Reserve University
Abstract
  • Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17-member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information.
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 13
Journal issue
  • 3
Page start
  • e1006678
Language
  • English
ISSN
  • 1553-7404
  • 1553-7390

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