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PLoS Genet. 2017 Mar 27;13(3):e1006678. doi: 10.1371/journal.pgen.1006678. eCollection 2017 Mar.

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

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Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States of America.
Biosocial Methods Collaborative, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, United States of America.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America.
Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, Virginia, United States of America.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.


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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