title: Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.
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.
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Karen Y
authors.identifier: 0000-0002-8686-7697
authors.initials: KY
authors.lastname: He
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Heming
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Brian E
authors.identifier: 0000-0003-1424-0673
authors.initials: BE
authors.lastname: Cade
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Priyanka
authors.identifier: 0000-0002-2332-6746
authors.initials: P
authors.lastname: Nandakumar
authors.affiliation: Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Ayush
authors.identifier: 0000-0002-7786-4670
authors.initials: A
authors.lastname: Giri
authors.affiliation: 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.
authors.forename: Erin B
authors.identifier: 0000-0003-4731-8158
authors.initials: EB
authors.lastname: Ware
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Haessler
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jennifer A
authors.identifier: 0000-0002-3575-5468
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Thu H
authors.initials: TH
authors.lastname: Le
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: 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.|Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Redline
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D015992:Body Mass Index; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D005192:Family Health; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors