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

• Published in: PLoS genetics 2017-03, Vol.13 (3), p.e1006678-e1006678
• Main Authors: He, Karen Y, Wang, Heming, Cade, Brian E, Nandakumar, Priyanka, Giri, Ayush, Ware, Erin B, Haessler, Jeffrey, Liang, Jingjing, Smith, Jennifer A, Franceschini, Nora, Le, Thu H, Kooperberg, Charles, Edwards, Todd L, Kardia, Sharon L R, Lin, Xihong, Chakravarti, Aravinda, Redline, Susan, Zhu, Xiaofeng
• Format: Article
• Language: English
• Subjects: Adult; Biology and Life Sciences; Blood pressure; Blood Pressure - genetics; Body Mass Index; Chromosome 16; Chromosomes, Human, Pair 16 - genetics; Coding; Epidemiology; Family Health; Family studies; Female; Gene Expression; Gene Frequency; Genetic aspects; Genetic Linkage; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genetic variation; Genetically modified mice; Genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genotype; Health aspects; Health sciences; Humans; Hypertension; Linkage analysis; Male; Medical research; Medicine; Medicine and Health Sciences; Middle Aged; Musculoskeletal system; Neural coding; Pedigree; Polymorphism, Single Nucleotide; Public health; RNA Splicing Factors - genetics; Skeletal muscle; Sleep disorders; Studies; Ventricle; White People - genetics; Womens health
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006678

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.