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

TitleRare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.
Publication TypeJournal Article
Year of Publication2017
AuthorsHe, KY, Wang, H, Cade, BE, Nandakumar, P, Giri, A, Ware, EB, Haessler, J, Liang, J, Smith, JA, Franceschini, N, Le, TH, Kooperberg, C, Edwards, TL, Kardia, SLR, Lin, X, Chakravarti, A, Redline, S, Zhu, X
JournalPLoS Genetics
Volume13
Issue3
Paginatione1006678
ISSN Number1553-7404
KeywordsAdult, Blood pressure, Body Mass Index, Chromosomes, Human, Pair 16, Family Health, Female, Gene Expression, Gene Frequency, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, RNA Splicing Factors, Whites
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.

DOI10.1371/journal.pgen.1006678
Citation Key12137
PubMed ID28346479
PubMed Central IDPMC5386302
Grant ListRC4 AG039029 / AG / NIA NIH HHS / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
RC2 AG036495 / AG / NIA NIH HHS / United States
U01 HG004603 / HG / NHGRI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
RC2 GM092618 / GM / NIGMS NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
R03 AG040698 / AG / NIA NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
T32 GM007814 / GM / NIGMS NIH HHS / United States
R01 HL046380 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
R01 HL098433 / HL / NHLBI NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
HHSN268201100004C / WH / WHI NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
R21 HL121429 / HL / NHLBI NIH HHS / United States
T32 HL007567 / HL / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States