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Blood Pressure

Linkage evidence and TOPMed whole genome sequencing identify multiple genes on chromosome 1 with rare variants associated with blood pressure

Authors
Karen Y. He, Heming Wang, Karen Schwander, Jennifer A. Smith, Tanika N. Kelly, Xiaofeng Zhu, Donna K. Arnett, on behalf of the TOPMed Blood Pressure Working Group
Name and Date of Professional Meeting
ASHG (October, 2018)
Associated paper proposal(s)
Working Group(s)
Abstract Text
Elevated blood pressure or hypertension is a major risk factor for coronary heart disease and cerebrovascular disease. The prevalence of hypertension in African Americans is among the highest in the world. We followed up a 33 Mb region with a linkage peak on 1q31 associated with pulse pressure (MLOD = 3.8) that was previously identified with 4,394 African American subjects (1,802 families) in the Family Blood Pressure Program, consisting of HyperGEN, GENOA, and GenNet. Here, we analyzed 2,806 African-American subjects in HyperGEN and GENOA that were whole-genome sequenced by TOPMed as a discovery cohort by conducting gene-based and single SNP association analysis in the linkage region for 3 blood pressure (BP) traits: SBP, DBP, and PP. We hypothesized that the linkage peak could be partially explained by low frequency and rare variants that are segregating in the families contributing to the linkage peak. Our analysis was restricted to variants that segregate at least twice within families that passed a variable threshold for family-specific LOD scores. We used functional annotation to focus on 174 protein-coding genes and analyzed functional coding variants and non-coding variants (MAF < 1%; CADD > 10) separately. Our analysis of selected functional coding and non-coding variants resulted in 46 unique genes with either burden or SKAT p < 0.05 for at least 1 BP trait in the discovery cohort. These 46 genes were carried forward for verification analysis in 9 independent TOPMed studies consisting of 27,214 individuals of African, European, and Asian descent. In the multiancestry meta-analysis of functional coding variants, we observed 2 genes significantly associated with SBP and passed Bonferroni correction for multiple testing (NAV1, p = 0.0016 for SKAT; PTPN7, p = 0.0012 for burden test). For non-coding variants, there was 1 gene significantly associated with PP and passed the multiple testing threshold (MR1, p = 1.37E-5 for burden test). MR1 is especially noteworthy because we identified 5 non-coding rare variants significantly associated with PP in the meta-analysis of African Americans (p = 0.0087 for burden test) and passed the Bonferroni correction in the meta-analysis of European Americans (p = 1.7E-4 for burden test). Additional tissue-specific functional annotation analysis and gene expression association analysis are currently underway.
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