BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries.
RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10− 7).
CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.
Digital Object Identifier (DOI)
KYH was partially supported by grant T32 HL007567 from the National Heart, Lung, and Blood Institute (NHLBI). This work was supported by HL086694 from NHLBI, HG003054 and HG011052 from the National Human Genome Research Institute.
All the TOPMed datasets generated and/or analyzed during the current study are available in the dbGaP repository and instructions for data access can be found at https://www.nhlbiwgs.org/topmed-data-access-scientific-community. The current study includes datasets: phs000956, phs001211, phs001644, phs001624, phs001612, phs000954, phs001368, phs000951, phs001218, phs001345, phs000974, phs001217, phs001395, phs001293, phs000964, phs001416, phs001215, phs000972, phs001387, phs001237. The UK Biobank data is available in the UK Biobank repository: ukbiobank.ac.uk.
He, Karen Y.; Kelly, Tanika N.; Wang, Heming; Liang, Jingjing; Zhu, Luke; Cade, Brian E.; Assimes, Themistocles L.; Becker, Lewis C.; Beitelshees, Amber L.; Bielak, Lawrence F.; Bress, Adam P.; Brody, Jennifer A.; Chang, Yen-Pei Christy; Chang, Yi-Cheng; de Vries, Paul S.; Duggirala, Ravindranath; Fox, Ervin R.; Franceschini, Nora; Furniss, Anna L.; Gao, Yan; and Arnett, Donna K., "Rare Coding Variants in RCN3 Are Associated with Blood Pressure" (2022). Epidemiology and Environmental Health Faculty Publications. 91.
Additional file 1. Supplemental Materials & Methods.
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Additional file 2: Table S1. Characteristics of UK Biobank European samples.
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Additional file 3: Fig. S1. TOPMed Freeze 8 phenotype distributions in African Americans.
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Additional file 4: Fig. S2. TOPMed Freeze 8 phenotype distributions in European Americans.
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Additional file 5: Fig. S3. TOPMed Freeze 8 phenotype distributions in East Asian/Asian Americans.
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Additional file 6: Fig. S4. TOPMed Freeze 8 phenotype distributions in Hispanic Americans.
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Additional file 7: Fig. S5. TOPMed Freeze 8 phenotype distributions in Samoans.
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Additional file 8. Members of the Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group.
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Additional file 9. Members of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium.