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.

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Published in BMC Genomics, v. 23, article no. 148.

© 2022 The Author(s)

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

The first 20 authors and the author from the University of Kentucky are shown on the author list above. Please refer to the downloaded document for the complete author list.

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Funding Information

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.

Related Content

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.

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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.