Rare coding variants in RCN3 are associated with blood pressure.

Area of Science:

• Genetics
• Cardiovascular Disease Research
• Genomic Medicine

Background:

• Genome-wide association studies (GWAS) have identified numerous blood pressure loci, but rare variant discovery remains difficult.
• Family-based linkage scans effectively identify rare genetic variants for blood pressure.
• The Trans-Omics for Precision Medicine (TOPMed) program provides a valuable resource for genetic studies.

Purpose of the Study:

• To identify low-frequency and rare genetic variants associated with blood pressure within known linkage regions on chromosomes 1 and 19.
• To analyze whole genome sequencing data from diverse ancestral groups within the TOPMed program.
• To leverage linkage evidence to enhance the identification of rare variants.

Main Methods:

• Genetic association analyses weighted by linkage evidence were performed.
• Whole genome sequencing data from 60,388 individuals across multiple TOPMed ancestral groups were utilized.
• Replication analysis was conducted using UK Biobank data.

Main Results:

• Low-frequency and rare variants in the RCN3 gene showed significant associations with blood pressure traits.
• These associations were observed in TOPMed samples and replicated in the UK Biobank.
• The association of RCN3 variants with diastolic blood pressure reached genome-wide significance (p = 2.01 × 10⁻⁷).

Conclusions:

• Low-frequency and rare variants in RCN3 contribute to blood pressure variation.
• Focusing association analyses within linkage regions improves the power to detect novel rare variants.
• This approach effectively reduces the multiple-testing burden in genetic studies of complex traits.