Genetic Architecture of N-Terminal Pro-B-Type Natriuretic Peptide in a Multiancestry Study Population

Authors

• Naman S Shetty
• Akhil Pampana
• Mokshad Gaonkar
• Amrita Nayak
• Harshvir S Bal
• Nirav Patel
• Nehal Vekariya
• J Gustav Smith
• Alanna C Morrison
• Bing Yu
• Bruce M Psaty
• Eric Boerwinkle
• James S Floyd
• Jerome I Rotter
• Kent D Taylor
• Leslie A Lange
• Marguerite R Irvin
• Mary Cushman
• Stephen S Rich
• Ramachandran S Vasan
• Thomas J Wang
• Xiuqing Guo
• Peng Li
• Garima Arora
• Pankaj Arora

Language

English

Publication Date

2-1-2026

Journal

Circulation: Genomic and Precision Medicine

DOI

\10.1161/CIRCGEN.124.005130

PMID

41603044

PMCID

PMC13321388

PubMedCentral® Posted Date

7-2-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: NPs (natriuretic peptides) are bioactive hormones crucial for regulating blood pressure, glucose homeostasis, and lipid metabolism. Despite the high heritability of circulating NP levels, the genetic determinants of NP regulation, particularly across ancestries and sexes, remain poorly understood. The objective of the current study was to identify genetic variants associated with NT-proBNP (N-terminal pro-B-type NP) levels in a multiancestry study population.

Methods: Whole genome sequencing and array-based data from 81 213 individuals without heart failure were analyzed from the Trans-Omics for Precision Medicine cohorts, UK Biobank, All of Us Research Program, and REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to identify common, rare, and structural variants associated with NT-proBNP levels. The main outcome of the study was rank-based inverse normal and standardized NT-proBNP levels. Genetic associations with NT-proBNP were examined, followed by gene prioritization, transcriptome-wide association studies, colocalization, and rare variant analyses.

Results: Nine novel loci and 3 previously reported loci were identified to be associated with NT-proBNP levels. Novel structural variants were detected across 12 loci. Similar effect sizes were observed for both common and rare variants. Key genes such as BAG3 (10q26.11) and SLC39A8 (4q24) were identified through gene prioritization, with prior animal models supporting their therapeutic relevance. Rare variant analysis identified 6 masks with significant associations, specifically non-coding masks, suggesting regulatory modulation of NT-proBNP.

Conclusions: This study identifies novel common, rare, and structural variants associated with NT-proBNP levels, highlighting the contribution of both coding and regulatory non-coding variation. These findings advance our understanding of the genetic architecture of NT-proBNP and may inform future cardiometabolic therapeutic strategies.

Keywords

Humans, Natriuretic Peptide, Brain, Female, Male, Peptide Fragments, Genome-Wide Association Study, Aged, Middle Aged, Polymorphism, Single Nucleotide, N-terminal pro-B-type natriuretic peptide, Multiancestry, rare variants, structural variants, common variants

Published Open-Access

yes

Recommended Citation

Shetty, Naman S; Pampana, Akhil; Gaonkar, Mokshad; et al., "Genetic Architecture of N-Terminal Pro-B-Type Natriuretic Peptide in a Multiancestry Study Population" (2026). Faculty, Staff and Student Publications. 1482.
https://digitalcommons.library.tmc.edu/uthsph_docs/1482