Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

van Duijvenboden, Stefan ; Ramírez, Julia (Universidad de Zaragoza) ; Young, William J. ; Olczak, Kaya J. ; Ahmed, Farah ; Alhammadi, Mohammed J.A.Y. ; Bell, Christopher G. ; Morris, Andrew P. ; Munroe, Patricia B.

Resumen: Genome-wide association studies of blood pressure (BP) have identified >1,000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, and DBH) and previously unreported BP candidate genes (NRIP1 and MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, gene expression and tissue abundance data, and literature review, we provide consolidated evidence for 436 BP candidate genes for future functional validation and discover several potential drug targets.

Idioma: Inglés

DOI: 10.1016/j.ajhg.2023.08.009

Año: 2023

Publicado en: AMERICAN JOURNAL OF HUMAN GENETICS 110, 10 (2023), 1718-1734
ISSN: 0002-9297

Factor impacto JCR: 8.1 (2023)

Categ. JCR: GENETICS & HEREDITY rank: 12 / 191 = 0.063 (2023) - Q1 - T1

Factor impacto CITESCORE: 14.7 - Genetics (clinical) (Q1) - Genetics (Q1)

Factor impacto SCIMAGO: 4.516 - Genetics (clinical) (Q1) - Genetics (Q1)

Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2021-128972OA-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/RYC2021-031413-I

Tipo y forma: Artículo (PostPrint)

Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)