Systematic characterization of regulatory variants of blood pressure genes

Winona Oliveros; Kate Delfosse; Daniella F Lato; Katerina Kiriakopulos; Milad Mokhtaridoost; Abdelrahman Said; Brandon J McMurray; Jared W L Browning; Kaia Mattioli; Guoliang Meng; James Ellis; Seema Mital; Marta Melé; Philipp G Maass

doi:10.1016/j.xgen.2023.100330

Systematic characterization of regulatory variants of blood pressure genes

Cell Genom. 2023 May 24;3(7):100330. doi: 10.1016/j.xgen.2023.100330. eCollection 2023 Jul 12.

Authors

Winona Oliveros¹, Kate Delfosse², Daniella F Lato², Katerina Kiriakopulos^{2

3}, Milad Mokhtaridoost², Abdelrahman Said², Brandon J McMurray², Jared W L Browning^{2

3}, Kaia Mattioli⁴, Guoliang Meng⁵, James Ellis^{5

3}, Seema Mital^{2

6

7}, Marta Melé¹, Philipp G Maass^{2

3}

Affiliations

¹ Life Sciences Department, Barcelona Supercomputing Center, 08034 Barcelona, Catalonia, Spain.
² Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁴ Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁶ Ted Rogers Centre for Heart Research, Toronto, ON M5G 1X8, Canada.
⁷ Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 0A4, Canada.

Abstract

High blood pressure (BP) is the major risk factor for cardiovascular disease. Genome-wide association studies have identified genetic variants for BP, but functional insights into causality and related molecular mechanisms lag behind. We functionally characterize 4,608 genetic variants in linkage with 135 BP loci in vascular smooth muscle cells and cardiomyocytes by massively parallel reporter assays. High densities of regulatory variants at BP loci (i.e., ULK4, MAP4, CFDP1, PDE5A) indicate that multiple variants drive genetic association. Regulatory variants are enriched in repeats, alter cardiovascular-related transcription factor motifs, and spatially converge with genes controlling specific cardiovascular pathways. Using heuristic scoring, we define likely causal variants, and CRISPR prime editing finally determines causal variants for KCNK9, SFXN2, and PCGF6, which are candidates for developing high BP. Our systems-level approach provides a catalog of functionally relevant variants and their genomic architecture in two trait-relevant cell lines for a better understanding of BP gene regulation.

Keywords: CRISPR prime editing; MPRA; blood pressure gene regulation; chromosome conformation capturing Hi-C Omni-C; genetic variant; genomic architecture; genomic marker; hypertension; massively parallel reporter assay; molecular precision medicine; regulatory variant.