TY - JOUR
T1 - Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation
AU - Kamali, Zoha
AU - Keaton, Jacob M.
AU - Javanmard, Shaghayegh Haghjooy
AU - Edwards, Todd L.
AU - Snieder, Harold
AU - Vaez, Ahmad
AU - International Consortium of Blood Pressure
AU - Million Veteran Program
AU - eQTLGen Consortium
AU - BIOS consortium
AU - Boomsma, Dorret
AU - de Geus, Eco J.C.
AU - Hottenga, Jouke Jan
AU - Willemsen, Gonneke
AU - van Dongen, Jenny
AU - Pool, René
AU - Jansen, Rick
AU - Penninx, Brenda WJH
N1 - Funding Information: Funding: This research was funded by Isfahan University of Medical Sciences, Isfahan, Iran, grant No. 397259. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Recent genome-wide association studies uncovered part of blood pressure’s heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressureassociated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.
AB - Recent genome-wide association studies uncovered part of blood pressure’s heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressureassociated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.
KW - blood pressure
KW - epigenome
KW - functional enrichment
KW - gene expression
KW - genome
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U2 - https://doi.org/10.3390/ijms23147557
DO - https://doi.org/10.3390/ijms23147557
M3 - Article
C2 - 35886906
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 14
M1 - 7557
ER -