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Large Genome-Wide Analysis Triples Known Number of Blood Pressure Risk Loci

NEW YORK (GenomeWeb) – Researchers uncovered 535 novel loci that influence blood pressure in people of European ancestry, nearly tripling the number of known risk loci.

High blood pressure is a major risk factor for both stroke and heart disease, and it has both environmental and genetic influences. Previously, 274 loci had been linked to blood pressure traits.

In a large study published today in Nature Genetics, an international team of researchers described drawing on data from more than one million people to tease out additional, novel loci linked to blood pressure traits like systolic blood pressure, diastolic blood pressure, and pulse pressure.

The researchers then traced these traits to more than 1,000 gene regions: Overall, they identified 535 novel loci and uncovered support in their data for all 274 previously known blood pressure loci. In addition, they validated a further 92 reported but not replicated loci, bringing the total number of blood pressure loci to 901. These loci also highlighted additional biological pathways involved in disease, which they said might help prevent cardiovascular disease. In a conditional analysis, they uncovered 163 secondary signals, 19 of which were SNPs in linkage disequilibrium with previously reported secondary signals. This, the researchers reported, pushed the total number of blood pressure signals to 1,064.

"We now know that there are over 1,000 genetic signals which influence our blood pressure," co-senior author Mark Caulfield from Queen Mary University of London said in a statement. "This provides us with many new insights into how our bodies regulate blood pressure, and has revealed several new opportunities for future drug development."

To find these signals, the researchers performed genome-wide association studies in two discovery cohorts: one that drew upon more than 500,000 individuals from the UK Biobank and one that relied on 300,000 individuals from 77 different studies. After a meta-analysis of those two discovery cohorts, which included individuals of European ancestry, the researchers performed both one- and two-stage analyses to home in on and validate hundreds of new blood pressure loci, using more than 200,000 additional individuals.

In a series of functional analyses, the researchers uncovered several ways in which these loci could influence blood pressure. For instance, they found that a number of these loci have roles in the TGFβ pathway, which is involved in sodium handling in the kidneys as well as in ventricular remodeling, and in the related SMAD pathway. Ingenuity pathway analysis likewise indicated an enrichment of these loci within pathways previously linked to cardiovascular disease, included ones that are targeted by antihypertensive drugs, like nitric oxide signaling. The analysis also suggested potential new targets, such as relaxin signaling.

The investigators also noted an enrichment of blood pressure loci in 50 different tissues and cells, particularly among the cardiovascular system and the heart, but also in adrenal tissue and adipose tissues.

They used these loci to develop a genetic risk score. Individuals from the UK Biobank dataset who fell in the top quintile of risk based on their score had a 10mmHg higher mean systolic blood pressure than bottom quintile. They noted that this score was further associated with increased risk of stroke, heart attack, and other cardiovascular outcomes.

"Knowing which genes cause high blood pressure may help us to spot the people who are at risk, before the damage is done," Jeremy Pearson, the associate medical director of the British Heart Foundation, said in a statement. "Those at risk can be treated — either with medication or lifestyle changes — potentially preventing thousands of heart attacks and strokes every year."

While this study focused on individuals of European ancestry, the researchers found that these SNPs and the genetic risk score they developed were also associated with blood pressure in individuals of African and South Asian ancestry from the UK Biobank dataset.