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UK Biobank Dataset Reveals More Than 100 Genetic Loci Linked to Blood Pressure

NEW YORK (GenomeWeb) – An international team of researchers has linked more than a hundred genetic loci to blood pressure in a new study.

Using the UK Biobank dataset, the team examined some 9.8 million SNVs in more than 140,000 people of European ancestry. As they reported in Nature Genetics today, the researchers validated 107 known and novel loci, including ones linked to blood pressure medication targets and ones expressed in blood vessels and cardiovascular tissue. The researchers also used their findings to develop a genetic risk score to predict stroke and heart disease risk.

"Finding 107 new genetic regions linked to blood pressure almost doubles the amount of genes we can evaluate to target for drug treatment," co­author Mark Caulfield from Queen Mary University of London said in a statement. "These exciting genetic regions could provide the basis for new innovative preventative therapies and lifestyle changes for this major cause of heart disease and stroke."

Caulfield and his colleagues conducted a genome-wide association study that drew on 140,886 people from the UK Biobank Cohort who had had their blood pressure — systolic, diastolic, and pulse pressure — measured twice clinically. At the same time, the researchers also examined exome data. Through this, they linked 240 loci to blood pressure: 218 from the GWAS and 22 from the exome-based analysis.

Of these, they validated 107 loci, 102 from the GWAS analysis and five from the exome analysis. Thirty-two of these loci were novel, the researchers noted.

Twenty-four of these validated loci were linked primarily to systolic blood pressure, 41 to diastolic, and 42 to pulse pressure, though some loci were linked to more than one blood pressure trait. For instance, NADK-CPSF3L, GTF2B, METTL21A-AC079767.3, and PAX2 were associated with all three traits.

Some of the signals the researchers picked up could be traced to known hypertension drug targets, such as the ACE locus, which is a target of ACE inhibitors, and PDE5A, which is a target of sildenafil. The researchers also noted that some of these loci have been linked to traits like myocardial infarction and coronary artery disease as well as to non-cardiovascular traits like Alzheimer's disease.

Caulfield and his colleagues annotated these 107 loci to 212 genes. An eQTL analysis found that about half the loci contained variants with eQTLs in at least one tissue, often arterial. Additional analyses found that these genes were enriched in the microvascular endothelium, aortic smooth muscle, vascular endothelium, and more, and that they were enriched in pathways linked to cardiovascular disease like α-adrenergic, CXCR4, endothelin signaling, and angiotensin receptor pathways.

Based on these loci, the researchers developed a genetic risk score. When they compared the lowest quintile of scores to the highest quintile, they noted a greater than two-fold increase in hypertension risk. In addition, a higher score was associated with an increased risk of stroke, coronary heart disease, and other cardiovascular disease.

"We cannot help our genetic makeup, but we can help our lifestyles and, in future, we may be able to alter our lifestyles while knowing whether we are at a genetic advantage or disadvantage," said author Paul Elliott from Imperial College London in a statement. "Doctors might eventually be able to determine a child's genetic risk of diseases such as high blood pressure, diabetes, and maybe even cancer, so that they can live well enough to try to counteract the genetic input."