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Multi-Ancestry GWAS Uncovers a Dozen New Loci Linked to Blood Pressure

NEW YORK (GenomeWeb) – In Nature Genetics, an international team described a dozen new loci influencing blood pressure patterns across individuals from multiple populations — a set that overlaps with variants implicated in epigenetic features of blood and other tissues.

Through a multi-stage genome-wide association study that relied on genotyping information for as many as 320,251 individuals of East Asian, South Asian, and European descent, the researchers focused in on SNPs at 12 blood pressure-associated sites in the genome, including loci previously linked to cardiac or metabolic functions.

In particular, the team saw blood pressure-linked variants in and around genes contributing to vascular smooth muscle and renal function. And a large proportion of the associated SNPs — or variants in linkage disequilibrium with them — turned up at sites already implicated in control of DNA methylation.

"We note an effect of genome-wide-associated sentinel SNPs on DNA methylation for traits in addition to blood pressure, suggesting that DNA methylation might have a wider role in linking common genetic variation to multiple phenotypes," the study's authors wrote.

More than a billion people around the world are affected by high blood pressure, the team explained, a condition that elevates the risk of heart disease, heart attack, stroke, and chronic kidney disease.

Because it occurs at especially high rates in East Asian and South Asian populations, the investigators reasoned that it might be possible to find both ancestry-specific and trans-ancestral genetic associations with high blood pressure.

The team started by analyzing imputed and directly genotyped SNPs in 31,516 individuals of East Asian ancestry, 35,352 individuals with European ancestry, and 33,126 individuals of South Asian descent, searching for variants associated with systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, and hypertension.

Through analyses on each population individually and in a meta-analysis of individuals from all three populations, the researchers initially identified 630 loci with suspected ties to at least one of the five blood pressure traits considered.

They then compared the top SNP at each site against data on as many as 87,205 individuals tested for various blood pressure traits for the International Consortium on Blood Pressure GWAS, narrowing in on 19 loci with potential ties to blood pressure that were not described in the past.

The team confirmed blood pressure associations for SNPs at 12 of the new loci through testing on another 48,268 East Asians, 68,456 Europeans, and 16,328 South Asians.

The analysis also verified almost two-dozen loci linked to blood pressure in the past and pointed to 17 sites in the genome with weaker ties to the traits of interest.

Variants at the 12 new loci seemed to have similar effects on the five traits in question, regardless of the population considered, while variants that first appeared to show population-specific effects in East Asians and Europeans did not pan out in replication testing.

By folding in linkage disequilibrium patterns for SNPs at the new blood pressure-associated sites, the researchers got a look at genes that fall near these linked SNPs — a collection that includes genes such as PDE3A, KCNK3, and PRDM6.

They also used these linkage patterns to look for overlap with DNA methylation-related SNPs, demonstrating that 28 of 35 SNPs at these loci seem to be linked to altered DNA methylation levels and related expression shifts in samples from thousands of Europeans or East Asians.

And the team saw similar effects in hundreds of cord blood samples subjected to methylation profiling, suggesting the effect is not simply a consequence of high blood pressure itself.

"The presence of these associations at an early stage of life, before substantial environmental exposure, lends support to the view that the sequence variants have a direct effect on DNA methylation and argues against reverse causation," the study authors wrote.