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Finnish Cardiometabolic Study Uncovers Strong Effect of Structural Variants

NEW YORK – Using genetic data for thousands of individuals from the Finnish population, an international team has tracked down more than a dozen loci linked to cardiometabolic traits, including two previously unappreciated structural variant (SV) sites that appear to have particularly strong ties to specific traits.

"Both SVs are ultra-rare in non-Finnish Europeans but present at elevated allele frequency in Finns — presumably due to historical population bottlenecks and expansions — which mirrors the findings from our recent study of coding variation, where many cardiometabolic trait-associated variants were enriched in Finns," co-senior author Ira Hall, a researcher affiliated with the Washington University School of Medicine McDonnell Genome Institute, the WashU department of medicine, and Yale University department of genetics, and his colleagues wrote.

As they reported in the American Journal of Human Genetics on Tuesday, the researchers considered whole-genome sequence (WGS) data for thousands of phenotyped Finns. Starting from a set of nearly 129,200 known SVs in genome sequences from 4,848 Finnish individuals, they searched for ties between 116 quantitatively measured cardiometabolic traits in relation to 64,572 relatively common or low-frequency SVs in 4,030 participants, uncovering suspicious variants that were subsequently investigated with exome sequence or genotyping data for 15,200 more individuals.

From a set of 15 loci with genome-wide significant associations to the traits examined, they narrowed in on nine cardiometabolic trait-related loci that corresponded to related phenotypes in their follow-up analyses, while validating associations at half a dozen cardiometabolic-associated sites in the genome.

"Our study leverages sensitive SV detection methods, extensive cardiometabolic quantitative trait measurements, and the unique population history of Finland," the authors explained. "Despite the relatively modest sample size and limited power of this study, we identified nine novel … and six known trait-associated loci."

The cardiometabolic trait-associated set included an ALB gene promoter deletion that corresponded to lower-than-usual levels of serum albumin, enhanced total cholesterol levels, and several other measurable cholesterol-related traits, the team reported, noting that the deletion appeared to be more common in Finnish individuals than in Europeans genotyped from outside of Finland for the 1000 Genomes Project.

The ALB promoter deletion "was 16-fold enriched in the Finnish population compared to non-Finnish Europeans from 1KG and was associated with 16 traits at genome-wide significance," the authors wrote.

The investigators also highlighted pyruvate- and alanine level-associated copy number variants in and around the PDPR gene in a "structurally complex genomic region that has accumulated many rearrangements over evolutionary time."

Within the set of cardiometabolic trait-associated sites reported in the past, meanwhile, the team pointed to a recurrent HP gene deletion with apparent ties to both blood cholesterol levels and to enhanced glycoprotein levels.

"Taken together, these results highlight the potential role of rare, large-effect SVs in the genetics of cardiometabolic traits," the authors reported, "and suggest that future comprehensive and well-powered WGS-based studies have the potential to contribute greatly to our understanding of common disease genetics."