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Finnish Exomes Yield New Trait, Disease Associations Involving Rare, Deleterious Variants

NEW YORK – By sequencing individuals from parts of Finland with a history of population isolation, bottlenecks, and expansion, researchers from Washington University, the University of Michigan, the University of California, Los Angeles, and elsewhere were able to narrow in on rare variants associated with clinically relevant cardiovascular or metabolic traits.

"We demonstrated that a well-powered exome sequencing study of deeply phenotyped individuals can identify numerous rare variants that are associated with medically relevant quantitative traits," corresponding authors Nelson Freimer, a neurobehavioral genetics researcher at UCLA, and Michael Boehnke, a biostatistics and statistical genetics researcher at the University of Michigan, and their colleagues wrote in a study published online today in Nature.

Freimer, Boehnke, and their colleagues did exome sequencing on almost 20,000 individuals from northern and eastern Finland, delving into the rare coding variants found in protein-coding parts of the genome and their potential associations with up to 64 quantifiable cardiometabolic traits. After folding in sequence data for nearly 25,000 more Finns profiled for other studies, they identified 43 trait associations involving 26 deleterious variants, including 19 alleles that appeared to be dramatically overrepresented in, or distinct to, the Finnish population.

The latter alleles "cluster geographically like Finnish Disease Heritage mutations," the authors noted, "indicating that the distribution of trait-associated rare alleles may vary significantly between locations within a country."

That "Finnish Disease Heritage" refers to the higher-than-usual rates reported in Finland for three-dozen Mendelian diseases. The enhanced prevalence of such conditions is thought to reflect the population bottlenecks that occurred at early Finnish settlements in southern and western parts of the country some 2,000 to 4,000 years ago, followed by population movements to northern and eastern Finland and significant population growth.

Based on results from prior exome sequencing-based association studies, the authors reasoned that "the power to detect associations to deleterious alleles is highest in populations that have expanded in isolation after recent bottlenecks, as alleles passing through the bottlenecks may increase to much higher frequencies than in other populations."

As part of the Finnish Metabolic Sequencing (FinMetSeq) project, researchers captured and successfully sequenced protein-coding portions of the genome in 19,292 individuals from parts of the country where disease clusters have been documented, identifying more than 1.3 million SNPs and almost 93,000 small insertions or deletions in the exomes.

Their initial analysis suggested FinMetSeq participants were prone to carrying rare, predicted-deleterious variants, but had fewer singleton or doubleton variants in their exomes than non-Finnish control exomes in the gnomAD database.

When the team searched for ties between rare, deleterious FinMetSeq variants and 64 clinically relevant quantitative traits, it saw 19 previously unappreciated deleterious variant associations for 11 of the traits. Another 24 new associations involving 20 traits turned up when the group analyzed FinMetSeq exomes alongside directly genotyped and imputed variants across the genome in 24,776 more Finns.

In the THBS4 and DLK1 genes, for example, the researchers focused in on damaging missense variants that coincided with reduced weight and height, respectively. Additional predicted deleterious or damaging variants showed ties to blood cholesterol levels or other blood serum profiles, fatty acid metabolism, blood pressure, and other disease-related traits.

"Our results support recent suggestions of continuity between the genetic architectures of complex traits and disorders that are classically considered monogenic," the authors reported, pointing to the clusters of trait-associated deleterious variants detected in Finland.

Still other associations turned up in the researchers' general association analysis, which included more common variants, though the researchers emphasized the distinct genetic relationships that they could unearth by tapping into the enhanced rare variant repertoire in the Finnish populations.

"We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power," the authors wrote, noting that "variants that we identified provide a useful starting point for studies aimed at uncovering biological mechanisms and fostering clinical translation."

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