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Coronary Artery Disease Loci Identified in Japanese GWAS, Trans-Ancestry Meta-Analysis

NEW YORK – A team of researchers from Japan has uncovered ancestry-specific risk factors for coronary artery disease (CAD) with a genome-wide association study that included more than 168,200 Japanese individuals with or without the complex, highly heritable heart condition.

"[O]ur large-scale analysis allowed us to gain an insight into the genetic architecture of CAD in the Japanese population and discover 43 previously unreported loci associated with CAD susceptibility," co-senior and -corresponding authors Issei Komuro, a researcher at the University of Tokyo, and Yoichiro Kamatani, a researcher affiliated with RIKEN, Kyoto University, and the University of Tokyo, and their colleagues wrote.

In a paper published in Nature Genetics on Monday, the team relied on haplotype clues gleaned from whole-genome sequence data for nearly 1,800 individuals with CAD and 2,636 without CAD from the BioBank Japan effort, as well as data from large international efforts such as the 1000 Genomes Project, to impute additional variants in the array-genotyped GWAS participants.

In the 25,892 CAD cases and 142,336 unaffected controls included in that GWAS, they identified common variants at eight risk loci not linked to CAD in the past, along with rare CAD-related variants that appear to impact disease severity in this population. The latter set included rare changes in genes already implicated in familial hypercholesterolemia, for example, which were overrepresented in individuals who developed serious conditions such as acute coronary syndrome.

From there, the team brought in data for additional CAD cases and controls from other populations for a "trans-ancestry meta-analysis" that encompassed more than 649,000 cases and controls. That approach provided a more extensive look at CAD risk, uncovering 175 loci with genome-wide significant ties to CAD — a set that included almost three dozen formerly unappreciated risk loci.

With the CAD-associated variants identified in the Japanese population and beyond, the researchers were able to fine-map the risk loci, while going on to develop a polygenic risk score (PRS) that showed promise for predicting CAD disease features.

"The allelic effects of these lead variants showed almost the same directionality between our Japanese GWAS and previously reported European GWAS," they reported. "This shared allelic effect enabled us to derive a CAD-PRS from a trans-ancestry meta-analysis for the Japanese population, which outperformed those derived from either Japanese or European GWAS results."

While past genetic studies have highlighted more than 160 loci that appear to be linked to CAD, the team explained, many of the known risk factors have been gleaned from association studies centered on individuals with European ancestry. In contrast, the latest findings support the notion that there is more to be learned about the genetics of disease risk and the severity of CAD cases that do develop by including cases and controls from as many populations as possible.

All told, the authors suggested, findings from the CAD-focused GWAS and meta-analysis

"improve the clinical characterization of CAD genetics, and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations."