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Large-Scale Japanese GWAS Uncovers Two Novel Loci Associated With Lung Cancer, Heart Disease

NEW YORK – To improve their understanding of disease biology in an East Asian population, researchers have conducted a genome-wide association study (GWAS) of more than 200,000 Japanese individuals across 42 diseases.

Reporting in Nature Genetics on Monday, researchers from Riken Center for Integrative Medical Sciences, University of Tokyo, the Broad Institute of MIT and Harvard, and elsewhere found 25 novel loci, and were able to identify and replicate two East Asian-specific missense variants associated with coronary artery disease and lung cancer.

"We sought to understand how the genetic basis of these diseases are similar or different to other non-Japanese populations," said Broad Institute's Soumya Raychaudhuri, co-corresponding author on the study.

Tapping into the BioBank Japan Project, the researchers analyzed 212,453 individuals across 42 diseases, with 32,793 being population-based controls.

Disease categories included 12 neoplastic diseases, five cardiovascular diseases, four allergic diseases, three infectious diseases, two autoimmune diseases, one metabolic disease, and 14 uncategorized diseases. The researchers found 320 independent signals in 276 loci for 27 diseases, winnowing this down to 25 novel loci.

"In addition to the novel loci, our data sheds light on many loci that are shared between Japanese and non-Japanese populations," said Raychaudhuri.

Three of the 25 novel loci were identified as East Asian-specific missense variants, which were not previously known in Japanese or non-Japanese populations. These three novel loci were associated with coronary artery disease (CAD), lung cancer, and keloid.

Of the three loci, two missense variants were successfully replicated: p.R220W of ATG16L2 (associated with CAD) and p.V326Aof POT1 (associated with lung cancer). Researchers carried out this replication study by analyzing two independent cohorts for CAD and lung cancer in the Japanese population. In these two groups, researchers looked for potential causal genes for CAD and lung cancer by analyzing 2,855 coronary artery disease cases alongside 15,211 controls and 2,440 lung cancer cases with 467 controls.

The researchers concluded that ATG16L2 may be a causal variant for CAD, since previous GWAS did not detect this locus in European populations. POT1 was found to be more strongly associated with lung cancer in females than males and also linked to the risk of five other neoplastic diseases.

To verify the novelty of these three disease-associated variants, along with those already known, the researchers observed allele frequencies between the East Asian and European populations of the 1000 Genomes Project Phase 3 (1KG Phase3). Approximately 8 million autosomal variants and about 200,000 X chromosome variants associated with the 42 diseases were tested in 1KG Phase3. The Japanese cohort demonstrated higher allele frequencies of novel and disease-associated variants compared to European populations. The observation of this test "highlights the importance of performing GWAS in non-European populations," according to the authors.

The study also revealed that important transcriptional programs underlying disease biology can be identified with genetic data. Using stratified linkage disequilibrium score regression (S-LDSC), researchers also estimated and investigated the enrichment of heritability within 2,868 annotations of 410 genome-wide transcription factors. They identified 378 significant enrichments across nine diseases, such as NKX3-1 for prostate cancer.

The researchers' next steps are to identify more genes responsible for multi-faceted, human diseases on a global scale.

"We are hoping to continue work to understand the genetic basis of complex human diseases in populations around the world to determine which genes are acting in concert in multiple populations, and which genes have unique population-specific mechanisms," said Raychaudhuri.

Kazuyoshi Ishigaki, lead author of the study who is affiliated with Riken and Broad Institute, added that distinguishing more of these shared genes between different populations will advance more of these type studies.

"Since we confirmed that many genetic signals are shared between populations, we believe combining genetic signals across multiple populations is a reasonable next step," Ishigaki said, "Such a strategy will increase the power of detecting genetic signals and will discover more novel findings."