Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease

Abstract

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD. Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans. Results: We identified 3 new loci on chromosome 1q21 ( CTSS ), 10q26 ( WDR11-FGFR2 ), and 11q22 ( RDX - FDX1 ). Quantitative trait locus analyses suggested the association of CTSS and RDX - FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans. Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

“…[17][18][19] The PheWAS of ABO variants identified associations with increased risk of deep vein thrombosis, pulmonary embolism, and other circulatory disorders, in line with prior studies, and recent studies among patients hospitalized with COVID-19. [20][21][22][23][24] Autoimmune conditions shared genetic variants with severe COVID-19, the direction of effect was for a reduced odd of these conditions. Based on existing data, we believe known protein-.…”

Integration of Multiple-Omics Data to Analyze the Population-Specific Differences for Coronary Artery Disease

“…Sex and ancestry were the potential causes of CAD differences [ 18 , 43 – 45 ]. However, previous studies were limited to small sample sizes, which made it difficult to overcome the defects of heterogeneity.…”

“…European ancestry GWAS was obtained from a meta-analysis of 14 GWAS of CAD comprising 22,233 cases and 64,762 controls by the CARDIoGRAMplusC4D Consortium [ 6 ]. East Asian ancestry GWAS was obtained from the GWAS Catalog which included 2,808 cases and 7,261 controls [ 18 , 19 ]. Both of them were each made up of a single population.…”

“…A deeper understanding of the genetic structure of other ethnic groups will lead to the development of drugs for population-specific targets and the precise treatment of patients. Previous studies have used the polygenic risk score (PRS) to assess the differences in clinical risk factors for CAD between Japanese and European populations and found several novel loci [ 17 , 18 ]. However, European ancestry GWAS from the CARDIoGRAMplusC4D 1000 Genomes meta-analysis of previous studies contains some Asian, Hispanic, and African ancestry, which may confuse population-specific loci [ 8 , 18 ].…”

A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

“…Furthermore, HGMA1 and C6orf106 have been reported to show a genetic association with body fat ratios in Caucasians ( Rask-Andersen et al, 2019 ), and both GRM4 and CUX2 were associated with the γ-GT-catalyzed reaction in excessive alcohol consumption ( Chen et al, 2020 ). Additionally, the CUX2 gene has been investigated in genome association studies related to serum uric acid levels, coronary artery disease, and hypertension ( Cho et al, 2020 ; German et al, 2020 ; Matsunaga et al, 2020 ). However, to the best of our knowledge, the association with anthropometric trait (especially the WHR) GWAS signals has never been reported previously.…”