Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease

Koyama, Satoshi; Ito, Kei; Terao, Chikashi; Akiyama, Masato; Horikoshi, Momoko; Momozawa, Yukihide; Matsunaga, Hiroshi; Ieki, Hirotaka; Ozaki, Kouichi; Onouchi, Yoshihiro; Takahashi, Atsushi; Nomura, Seitaro; Morita, Hiroyuki; Akazawa, Hiroshi; Kim, Changhoon; Seo, Jeong Sun; Higasa, Koichiro; Iwasaki, Motoki; Yamaji, Taiki; Sawada, Norie; Tsugane, Shoichiro; Koyama, Teruhide; Ikezaki, Hiroaki; Takashima, Naoyuki; Tanaka, Keitaro; Arisawa, Kokichi; Kuriki, Kiyonori; Naito, Mariko; Wakai, Kenji; Suna, Shinichiro; Sakata, Yasuhiko; Sato, Hiroshi; Hori, Masatsugu; Sakata, Yasushi; Matsuda, Koichi; Murakami, Yoshinori; Aburatani, Hiroyuki; Kubo, Michiaki; Matsuda, Fumihiko; Kamatani, Yoichiro; Komuro, Issei

doi:10.1038/s41588-020-0705-3

Cited by 243 publications

(239 citation statements)

References 68 publications

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“…Similarly, the LD structure among human populations plays a key role in the functional implication of the variants identified by GWAS (38, 39). Indeed, it has been proposed that cross-ancestry meta-analyses can be a useful tool to fine map causal loci responsible for GWS loci (40-42). Our study demonstrates that both allele frequency and LD differences among human populations are significant contributors to the cross-ancestry heterogeneity across the human phenotypic spectrum.…”

Section: Discussionmentioning

confidence: 99%

Cross-Population Genetic Variation of Loci Identified by Genome-Wide Association Studies conducted in British participants of European-descent from the UK Biobank

Lillo

D’Antona

Pathak

et al. 2020

Preprint

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To provide novel insight regarding the inter-population diversity of loci associated with complex traits, we integrated genome-wide data from UK Biobank (UKB) and 1,000 Genomes Project (1KG) data representative of the genetic diversity among worldwide populations. We investigated genome-wide data of 4,359 traits from 361,194 UKB participants of European descent. Using 1KG data, we explored the allele frequency differences and linkage disequilibrium (LD) structure of UKB genome-wide significant (GWS) loci across worldwide populations. Functional annotation data were used to identify regulatory elements and evaluate the tagging properties of GWS variants. No significant difference was observed in allele frequency between UKB and 1KG GBR (British in England and Scotland). Considering other population groups, we identified genome-wide significant alleles with frequencies different from what expected by chance: UKB vs. 1KG Europeans without GBR (rs74945666; allele=T [0.908 vs. 0.03], standing height pGWAS=1.48x10-17), UKB vs. 1KG African (rs556562; allele=A [0.942 vs. 0.083], platelet count pGWAS=4.84x10-15), UKB vs. 1KG Admixed Americans (rs1812378; allele=T [0.931 vs. 0.089], standing height pGWAS=4.23x10-12), UKB vs. 1KG East Asian (rs55881864; allele=T [0.911 vs. 0.001], monocyte count pGWAS=7.29x10-13), and UKB vs. South Asian (rs74945666; allele=T [0.908 vs. 0.061], standing height pGWAS=1.48x10-17). LD-structure analysis and computational prediction showed differences in how these alleles tag functional elements across human populations. In conclusion, the human diversity of certain GWS loci appear to be affected by local adaptation while in other cases the associations may be biased by residual population stratification.

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Section: Discussionmentioning

confidence: 99%

Cross-Population Genetic Variation of Loci Identified by Genome-Wide Association Studies conducted in British participants of European-descent from the UK Biobank

Lillo

D’Antona

Pathak

et al. 2020

Preprint

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“…Large-scale population genetic studies provide an opportunity to improve our understanding of the inherited basis of complex traits. Twin studies report a heritability of 40-60% for fatal CAD 6,7 and genome-wide association studies (GWAS) to date have identified 208 susceptibility loci 8,9 . These loci explain a modest fraction (~15%) of this heritability, have largely been identified in European populations, and are exclusively autosomal 8,9 .…”

Section: Introductionmentioning

confidence: 99%

“…Twin studies report a heritability of 40-60% for fatal CAD 6,7 and genome-wide association studies (GWAS) to date have identified 208 susceptibility loci 8,9 . These loci explain a modest fraction (~15%) of this heritability, have largely been identified in European populations, and are exclusively autosomal 8,9 . Approximately one half of established loci appear to confer risk through effects on traditional risk factors [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

A large-scale multi-ethnic genome-wide association study of coronary artery disease

Assimes

Tcheandjieu

Zhu

et al. 2021

Preprint

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Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.

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“…But whether it can help us to understand the "common" heart failure (HF) encountered in our daily clinical practice is controversial. On the other hand, with the advent of genome-wide association studies (GWAS), >200 disease-susceptibility loci have been identified thus far in common cardiovascular diseases such as atrial fibrillation (AF) (2) and ischemic heart disease (IHD) (3), which are caused by the accumulation of weak-effect genetic polymorphisms that differ from monogenic diseases such as hereditary cardiomyopathies (Mendelian diseases). Although these advances in technology and methods are gradually revealing the genetic background of many cardiovascular diseases, not many studies have been able to approach the genetic background of "common" HF.…”

Section: Introductionmentioning

confidence: 99%

The Evolving Story in the Genetic Analysis for Heart Failure

Miyazawa

Ito

2021

Front. Cardiovasc. Med.

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Genomic studies of cardiovascular diseases have achieved great success, not only in Mendelian genetic diseases such as hereditary arrhythmias and cardiomyopathies, but also in common diseases such as ischemic heart disease and atrial fibrillation. However, only limited success has been achieved in heart failure due to the complexity of its disease background. In this paper, we will review the genetic research for heart failure to date and discuss how we can discover new aspects of heart failure from the viewpoint of genomic perspective.

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Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease

Cited by 243 publications

References 68 publications

Cross-Population Genetic Variation of Loci Identified by Genome-Wide Association Studies conducted in British participants of European-descent from the UK Biobank

Cross-Population Genetic Variation of Loci Identified by Genome-Wide Association Studies conducted in British participants of European-descent from the UK Biobank

A large-scale multi-ethnic genome-wide association study of coronary artery disease

The Evolving Story in the Genetic Analysis for Heart Failure

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