Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases

Kanai, Masahiro; Akiyama, Masato; Takahashi, Atsushi; Matoba, Nana; Momozawa, Yukihide; Ikeda, Masashi; Iwata, Nakao; Ikegawa, Shiro; Hirata, Makoto; Matsuda, Koichi; Kubo, Michiaki; Okada, Yukinori; Kamatani, Yoichiro

doi:10.1038/s41588-018-0047-6

Cited by 654 publications

(842 citation statements)

References 60 publications

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“…Altogether, these results strongly support the role of PLXDC2 in the regulation of F5 gene, and more generally in the coagulation cascade. Interestingly, the PLXDC2 rs927826 has recently been found associated with activated partial thromboplastin time in a Japanese population, but with no formal replication of the statistical findings or experimental validation . We did not observe such association in our population but did observe an association of rs927826 with prothrombin time (Table S4).…”

Section: Discussioncontrasting

confidence: 69%

“…Interestingly, the PLXDC2 rs927826 has recently been found associated with activated partial thromboplastin time in a Japanese population, but with no formal replication of the statistical findings or experimental validation. 18 We did not observe such association in our population but did observe an association of rs927826 with prothrombin time (Table S4). This polymorphism is in very strong LD (r 2 > .80) with other PLXDC2 SNPs (Table S5), all located in intronic regions subject to epigenetic regulation, 19 but only the rs927826 is so far predicted to affect transcription factors' binding.…”

Section: Discussionmentioning

confidence: 51%

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A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

Thibord

Hardy

Ibrahim‐Kosta

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process. Objective To detect novel genetic loci participating to the regulation of FV plasma levels. Methods We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals. Results In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10−15 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions. Conclusion Our study identified PLXDC2 as a new molecular player of the coagulation process.

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 51%

A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

Thibord

Hardy

Ibrahim‐Kosta

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Summary statistics from the GWAS meta-analyses for vascular risk factors and intermediate or related vascular phenotypes (BP, blood lipids, T2D, cIMT, cPL, AF, VTE, CAD, and WMH) were acquired from the respective consortia, as detailed in Supplementary Table 12. For LD-score regression in East Asians, we further received prepublication access to summary statistics of GWAS for blood lipids conducted in BioBank Japan 91 , as described in the Supplementary Note. For each trait, we filtered the summary statistics to the subset of HapMap 3 SNPs to decrease the potential for bias due to poor imputation quality.…”

Section: Methodsmentioning

confidence: 99%

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

2018

Self Cite

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Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

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“…In principle, we might imagine selecting a variant and counting how many phenotypes are associated with it. Indeed, several versions of this analysis have been performed for different lists of traits (8,2,3,9).…”

Section: Introductionmentioning

confidence: 99%

HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases

Jordan

Verbanck

2018

Preprint

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Understanding the nature and extent of horizontal pleiotropy, where one genetic variant has independent effects on multiple observable traits, is vitally important for our understanding of the genetic architecture of human phenotypes, as well as the design of genome-wide association studies (GWASs) and Mendelian randomization (MR) studies. Many recent studies have pointed to the existence of horizontal pleiotropy among human phenotypes, but the exact extent remains unknown, largely due to difficulty in disentangling the inherently correlated nature of observable traits. Here, we present a statistical framework to isolate and quantify horizontal pleiotropy in human genetic variation using a two-component pleiotropy score computed from summary statistic data derived from published GWASs. This score uses a statistical whitening procedure to remove correlations between observable traits and normalize effect sizes across all traits, and is able to detect horizontal pleiotropy under a range of different models in our simulations. When applied to real human phenotype data using association statistics for 1,564 traits measured in 337,119 individuals from the UK Biobank, our score detects a significant excess of horizontal pleiotropy. This signal of horizontal pleiotropy is pervasive throughout the human genome and across a wide range of phenotypes and biological functions, but is especially prominent in regions of high linkage disequilibrium and among phenotypes known to be highly polygenic and heterogeneous. Using our pleiotropy score, we identify thousands of loci with extreme levels of horizontal pleiotropy, a majority of which have never been previously reported in any published GWAS. This highlights an under-recognized class of genetic variation that has weak effects on many distinct phenotypes but no specific marked effect on any one phenotype. We show that a large fraction of these loci replicate using independent datasets of GWAS summary statistics. Our results highlight the central role horizontal pleiotropy plays in the genetic architecture of human phenotypes, and the importance of modeling horizontal pleiotropy in genomic medicine.

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Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases

Cited by 654 publications

References 60 publications

A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases

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