Consensus Genome-Wide Expression Quantitative Trait Loci and Their Relationship with Human Complex Trait Disease

Yu, Chen-Hsin Albert; PalLipika, R; MoultJohn,

doi:10.1089/omi.2016.0063

Cited by 49 publications

(50 citation statements)

References 74 publications

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“…It may be that in some cases, lower levels of function change are sufficient to contribute to disease risk of particular proteins. In support of that, there is extensive evidence of association of disease risk with eQTL relationships (SNPs associated with a change in expression), where the loss of function is usually less than two fold [69]. In this study, we find a further 124 loci that have a candidate SNP with predicted low impact.…”

Section: Resultssupporting

confidence: 52%

“…Potential mechanisms involving SNPs that change gene expression are also common, with eQTL studies suggesting an average of up to one SNP affecting expression per gene [69]. Thus for the same reasons as with missense, we would not expect a significantly higher occurrence of eQTL mechanisms in disease loci than chance.…”

Section: Discussionmentioning

confidence: 98%

“…In that case, the random expectation was based on the number of SNPs on the microarray chip use in the GWA study. Most eQTL relationships involve SNPs very close (~85% within 200Kb) to genes [69], whereas the set on the microarray are much more broadly distributed. On that basis, the apparent eQTL enrichment may be an artifact of the choice of control set.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

Pal

Moult

2015

Journal of Molecular Biology

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Recent genome wide association studies have led to the reliable identification of SNPs at a number of loci associated with increased risk of specific common human diseases. Each such locus implicates multiple possible candidate SNPs for involvement in disease mechanism. A variety of mechanisms may link the presence of a SNP to altered in vivo gene product function and hence contribute to disease risk. Here we report an analysis of the role of one of these mechanisms, missense SNPs (msSNPs) in proteins in seven complex trait diseases. Linkage disequilibrium information was used to identify possible candidate msSNPs associated with increased disease risk at each of 356 loci for the seven diseases. Two computational methods were used to estimate which of these SNPs has a significant impact on in vivo protein function. 69% of the loci have at least one candidate msSNP and 33% have at least one predicted high impact msSNP. In some cases, these SNPs are in well-established disease related proteins, such as MST1 (macrophage stimulating 1) for Crohn’s disease, In others, they are in proteins identified by GWAS as likely candidates for disease relevance, but previously without known mechanism, such as ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) for Coronary Artery Disease. In still other cases, the missense SNPs are in proteins not previously suggested as disease candidates, such as TUBB1 (tubulin, beta 1, class VI) for Hypertension. Together, these data support a substantial role for this class of SNPs in susceptibility to common human disease.

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Section: Resultssupporting

confidence: 52%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

Pal

Moult

2015

Journal of Molecular Biology

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“…Both regulatory sites contain strong candidate progesterone-binding sequences 22 (Online Figure IVF), consistent with the observed progesterone receptor binding. The 15kb upstream region of PDK4 also contains three single nucleotide polymorphisms (SNPs) that act as expression quantitative trait loci (eQTLs) for PDK4 expression 23, 24 (Online Figure IVF). Strikingly, two of these three eQTLs are found within the two progesterone receptor-bound regions.…”

Section: Resultsmentioning

confidence: 99%

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Liu

Rowe

Yang

et al. 2017

Circulation Research

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Rationale Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. Objective To determine the mechanisms underlying cardiac substrate use during pregnancy. Methods and Results We use here 13C-glucose, 13C-lactate, and 13C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not appear altered. Insulin signaling appears intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 and GLUT4, are also unchanged. Rather, we find that the pregnancy hormone progesterone induces pyruvate dehydrogenase kinase (PDK)-4 in cardiomyocytes, and that elevated PDK4 levels in late pregnancy lead to inhibition of pyruvate dehydrogenase (PDH) and pyruvate flux into the TCA cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Conclusions Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.

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“…Additional studies on consensus genome-wide expression quantitative trait loci in relation to complex phenotypes might offer new promise in human genetics (Yu et al, 2016). While the GWASs of idiosyncratic DIH warrant further research attention in world populations, we suggest a discursive discovery paradigm whereby the findings from the GWASs fed into candidate gene studies to effectively follow-up on the emerging molecular leads from the GWAS research paradigm.…”

Section: Looking Ahead and Future Perspectivesmentioning

confidence: 94%

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

Petros

Makonnen

Aklillu

2017

OMICS: A Journal of Integrative Biology

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Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 b-galactosamide a-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

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Consensus Genome-Wide Expression Quantitative Trait Loci and Their Relationship with Human Complex Trait Disease

Cited by 49 publications

References 74 publications

Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

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