A Phenomics-Based Strategy Identifies Loci on APOC1, BRAP, and PLCG1 Associated with Metabolic Syndrome Phenotype Domains

Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS Genetics (Impact Factor: 7.53). 10/2011; 7(10):e1002322. DOI: 10.1371/journal.pgen.1002322
Source: PubMed


Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.

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    • "SNP rs2133189 was previously linked to coronary artery disease (CAD) susceptibility [54] and is strongly linked here to peripheral artery plaque expression levels of AIDA (P < 2.1E-20). Other peripheral plaque eQTLs for SNPs previously linked to CAD or myocardial infarction include BTN3A1 (rs6929846 eQTL P < 2.8E-07, myocardial infarction P < 3.5E-24 [55]), ZNF344 (rs4803750 eQTL P < 3.8E-05, atherogenic dyslipidemia P < 1.3E-33 [56]), NBEAL1 (rs6725887 eQTL P < 2.7E-06, CAD P < 1.1E-09 [57]), ENST00000318084 (rs10764881 eQTL P < 2.7E-05, CAD P < 1.4E-09 [58]). "
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    ABSTRACT: Background Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs. Results We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5′ or 3′ positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/]. Conclusions Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-532) contains supplementary material, which is available to authorized users.
    BMC Genomics 06/2014; 15(1):532. DOI:10.1186/1471-2164-15-532 · 3.99 Impact Factor
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    • "These lines of evidence suggest that BRAP can control different kinds of intracellular signals. Interestingly, recent genetic analyses have revealed that BRAP is associated with several human disorders caused by inflammatory dysfunction, including myocardial infarction, carotid atherosclerosis and central obesity [14]-[16]. "
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    ABSTRACT: Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P = 2.31E-6, OR = 0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P = 1.43E-6, OR = 0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P = 0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.
    PLoS ONE 01/2014; 9(1):e86037. DOI:10.1371/journal.pone.0086037 · 3.23 Impact Factor
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    • "In addition, genetic disruption of Brap2 in C. elegans impairs expression of p21 in response to oxidative stresses [9] and Brap2 acts as an anchor protein for p21 through direct interaction [10], suggesting that Brap2 can control different kinds of intracellular signals. Interestingly, recent genome-wide analyses have revealed that Brap2 is associated with several human disorders caused by inflammatory dysfunction, including myocardial infarction, carotid atherosclerosis and central obesity [11]–[13]. In addition, Brap2 expression is induced by inflammatory stimulation such as lipopolysaccharide (LPS) [12]. "
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    ABSTRACT: Nuclear factor-kappaB (NF-κB) is critical for the expression of multiple genes involved in inflammatory responses and cellular survival. NF-κB is normally sequestered in the cytoplasm through interaction with an inhibitor of NF-κB (IκB), but inflammatory stimulation induces proteasomal degradation of IκB, followed by NF-κB nuclear translocation. The degradation of IκB is mediated by a SCF (Skp1-Cullin1-F-box protein)-type ubiquitin ligase complex that is post-translationaly modified by a ubiquitin-like molecule Nedd8. In this study, we report that BRCA1-associated protein 2 (Brap2) is a novel Nedd8-binding protein that interacts with SCF complex, and is involved in NF-κB translocation following TNF-α stimulation. We also found a putative neddylation site in Brap2 associated with NF-κB activity. Our findings suggest that Brap2 is a novel modulator that associates with SCF complex and controls TNF-α-induced NF-κB nuclear translocation.
    PLoS ONE 03/2013; 8(3):e58911. DOI:10.1371/journal.pone.0058911 · 3.23 Impact Factor
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