ABSTRACT
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
Subject(s)
DNA Methylation/genetics , DNA/metabolism , Gene Expression Regulation/genetics , Genetic Predisposition to Disease/genetics , Quantitative Trait Loci/genetics , Chromosome Mapping , Epigenesis, Genetic/genetics , Genome-Wide Association Study , Humans , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait, Heritable , Transcriptome/geneticsABSTRACT
BACKGROUND: PIWI-interacting RNAs (piRNAs), the largest class of noncoding RNAs in mammals, cooperate with PIWI proteins to safeguard the genome from insertional mutations during germline development. Although a growing number of studies have linked the PIWI-piRNA pathway to carcinogenesis, the role of piRNAs in glioma has not been explored. METHODS: Utilizing directly measured and imputed genotypes from the GliomaScan genome-wide association study (1,840 cases and 2,401 controls), genetic variants in 1,428 piRNAs were analyzed for association with glioma risk. In vitro assays were performed to interrogate the functional impact of a top identified piRNA and its variant allele. RESULTS: Variants in five piRNAs were considered to be associations of interest and four of these showed narrow clusters of enhanced association signals surrounding the index variant. Functional analyses of one of these piRNAs, piR-598, revealed that transfection of the wild-type piRNA impacted expression of genes involved in cell death/survival and reduced glioma cell viability and colony formation. However, upon delivery of piR-598 containing the variant allele at rs147061479 [OR, 1.80; 95% confidence interval (CI), 1.33-2.46; P = 1.69 × 10(-4)], cell proliferation was sharply increased. CONCLUSIONS: The genetic association analysis identifies several piRNAs associated with glioma risk, and follow-up functional analyses suggest that variant rs147061479 in piR-598 increases glioma risk by abolishing the tumor-suppressive function of piR-598, instead conferring growth-promoting properties. IMPACT: This transdisciplinary study demonstrates a role of piRNAs in gliomagenesis by evidence from both post-GWAS and in vitro functional analyses and supports expanded investigation into the link between the PIWI-piRNA pathway and cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1073-80. ©2016 AACR.
Subject(s)
Argonaute Proteins/genetics , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , Glioma/genetics , RNA, Small Interfering/genetics , Argonaute Proteins/metabolism , Biomarkers, Tumor/metabolism , Case-Control Studies , Cell Line, Tumor , Cohort Studies , Databases, Genetic , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Genetic Variation , Genome-Wide Association Study , Glioma/metabolism , Humans , RNA, Small Interfering/metabolism , Risk FactorsABSTRACT
Well defined hollow iron oxide nanoshells are active, selective and recyclable catalysts for the oxidation of styrene into benzaldehyde using difficult-to-activate molecular oxygen as the sole oxidant. Using no noble metals, unprecedented conversion of 90% was maintained while high selectivity of 73% was able to be achieved.