In QED, an external electromagnetic field can be accounted for non-perturbatively by replacing the causal propagators used in Feynman diagram calculations with Green’s functions for the Dirac ...equation under the external field. If the external field destabilises the vacuum, then it is a difficult problem to determine which Green’s function is appropriate, and multiple approaches have been developed in the literature whose equivalence, in many cases, is not clear. In this paper, we demonstrate for a broad class of external fields that includes all that act for a finite time, that four Green’s functions used in the literature are equivalent: Schwinger’s “proper-time” propagator; the “causal propagator” used in the “Bogoliubov transformation” method based on the canonical quantization of the field operator; and two defined using analytic continuation from complexified parameters. To do so, we formulate Schwinger’s “proper-time quantum mechanics" as a Schrödinger wave mechanics, and use this to re-derive Schwinger’s expression for the propagator as a statement relating solutions of the inhomogeneous Dirac equation to those of the inhomogeneous “proper-time Dirac equation”. This is done by constructing direct integral spectral decompositions of the Hamiltonians of both equations, and deriving a form for solutions of the inhomogeneous Dirac equation in terms of these decompositions. We then show that all four propagators return solutions of the inhomogeneous Dirac equation that satisfy the same boundary condition, which under a physically reasonable assumption is sufficient to specify the solution uniquely.
Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide
. Both IOP and POAG are highly ...heritable
. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)
that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported
. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.
Long non-coding RNAs (lncRNAs) play crucial roles in human physiology, and have been found to be associated with various cancers. Transcribed ultraconserved regions (T-UCRs) are a subgroup of lncRNAs ...conserved in several species, and are often located in cancer-related regions. Breast cancer is the most common cancer in women worldwide and the leading cause of female cancer deaths. We investigated the association of genetic variants in lncRNA and T-UCR regions with breast cancer risk to uncover candidate loci for further analysis. Our focus was on low-penetrance variants that can be discovered in a large dataset. We selected 565 regions of lncRNAs and T-UCRs that are expressed in breast or breast cancer tissue, or show expression correlation to major breast cancer associated genes. We studied the association of single nucleotide polymorphisms (SNPs) in these regions with breast cancer risk in the 122970 case samples and 105974 controls of the Breast Cancer Association Consortium's genome-wide data, and also by
functional analyses using Integrated Expression Quantitative trait and
prediction of GWAS targets (INQUISIT) and expression quantitative trait loci (eQTL) analysis. The eQTL analysis was carried out using the METABRIC dataset and analyses from GTEx and ncRNA eQTL databases. We found putative breast cancer risk variants (
< 1 × 10
) targeting the lncRNA
in INQUISIT and eQTL analysis. In addition, putative breast cancer risk associated SNPs (
< 1 × 10
) in the region of two T-UCRs, uc.184 and uc.313, located in protein coding genes
and
, respectively, targeted these genes in INQUISIT and in eQTL analysis. Other non-coding regions containing SNPs with the defined p-value and highly significant false discovery rate (FDR) for breast cancer risk association were discovered that may warrant further studies. These results suggest candidate lncRNA loci for further research on breast cancer risk and the molecular mechanisms.
Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in non-coding regions and likely modulate cancer ...risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS.
Here, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants.
We demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.
Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal ...regulatory DNA elements that control gene expression.
We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region.
Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.
Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known ...variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear.
We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer-associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared.
Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 × 10(-16)). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 × 10(-6)). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio OR= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk.
Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored.
Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. ...However, the contribution of non-coding RNAs to complex traits is not clear.
Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants.
We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.
About the Authors: Georgia Chenevix-Trench Roles Conceptualization, Writing – original draft * E-mail: georgiaT@qimr.edu.au Affiliation: Queensland Institute of Medical Research Berghofer, Herston, ...Queensland, Australia ORCID logo http://orcid.org/0000-0002-1878-2587 Jonathan Beesley Roles Writing – review & editing Affiliation: Queensland Institute of Medical Research Berghofer, Herston, Queensland, Australia Paul D. P. Pharoah Roles Writing – original draft Affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom Andrew Berchuck Roles Writing – review & editing Affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, United States of America Citation: Chenevix-Trench G, Beesley J, Pharoah PDP, Berchuck A (2018) The importance of using public data to validate reported associations.The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7).In an analysis by the Ovarian Cancer Association Consortium (OCAC) 2, in over 25,000 ovarian cancer cases and 40,000 controls, no significant association was found for overall ovarian cancer risk (P = 0.24) or for any histological subtypes examined (P = 0.20 for high-grade serous ovarian cancer).
The TERT-CLPTM1L region of chromosome 5p15.33 is a multi-cancer susceptibility locus that encodes the reverse transcriptase subunit, hTERT, of the telomerase enzyme. Numerous cancer-associated ...single-nucleotide polymorphisms (SNPs), including rs10069690, have been identified within the hTERT gene. The minor allele (A) at rs10069690 creates an additional splice donor site in intron 4 of hTERT, and is associated with an elevated risk of multiple cancers including breast and ovarian carcinomas. We previously demonstrated that the presence of this allele resulted in co-production of full length (FL)-hTERT and an alternatively spliced, INS1b, transcript. INS1b does not encode the reverse transcriptase domain required for telomerase enzyme activity, but we show here that INS1b protein retains its ability to bind to the telomerase RNA subunit, hTR. We also show that INS1b expression results in decreased telomerase activity, telomere shortening, and an increased telomere-specific DNA damage response (DDR). We employed antisense oligonucleotides to manipulate endogenous transcript expression in favor of INS1b, which resulted in a decrease in telomerase activity. These data provide the first detailed mechanistic insights into a cancer risk-associated SNP in the hTERT locus, which causes cell type-specific expression of INS1b transcript from the presence of an additional alternative splice site created in intron 4 by the risk allele. We predict that INS1b expression levels cause subtle inadequacies in telomerase-mediated telomere maintenance, resulting in an increased risk of genetic instability and therefore of tumorigenesis.
The multi-cancer susceptibility locus at 5p15.33 includes
, encoding the telomerase catalytic subunit. Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms ...(SNPs) in the
promoter associated with decreased breast cancer risk, although the precise causal variants and their mechanisms of action have remained elusive. Luciferase reporter assays indicated that the protective haplotype reduced
promoter activity in human mammary epithelial and cancer cells in an estrogen-independent manner. Using single variant constructs, we identified rs3215401 and rs2853669 as likely functional variants. Silencing of MYC decreased
promoter activity but neither MYC nor ETS2 silencing conferred allele-specificity. In chromatin immunoprecipitation experiments, the ETS protein GABPA, but not ETS2 or ELF1, bound rs2853669 in an allele-specific manner in mammary epithelial cells. Investigation of open chromatin in mammoplasty samples suggested involvement of three additional variants, though not rs3215401 or rs2853669. Chromosome conformation capture revealed no interaction of the
promoter with regulatory elements in the locus, indicating limited local impact of candidate variants on the
promoter. Collectively, our functional studies of the
-
breast cancer susceptibility locus describe rs2853669 as a functional variant of this association signal among three other potentially causal variants and demonstrate the versatile mechanisms by which
promoter variants may affect breast cancer risk.
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