68 research outputs found
Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci
Background: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. Results: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. Discussion: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.Peer reviewe
The dynamics of vortex generation in superfluid 3He-B
A profound change occurs in the stability of quantized vortices in externally
applied flow of superfluid 3He-B at temperatures ~ 0.6 Tc, owing to the rapidly
decreasing damping in vortex motion with decreasing temperature. At low damping
an evolving vortex may become unstable and generate a new independent vortex
loop. This single-vortex instability is the generic precursor to turbulence. We
investigate the instability with non-invasive NMR measurements on a rotating
cylindrical sample in the intermediate temperature regime (0.3 - 0.6) Tc. From
comparisons with numerical calculations we interpret that the instability
occurs at the container wall, when the vortex end moves along the wall in
applied flow.Comment: revised & extended version. Journal of Low Temperature Physics,
accepted (2008
Alterations of the retinoblastoma gene in metastatic breast cancer
Germline mutations affecting the retinoblastoma gene (RB1) predispose to inherited retinoblastomas but also other malignancies, including breast cancer. While somatic RB1 mutations have been detected in different malignancies, information about the potential role of RB1 mutations in breast cancer is limited. Recently, we discovered RB1 mutations to be associated with resistance to anthracyclines/mitomycin in primary breast cancer. The present work is the first report evaluating RB1 mutation and epigenetic status in metastatic breast cancer. Among 148 breast cancer samples analyzed by MLPA, four samples harbored intragenic deletions/duplications: Thus, exons 1–2 were deleted in two tumors and exons 21–23 in one tumor, while one sample harbored duplication of exons 18–23. The entire RB1 gene was duplicated in two tumors and multiple amplifications were revealed in one sample. Reduced copy number was observed in 17 samples (11.5%). No point mutation or promoter hypermethylation was discovered (n = 38 and 114 tumors analyzed, respectively). Interestingly, among seven tumors expressing lack of response to epirubicin, two samples harbored alterations in RB1, contrasting none out of 16 tumors with stable disease or an objective response (P = 0.08). In summary, the frequency of RB1 alterations in metastatic lesions was not increased when compared to primary breast cancer, indicating that RB1 alterations do not play a major role in metastatic development. While a non-significant association suggesting RB1 alterations to be linked to therapy resistance was observed, our data do not suggest a major role for RB1 alterations explaining acquired drug resistance
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The Role of KRAS rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing
Purpose
An assay for the single nucleotide polymorphism (SNP) rs61764370 has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′UTR miRNA binding site of the KRAS oncogene, and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published paper, analyzing fewer than 1,000 subjects in total, has examined this association.
Experimental Design
Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from nineteen studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival data and eighteen studies with all-cause mortality data.
Results
No evidence of association was observed between genotype and risk of unselected EOC (odds ratio (OR)=1.02, 95% confidence interval (CI)=0.95–1.10), serous EOC (OR=1.08, 95%CI=0.98–1.18), familial EOC (OR=1.09, 95%CI=0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR=1.09, 95%CI=0.88–1.36). There was little evidence for association with survival time among unselected cases (hazard ratio (HR)=1.10, 95%CI=0.99–1.22), among serous cases (HR=1.12, 95%CI=0.99–1.28), or with progression-free survival in 540 cases treated with carboplatin and paclitaxel (HR=1.18, 95%CI=0.93–1.52).
Conclusions
These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction therefore appears unwarranted
Second primary malignancies and excess mortality after retinoblastoma
Leeuwen, F.E. van [Promotor]Ringens, P.J. [Promotor]Moll, A.C. [Copromotor]Imhof, S.M. [Copromotor
Sources of Inequality at Birth: The Interplay Between Genes and Parental Socioeconomic Status
IVF and retinoblastoma revisited
Item does not contain fulltextOBJECTIVE: To evaluate the suggested association between IVF, retinoblastoma, and tumor methylation characteristics. DESIGN: Laboratory analysis. SETTING: National Retinoblastoma Center in the Netherlands. PATIENT(S): Retinoblastoma tumors from seven children conceived by IVF or intracytoplasmic sperm injection (ICSI). INTERVENTION(S) AND MAIN OUTCOME MEASURE(S): DNA from frozen retinoblastoma tumors was tested for mutations in the RB1 gene and for methylation status of the RB1 promoter. RESULT(S): For all tumors two causative RB1 mutations were found. None of the tumors showed hypermethylation of the RB1 promoter. CONCLUSION(S): Examination of retinoblastoma tumors of seven children conceived by IVF or ICSI did not show hypermethylation of the RB1 promoter. This demonstrates that an association between IVF or ICSI and retinoblastoma through this epigenetic mechanism is unlikely.1 januari 201
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