Project description:Suicidal behavior (SB) has a complex etiology of genes, environment or both. One of the genetic components in SB could be copy number variations (CNVs), since CNVs are implicated in a range of neurodevelopmental disorders. However, a recently published genome-wide and case-control study failed to observe a significant role of CNVs in SB (see E-MTAB-3519). Here we complement those initial observations by conducting a brief CNV-association study, for the first time in a family-based trio-sample with severe suicide attempt (SA) outcome in offspring (n=660 trios; the \GISS\ sample, see http://www.ncbi.nlm.nih.gov/pubmed/23422793 and refs therein). For association testing, we here used the FBAT-CNV methodology (http://www.ncbi.nlm.nih.gov/pubmed/18228561), which allows for CNV association testing directly on the raw intensity values (Illumina \log R ratio\), evaluating any type of CNVs (e.g. de novo or inherited) without reliance on CNV calling algorithms and robust to control selection biases. Here we have deposited these raw logR-values for 88,450 on-chip CNV-loci of the HumanOmni1-Quad_v1 chip, arranged in a standard pedigree format used as input for FBAT-CNV analysis in SVS software (goldenhelix.com): column 1 is the family ID, column 2 is the Subject type (1 = offspring, 2 = mother, 3 = father), column 3 is the father ID (? for missing), column 4 is the mother ID (? for missing), column 5 is the sex (1 = female, 0 = male), column 6 is the affection status (1 = suicide attempt, 0 = not affected) and columns 7 and onward are the logR-values for each CNV-loci as is listed in the header row. We observed experiment-wide significant association (P ≤ 5.6 x 10-7) of two proximal CNVs at chromosome 14 (Illumina markers cnvi0108946 and cnvi0118308, with NCBI 36.3 start positions 22794779 and 22582820). However, these CNV-associations mapped to T-cell receptor regions, and therefore most likely reflect inter-individual variation in somatic rearrangements occurring in white blood cells (as our source of DNA was blood), rather than association with SA. In conclusion, our results did not suggest any major role of CNVs in SA etiology, in line with the results of the recent case-control study (see E-MTAB-3519).

Project description:Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitor, decitabine (5-aza-2'-deoxycitidine), is proving efficacious for hematological neoplasms especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response seen in patients. Transient exposure of leukemic and solid tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity or apoptosis, produces sustained reduced tumorigenicity, and for leukemia cells, diminished long-term self-renewal. These effects appear triggered by cellular reprogramming and include sustained decreases in promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, most of which are high priority targets for pharmacologic anti-cancer strategies. Thus, low dose decitabine regimens appear to have broad applicability for cancer management. [Gene expression profiling] Leukemia cell lines Kasumi-1 and KG1A are treated with 10nM DAC during 72 hours and gene expression was assayed at day 3, 7 and 14 after the start of the treatment. Appropriate mock treated samples were used as control in each case. In addition, Kasumi-1 cells were also treated with a higher dose of DAC (500nM), 100nM ARA-C and 300 nM TSA, again controlled against mock treated Kasumi-1 cells, to separate dose and agent dependent effects. MCF7 was studied as an example of a solid tumor cell line. Therefore MCF7 cells were treated with 100nM DAC and results were assayed at day 1, day 3 and day 10. [Methylation profiling] The effects of the demethylating agent DAC were studied in the leukemia cell line Kasumi-1 over a 28 day time course. Intermediate time points were studied at days 3, 7, 14 and 21. These results were verfied in KG1A and KG1 leukemia cell lines, at one selected time point. The effects on one primary sample were also studied. Four normal leukemia samples (PL1, 2, 4 and 5) were used as general controls. The effect of DAC was compared to ARA-C, TSA. Both mock treated and day 3 DAC treated Kasumi-1 cells were repeated. These results were verified at one selected time point for the DAC treated MCF7 breast cancer cell line.

Dataset Information

DAC for the family-based genome-wide association study on CRSwNP

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets