Unknown,Transcriptomics,Genomics,Proteomics

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A Genome-Wide Copy Number Variant Study of Suicidal Behavior

ABSTRACT: Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.

INSTRUMENT(S): Illumina Omni1-Quad Beadchip

ORGANISM(S): Homo sapiens

SUBMITTER: Gustavo Turecki

PROVIDER: E-MTAB-3519 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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:Genetic variation is responsible for the generation of phenotypic diversity, including susceptibility to disease. Two major types of variation are known: single nucleotide polymorphisms (SNPs) and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. Variation caused by CNVs has exceeded the amount of SNP-based differences expected to exist between two unrelated humans. Furthermore, many CNVs have been associated with disease predisposition. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. Here we show that CNVs are frequent in healthy somatic cells of adult humans. We tested 34 tissue samples from three subjects and, having analyzed for each tissue <10-6 of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82-176 kb, often encompassing known genes, potentially affecting gene function. Our results point to a paradigm shift in the genetics of somatic cells and indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. A considerable number of phenotypes and diseases affecting humans are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues in order to better address mosaicism in the studies of somatic disorders. Furthermore, forensic medicine laboratories should be sensitized to the issue of underestimated frequency of somatic CNV mosaicism. Keywords: copy number variation (CNV), phenotype diversity, somatic cells 31 experiments; each experiment consists of two hybridizations, i.e. regular and dye-swap (62 hybridizations in total); cerebellum from corresponding subject was used as a reference; additionally 12 control self-self hybridizations are included (cerrebellum vs self)

Project description:Terminalia arjuna (Roxb.) Wight & Arn., a well known Traditional medicine an. popularly known as Arjuna, has a long antiquity of its role as a cardiac stimulant, and has been stipulated in the treatment of hypercholesterolemia, heart failure and atherosclerosis. The present study was carried out to access the effects of Terminalia arjuna as an adjuvant therapy in angiographically proven patients with stable coronary artery disease who were on conventional medications. The goal of the study was to establish whether Terminalia arjuna exerts beneficial effects in targetting disease signatures which remain unresponsive to the standard therapies currently employed in the clinics. The present study scientifically validates the therapeutic effects of this medicinal plant as an adjuvant therapy along with conventional drugs routinely used in the clinics for prevention and treatment of coronary artery disease. To access the effect of T.arjuna, a placebo-controlled, double blind randomized study was carried out in 100 angiographically proven non-diabetic patients with coronary artery disease having disease more than 3 months prior to their enrollment and using any combination of cardiac-related medications including ASA, ACEIs, ARBs, β-blockers and statins (Trial Registration Number : REF/2013/03/004810). Out of total 100 patients, 50 patients were on drug A and 50 patients were on drug B for a total duration of 6 months (Follow-up at 3 and 6 months). Both Drug as well as placebo was given in the form of capsule (500mg) provided by The Himalaya Drug Company, Bangalore. Method of concealment was through coded identical containers. All the participants, investigator, outcome Assessor and data-entry operator were blinded during the whole study. Micro-array was performed in 2 randomly selected patients in each sub-group i.e. Terminalia arjuna or Placebo at 3 and 6 months respectively. RNA extraction and hybridization was carried out using Affymetrix microarrays. Differential expression of genes in T.arjuna-treated and Placebo groups was studied to understand the specificity, efficacy and mechanism of action of T.arjuna.

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A Genome-Wide Copy Number Variant Study of Suicidal Behavior

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