We investigated the involvement of rare (<1%) copy number variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip® 500K Mapping Array. ...Large CNVs >1 Mb were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0–15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the combined significance level for all three studies achieving P = 5 × 10−5. One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.
A shift has occurred in interventional cardiology from transfemoral to transradial access due to a 70%-80% decrease in complications. This shift has not yet taken place in other interventional ...specialties, perhaps owing to the lack of generalizability of findings in the cardiology data.
Our aim was to assess data from the recent mechanical thrombectomy prospective trials to better understand the access-site complication rate.
Articles were systematically sourced from the National Center for Biotechnology Information PubMed archive.
According to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, prospective, randomized controlled trials published after 2008 with mention of major and/or minor femoral access-site complications in neuroendovascular mechanical thrombectomies were included.
Major and minor femoral access-site complications were extracted. A total complication rate was calculated with major access-site complications alone and combined with minor access-site complications.
Seven prospective studies of 339 total screened met the inclusion criteria. Eleven major access-site complications were identified in of 660 total interventions, revealing a major access-site complication rate of 1.67% for patients undergoing mechanical thrombectomy with transfemoral access. If minor access-site complications were included, 35 total incidents were detected in 763 interventions, resulting in a total complication rate of 4.59%.
Multiple unspecified vessel and procedure-related complications were mentioned in the studies.
The overall rate of major access-site complications was 1.67% in this review, which is not low and poses a risk to patients. We suggest further investigation into the feasibility and complication rates of alternative access sites for neurointerventional procedures.
The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement ...component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models.
Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples.
We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected).
These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4's developmental role.
Genomic microarrays in the spotlight Mantripragada, Kiran K; Buckley, Patrick G; Diaz de Ståhl, Teresita ...
Trends in genetics,
02/2004, Letnik:
20, Številka:
2
Journal Article
Recenzirano
Microarray-based comparative genomic hybridization (array-CGH) has emerged as a revolutionary platform, enabling the high-resolution detection of DNA copy number aberrations. In this article we ...outline the use and limitations of genomic clones, cDNA clones and PCR products as targets for genomic microarray construction. Furthermore, the applications and future aspects of these arrays for DNA copy number analysis in research and diagnostics, epigenetic profiling and gene annotation are discussed. These recent developments of genomic microarrays mark only the beginning of a new generation of high-resolution and high-throughput tools for genetic analysis.
Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that predisposes to benign and malignant tumors. The lifetime
risk of a malignant peripheral nerve sheath tumor (MPNST) in ...NF1 is ∼10%. These tumors have a poor survival rate and their
molecular basis remains unclear. We report the first comprehensive investigation of DNA copy number across multitude of genes
in NF1 tumors using high-resolution array comparative genomic hybridization (CGH), with the aim to identify molecular signatures
that delineate malignant from benign NF1 tumors.
Experimental Design: We constructed an exon-level resolution microarray encompassing 57 selected genes and profiled DNA from 35 MPNSTs, 16 plexiform,
and 8 dermal neurofibromas. Bioinformatic analysis was done on array CGH data to identify concurrent aberrations in malignant
tumors.
Results: The array CGH profiles of MPNSTs and neurofibromas were markedly different. A number of MPNST-specific alterations were identified,
including amplifications of ITGB4, PDGFRA, MET, TP73 , and HGF plus deletions in NF1, HMMR/RHAMM, MMP13, L1CAM2, p16INK4A/CDKN2A , and TP53 . Copy number changes of HMMR/RHAMM, MMP13, p16INK4A/CDKN2A , and ITGB4 were observed in 46%, 43%, 39%, and 32%, respectively of the malignant tumors, implicating these genes in MPNST pathogenesis.
Concomitant amplifications of HGF, MET , and PDGFRA genes were also revealed in MPNSTs, suggesting the putative role of p70S6K pathway in NF1 tumor progression.
Conclusions: This study highlights the potential of array CGH in identifying novel diagnostic markers for MPNSTs.
The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this ...risk variant affects reward responsiveness because reward processing is one of the central cognitive-motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders.
Previous studies suggest that a single nucleotide polymorphism in the catechol‐O‐methyltransferase (COMT) gene (val158met) may modulate reward‐guided decision making in healthy individuals. The ...polymorphism affects dopamine catabolism and thus modulates prefrontal dopamine levels, which may lead to variation in individual responses to risk and reward. We previously showed, using tasks that index reward responsiveness (measured by responses bias towards reinforced stimuli) and risk taking (measured by the Balloon Analogue Risk Task), that COMT met homozygotes had increased reward responsiveness and, thus, an increased propensity to seek reward. In this study, we sought to replicate these effects in a larger, independent cohort of Caucasian UK university students and staff with similar demographic characteristics (n = 101; 54 females, mean age: 22.2 years). Similarly to our previous study, we observed a significant trial × COMT genotype interaction (P = 0.047; η2 = 0.052), which was driven by a significant effect of COMT on the incremental acquisition of response bias response bias at block 3 − block 1 (met/met > val/val: P = 0.028) and block 3 − block 2 (met/met > val/val: P = 0.007), suggesting that COMT met homozygotes demonstrated higher levels of reward responsiveness by the end of the task. However, we failed to see main effects of COMT genotype on overall response bias or risk‐seeking behaviour. These results provide additional evidence that prefrontal dopaminergic variation may have a role in reward responsiveness, but not risk‐seeking behaviour. Our findings may have implications for neuropsychiatric disorders characterized by clinical deficits in reward processing such as anhedonia.
Bar plots represent mean ± SEM. COMT val158met genotype differences in propensity for change in response bias (change in response bias: block 3 criterion − block 1 criterion). COMT met homozygotes show a significant adjustment in response bias from (a) block 1 to block 3 of the trial compared to val/val genotype group and from (b) block 2 to block 3 of the trial compared to both val/met and val/val genotype groups (*P < 0.05, **P < 0.01). Smaller values for criterion represent an increase in response bias.
Correction to: Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97 The ninth author’s name was presented incorrectly. It should have been listed as LF Jarskog.
Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to ...regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10
) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.
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