Genetics Unit

San Giovanni al Natisone, Italy

Genetics Unit

San Giovanni al Natisone, Italy
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Bonvicini C.,Genetics Unit | Faraone S.V.,SUNY Upstate Medical University | Scassellati C.,Genetics Unit
World Journal of Biological Psychiatry | Year: 2017

Objectives: Elucidating the biological mechanisms involved in attention-deficit/hyperactivity disorder (ADHD) has been challenging. Relatively unexplored is the fact that these mechanisms can differ with age. Methods: We present an overview on the major differences between children and adults with ADHD, describing several studies from genomics to metabolomics performed in ADHD children and in adults (cADHD and aADHD, respectively). A systematic search (up until February 2016) was conducted. Results: From a PRISMA flow-chart, a total of 350 and 91 genomics and metabolomics studies were found to be elligible for cADHD and aADHD, respectively. For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4 and MAOA) and neurodevelopmental (LPHN3 and DIRAS2) systems and OPRM1 (Yates corrected P = 0.016; OR = 2.27 95%CI: 1.15–4.47). Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4 and SPOCK3; Yates corrected P = 0.007; OR = 3.30 95%CI: 1.33–8.29). In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS and OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin. Conclusions: Through a convergent functional genomics, this review contributes to clarification of which genetic/biological mechanisms differ with age. The effects of some genes do not change throughout the lifetime, whereas others are linked to age-specific stages. Additional research and further studies are needed to generate firmer conclusions that might someday be useful for predicting the remission and persistence of the disorder. Despite the limitations, some of these genes/proteins could be potential useful biomarkers to discriminate cADHD from aADHD. © 2017 Informa UK Limited, trading as Taylor & Francis Group

Beretta S.,University of Milan Bicocca | Maj C.,Genetics Unit | Merelli I.,CNR Institute of Biomedical Technologies
Procedia Computer Science | Year: 2017

MicroRNAs (miRNAs) are small non-coding RNA molecules that have an important role in a wide range of biological processes, since they interact with specific mRNAs affecting the expression of the corresponding proteins. The role of miRNA can be deeply influenced by Single Nucleotide Polymorphisms (SNPs), in particular in their seed sites, since these variations may modify their affinity with particular transcripts, but they may also generate novel binding capabilities for specific miRNA binding sites or destroy them. Several computational tools for miRNA-target site predictions have been developed, but the obtained results are often not in agreement, making the study the binding sites hard, and the analysis of SNP effects even harder. For these reasons, we developed a web application called Rank miRNA, which allows to retrieve and aggregate the results of three prediction tools, but also to process and compare new input miRNA sequences, allowing the analysis of how variations impact on their function. Therefore, our tool is also able to predict the impact of SNPs (and any other kind of variations) on miRNA-mRNA binding capability and also to find the target genes of (potentially new) miRNA sequences. We evaluated the performance of Rank miRNA on specific human SNPs, which are likely to be involved in several mental disorder diseases, showing the potentiality of our tool in helping the study of miRNA-target interactions. © 2017 The Authors. Published by Elsevier B.V.

Anacker C.,King's College London | Anacker C.,National Health Research Institute | Cattaneo A.,University of Brescia | Luoni A.,University of Milan | And 14 more authors.
Neuropsychopharmacology | Year: 2013

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus. © 2013 American College of Neuropsychopharmacology. All rights reserved.

Anacker C.,King's College London | Anacker C.,National Health Research Institute | Zunszain P.A.,King's College London | Cattaneo A.,King's College London | And 7 more authors.
Molecular Psychiatry | Year: 2011

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (16%) and mature, microtubulin- associated protein-2 (MAP2)-positive neurons (26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27 Kip1 and p57 Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans. © 2011 Macmillan Publishers Limited All rights reserved.

Lindhurst M.J.,U.S. National Institutes of Health | Parker V.E.R.,University of Cambridge | Payne F.,Wellcome Trust Sanger Institute | Sapp J.C.,U.S. National Institutes of Health | And 27 more authors.
Nature Genetics | Year: 2012

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110Î ± catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP 3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target. © 2012 Nature America, Inc. All rights reserved.

Maina G.,University of Turin | Rosso G.,University of Turin | Zanardini R.,Neuropsychopharmacology Unit | Bogetto F.,University of Turin | And 3 more authors.
Journal of Affective Disorders | Year: 2010

Background: There is lack of data regarding BDNF serum levels in patients with obsessive-compulsive disorder (OCD). The aims of the present study were: 1) to assess the serum BDNF content in a sample of drug-naïve patients with OCD and 2) to assess whether putative alterations in peripheral BDNF may be associated to OCD severity and clinical characteristics. Methods: Twenty-four drug-naïve patients with a principal diagnosis of OCD were recruited. In parallel, a control group of 24 unrelated volunteers matched for gender and age was enrolled. Serum BDNF levels were measured by ELISA method. Results: The results showed that BDNF levels were decreased in OCD patients when compared to controls (36.90 ± 6.42 ng/ml versus 41.59 ± 7.82 ng/ml; p = 0.043). No correlations were evidenced between serum BDNF content and the severity of OCD symptoms measured as Y-BOCS scores or other clinical variables. Limitations: The choice of drug-naïve patients with obsessive-compulsive disorder had limited the size of the sample and excluded the recruitment of patients with a severe symptomatology. Conclusions: Our findings reveal for the first time in OCD patients a decrease in serum BDNF levels. These data corroborate the hypothesis of a dysfunction in the neurotrophin expression in the OCD pathogenetic mechanism and provide the rationale for further investigations directed to the identification of novel biomarkers and new therapeutic strategies for antiobsessional treatments. © 2009 Elsevier B.V. All rights reserved.

Crea F.,Cancer Research Center | Sun L.,Frederick National Laboratory for Cancer Research | Pikor L.,Genetics Unit | Frumento P.,Karolinska Institutet | And 3 more authors.
British Journal of Cancer | Year: 2013

Background:Polycomb group genes (PcGs) are epigenetic effectors implicated in most cancer hallmarks. The mutational status of all PcGs has never been systematically assessed in solid tumours.Methods:We conducted a multi-step analysis on publically available databases and patient samples to identify somatic aberrations of PcGs.Results:Data from more than 1000 cancer patients show for the first time that the PcG member PHC3 is amplified in three epithelial neoplasms (rate: 8-35%). This aberration predicts poorer prognosis in lung and uterine carcinomas (P<0.01). Gene amplification correlates with mRNA overexpression (P<0.01), suggesting a functional role of this aberration.Conclusion:PHC3 amplification may emerge as a biomarker and potential therapeutic target in a relevant fraction of epithelial tumours. © 2013 Cancer Research UK.

Bonvicini C.,Genetics Unit | Faraone S.V.,SUNY Upstate Medical University | Faraone S.V.,University of Bergen | Scassellati C.,Genetics Unit
Molecular Psychiatry | Year: 2016

The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD. © 2016 Macmillan Publishers Limited.

Cattaneo A.,University of Brescia | Cattaneo A.,Genetics Unit | Sesta A.,University of Brescia | Sesta A.,Genetics Unit | And 5 more authors.
Neuropsychopharmacology | Year: 2010

Major depression is a disease characterized by an inability of neuronal systems to show appropriate adaptive plasticity especially under challenging conditions, such as stress. Conversely, pharmacological intervention may normalize such defects through the modulation of factors that might act in concert for the functional recovery of depressed patients, like the neuropeptide VGF, which has previously shown to possess antidepressant like activity. We analyzed VGF mRNA levels in the brain of rodents exposed to stress or treated with antidepressant drugs. In addition, we assessed VGF expression in leukocytes obtained from 25 drug-free depressed patients before and during antidepressant treatment. We found a persistent reduction of VGF expression after exposure to prenatal stress and an upregulation of its levels following chronic treatment with different antidepressant drugs. Moreover, VGF mRNA levels were significantly reduced in drug-free depressed patients, as compared with controls, and were modulated in response to effective antidepressant treatment. Our data provide further support to the role of VGF in mood disorders and suggest that VGF could be a more specific biomarker for treatment responsiveness. © 2010 Nature Publishing Group All rights reserved.

Cattaneo A.,Genetics Unit | Bocchio-Chiavetto L.,Neuropsychopharmacology Unit | Zanardini R.,Neuropsychopharmacology Unit | Milanesi E.,Genetics Unit | And 4 more authors.
International Journal of Neuropsychopharmacology | Year: 2010

Consistent data coming from biochemical studies have evidenced a brain-derived neurotrophic factor (BDNF) serum reduction in depressed patients compared to controls and a restoration following antidepressant treatment. However, to date, no study has evaluated whether BDNF synthesis in leukocytes could contribute to such modulation. Therefore, in this study, we analysed BDNF mRNA levels in leukocytes from 21 depressed patients prior to and during escitalopram treatment and from 23 control subjects showing that BDNF mRNA levels were decreased in drug-free depressed patients and that 12 wk escitalopram treatment was able to reverse this deficit. Interestingly, changes in BDNF mRNA levels paralleled BDNF serum increase during antidepressant treatment, and were correlated with symptoms improvement. Our results indicate that BDNF serum modulation observed in depressed patients is associated with BDNF synthesis alteration in leukocytes and suggest that these peripheral cells might play an active role in the mechanisms of action of antidepressants. Copyright © 2009 CINP.

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