Publications by authors named "Pierandrea Muglia"

89 Publications

Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach.

Brain Commun 2020 2;2(2):fcaa183. Epub 2020 Nov 2.

Epilepsy Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain.

Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10-15% transient GABA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo  = 26; padsevonil  = 24). Their median age was 36 years (range 18-60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14;  = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted  = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.
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http://dx.doi.org/10.1093/braincomms/fcaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677606PMC
November 2020

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Nat Commun 2020 10 1;11(1):4932. Epub 2020 Oct 1.

Oasi Research Institute-IRCCS, Troina, Italy.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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http://dx.doi.org/10.1038/s41467-020-18723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681PMC
October 2020

Use of a physiologically based pharmacokinetic-pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial.

Br J Clin Pharmacol 2021 03 6;87(3):1378-1389. Epub 2020 Sep 6.

UCB Biopharma SPRL, Braine l'Alleud, Belgium.

Aims: To build and verify a physiologically based pharmacokinetic (PBPK) model for radiprodil in adults and link this to a pharmacodynamic (PD) receptor occupancy (RO) model derived from in vitro data. Adapt this model to the paediatric population and predict starting and escalating doses in infants based on RO. Use the model to guide individualized dosing in a clinical trial in 2- to 14-month-old children with infantile spasms.

Methods: A PBPK model for radiprodil was developed to investigate the systemic exposure of the drug after oral administration in fasted and fed adults; this was then linked to RO via a PD model. The model was then expanded to include developmental physiology and ontogeny to predict escalating doses in infants that would result in a specific RO of 20, 40 and 60% based on average unbound concentration following a twice daily (b.i.d.) dosing regimen. Dose progression in the clinical trial was based on observed concentration-time data against PBPK predictions.

Results: For paediatric predictions, the elimination of radiprodil, based on experimental evidence, had no ontogeny. Predicted b.i.d. doses ranged from 0.04 mg/kg for 20% RO, 0.1 mg/kg for 40% RO to 0.21 mg/kg for 60% RO. For all infants recruited in the study, observed concentration-time data following the 0.04 mg/kg and subsequent doses were within the PBPK model predicted 5 and 95 percentiles.

Conclusion: To our knowledge, this is the first time a PBPK model linked to RO has been used to guide dose selection and escalation in the live phase of a paediatric clinical trial.
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http://dx.doi.org/10.1111/bcp.14528DOI Listing
March 2021

Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder.

Transl Psychiatry 2020 04 14;10(1):106. Epub 2020 Apr 14.

Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento (TN), Italy.

Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD.
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http://dx.doi.org/10.1038/s41398-020-0778-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156413PMC
April 2020

Radiprodil, a NR2B negative allosteric modulator, from bench to bedside in infantile spasm syndrome.

Ann Clin Transl Neurol 2020 03 27;7(3):343-352. Epub 2020 Feb 27.

UCB Pharma, Braine-L'Alleud, Belgium.

Objective: Infantile spasm syndrome (ISS) is an epileptic encephalopathy without established treatment after the failure to standard of care based on steroids and vigabatrin. Converging lines of evidence indicating a role of NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor on the onset of spams in ISS patients, prompted us to test radiprodil, a negative allosteric NR2B modulator in preclinical seizure models and in infants with ISS.

Methods: Radiprodil has been tested in three models, including pentylenetetrazole-induced seizures in rats across different postnatal (PN) ages. Three infants with ISS have been included in a phase 1b escalating repeated dose study.

Results: Radiprodil showed the largest protective seizure effects in juvenile rats (maximum at PN12, corresponding to late infancy in humans). Three infants resistant to a combination of vigabatrin and prednisolone received individually titrated doses of radiprodil for up to 34 days. Radiprodil was safe and well tolerated in all three infants, and showed the expected pharmacokinetic profile. One infant became spasm-free and two showed clinical improvement without reaching spasm-freedom. After radiprodil withdrawal, the one infant continued to be spasm-free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other antiepileptic drugs.

Interpretation: Radiprodil showed prominent anti-seizure effect in juvenile animals, consistent with the prevalent expression of NR2B subunit of the NMDA receptor at this age in both rodents and humans. The clinical testing, although preliminary, showed that radiprodil is associated with a good safety and pharmacokinetic profile, and with the potential to control epileptic spasms.
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http://dx.doi.org/10.1002/acn3.50998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085998PMC
March 2020

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants.

Alzheimers Dement (N Y) 2019 20;5:814-824. Epub 2019 Nov 20.

Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, UK.

Introduction: The role of 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).

Methods: We dissected genetic profiles within the region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls.

Results: -L/-ε4 alleles were associated with DLB (OR  = 3.61; value = 3.23 × 10; OR  = 3.75; value = 4.90 × 10) and earlier age at onset of DLB (HR  = 1.33, value = .031; HR  = 1.46, value = .004), but not with PDD. The -L/-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR  = 4.40, value = 1.15 × 10; OR  = 5.65, value = 2.97 × 10) but was not significant in DLB without AD. Meta-analyses combining all -ε4 data in DLB confirmed our findings (OR = 2.93, value = 3.78 × 10; OR = 5.36, value = 1.56 × 10).

Discussion: -ε4/ -L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.
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http://dx.doi.org/10.1016/j.trci.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880091PMC
November 2019

Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions.

Drugs 2019 Dec;79(18):1917-1935

UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK.

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.
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http://dx.doi.org/10.1007/s40265-019-01223-9DOI Listing
December 2019

A single-center, open-label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers.

Epilepsia 2019 05 29;60(5):958-967. Epub 2019 Mar 29.

Department of Radiology and Biomedical Imaging, Positron Emission Tomography Center, Yale University, New Haven, Connecticut.

Objective: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer C-UCB-J (EP0074; NCT02602860).

Methods: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC ) were determined from calculated SO.

Results: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC of BRV (0.46 μg/mL) was 8.7-fold lower than of LEV (4.02 μg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough).

Significance: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.
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http://dx.doi.org/10.1111/epi.14701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532410PMC
May 2019

The Italian autism network (ITAN): a resource for molecular genetics and biomarker investigations.

BMC Psychiatry 2018 11 21;18(1):369. Epub 2018 Nov 21.

Centre for Integrative Biology, University of Trento, Trento, Italy.

Background: A substantial genetic component accounts for Autism Spectrum Disorders (ASD) aetiology, with some rare and common genetic risk factors recently identified. Large collections of DNAs from thoroughly characterized ASD families are an essential step to confirm genetic risk factors, identify new variants and investigate genotype-phenotype correlations. The Italian Autism Network aimed at constituting a clinical database and a biorepository of samples derived from ASD subjects and first-degree relatives extensively and consistently characterized by child psychiatry centers in Italy.

Methods: The study was approved by the ethical committee of the University of Verona, the coordinating site, and by the local ethical committees of each recruiting site. Certified staff was specifically trained at each site for the overall study conduct, for clinical protocol administration and handling of biological material. A centralized database was developed to collect clinical assessment and medical records from each recruiting site. Children were eligible for recruitment based on the following inclusion criteria: age 4-18 years, at least one parent or legal guardian giving voluntary written consent, meeting DSM-IV criteria for Autistic Disorder or Asperger's Disorder or Pervasive Developmental Disorder NOS. Affected individuals were assessed by full psychiatric, neurological and physical examination, evaluation with ADI-R and ADOS scales, cognitive assessment with Wechsler Intelligence Scale for Children or Preschool and Primary, Leiter International Performance Scale or Griffiths Mental Developmental Scale. Additional evaluations included language assessment, the Krug Asperger's Disorder Index, and instrumental examination such as EEG and structural MRI. DNA, RNA and plasma were collected from eligible individuals and relatives. A central laboratory was established to host the biorepository, perform DNA and RNA extraction and lymphocytes immortalisation.

Discussion: The study has led to an extensive collection of biological samples associated with standardised clinical assessments from a network of expert clinicians and psychologists. Eighteen sites have received ADI/ADOS training, thirteen of which have been actively recruiting. The clinical database currently includes information on 812 individuals from 249 families, and the biorepository has samples for 98% of the subjects. This effort has generated a highly valuable resource for conducting clinical and genetic research of ASD, amenable to further expansion.
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http://dx.doi.org/10.1186/s12888-018-1937-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247619PMC
November 2018

Long-term seizure outcomes in patients with drug resistant epilepsy.

Seizure 2018 Nov 1;62:74-78. Epub 2018 Oct 1.

Department of Neurology, Hôpital Erasme, Brussels, Belgium. Electronic address:

Purpose: Despite the availability of a broad range of treatments for epilepsy, a significant proportion of patients have ongoing seizures. This study aims to characterize the drug resistant population and to report long-term outcomes of patients undergoing different types of pharmacological and surgical treatment.

Methods: Adult patients with drug resistant epilepsy (DRE) were identified from a largely retrospective database of 900 consecutive patients with epilepsy, recruited from two reference centers for DRE in Belgium. We report treatment trajectories and long-term seizure outcomes in the different treatment groups.

Results: 640 patients had DRE. 249 (38.9%) underwent presurgical assessment, followed by surgical treatment in 197 (30.8%), resulting in seizure freedom in 86 (13.4%). 443 patients (69.2%) were treated only with further AED trials, of which 163 (25.5%) became seizure free. In the 391 patients with ongoing seizures (61.1%), mean age was 43.2 years, mean disease duration 23 years and mean number of AED trials 6.9. 291 (74.4%) had tonic-clonic seizures, and 43 (11.0%) had one or more episodes of status epilepticus. Patients with hippocampal sclerosis were significantly more likely to be seizure free, while patients with malformation of cortical development and those with temporal lobe epilepsy of unknown etiology were more likely to have ongoing seizures.

Conclusion: Our findings demonstrate that - even with adequate access to surgical treatment and further AED trials - 61.1% of patients with DRE had ongoing seizures. This illustrates that there is a scope for ongoing development of novel treatments for DRE.
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http://dx.doi.org/10.1016/j.seizure.2018.09.020DOI Listing
November 2018

Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder.

Psychiatr Genet 2018 10;28(5):77-84

Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine.

Objective: Glycogen synthase kinase 3β (GSK3β) has been implicated in mood disorders. We previously reported associations between a GSK3β polymorphism and hippocampal volume in major depressive disorder (MDD). We then reported similar associations for a subset of GSK3β-regulated genes. We now investigate an algorithm-derived comprehensive list of genes encoding proteins that directly interact with GSK3β to identify a genotypic network influencing hippocampal volume in MDD.

Participants And Methods: We used discovery (N=141) and replication (N=77) recurrent MDD samples. Our gene list was generated from the NetworKIN database. Hippocampal measures were derived using an optimized Freesurfer protocol. We identified interacting single nucleotide polymorphisms using the machine learning algorithm Random Forest and verified interactions using likelihood ratio tests between nested linear regression models.

Results: The discovery sample showed multiple two-single nucleotide polymorphism interactions with hippocampal volume. The replication sample showed a replicable interaction (likelihood ratio test: P=0.0088, replication sample; P=0.017, discovery sample; Stouffer's combined P=0.0007) between genes associated previously with endoplasmic reticulum stress, calcium regulation and histone modifications.

Conclusion: Our results provide genetic evidence supporting associations between hippocampal volume and MDD, which may reflect underlying cellular stress responses. Our study provides evidence of biological mechanisms that should be further explored in the search for disease-modifying therapeutic targets for depression.
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http://dx.doi.org/10.1097/YPG.0000000000000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531290PMC
October 2018

Methylphenidate enhances implicit learning in healthy adults.

J Psychopharmacol 2018 01 26;32(1):70-80. Epub 2017 Sep 26.

1 Department of Psychiatry, University of Oxford, Oxford, UK.

Background And Purpose: One limiting factor in the development of pharmacological interventions to enhance cognition is the absence of biomarkers that can be used in healthy volunteers to screen novel compounds. Drug discovery has tended to rely heavily on explicit measures of cognition, but these are typically insensitive to cognition-enhancing effects in healthy volunteers. This study investigated whether a novel battery of implicit cognition measures is sensitive to the effects of methylphenidate (Ritalin) in healthy volunteers.

Experimental Approach: Eighty healthy volunteers were randomised to receive either a single (10 mg) dose of methylphenidate or matched placebo. Participants completed a battery of tasks measuring implicit cognition (location priming, contextual cueing, implicit task switching). The effect of methylphenidate on standard, explicit measures of cognition was also assessed.

Key Results: Methylphenidate enhanced implicit learning on the location priming task and the implicit task-switching task. In line with previous work, we found that these effects were greater in male volunteers. There was no evidence for improved learning in any of the explicit measures.

Conclusion And Implications: These results demonstrate that implicit measures of cognition are sensitive to pharmacological interventions in healthy volunteers. As such, implicit cognition measures may be a useful way of screening and tracking cognitive effects of novel agents in experimental medicine studies.
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http://dx.doi.org/10.1177/0269881117731472DOI Listing
January 2018

Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets.

PLoS One 2017 30;12(8):e0182887. Epub 2017 Aug 30.

UCB BioPharma, Braine L'Alleud, Belgium.

Objective: Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD).

Background: In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications.

Methods: Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD.

Results: When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects.

Conclusion: We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182887PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576667PMC
October 2017

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

Clin Transl Sci 2018 01 27;11(1):63-70. Epub 2017 Jul 27.

Critical Path Institute, Tucson, Arizona, USA.

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.
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http://dx.doi.org/10.1111/cts.12492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759747PMC
January 2018

GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors.

Neuropharmacology 2017 Sep 19;123:322-331. Epub 2017 May 19.

UCB BioPharma Sprl, Neurosciences Therapeutic Area, Chemin du Foriest, B-1420 Braine l'Alleud, Belgium. Electronic address:

De novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg was completely abolished in N615I and V618G variants. In fact, Mg enhanced glutamate responses in those variants. The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg insensitive variants, radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg. The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations.
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http://dx.doi.org/10.1016/j.neuropharm.2017.05.017DOI Listing
September 2017

Metoprolol-pridopidine drug-drug interaction and food effect assessments of pridopidine, a new drug for treatment of Huntington's disease.

Br J Clin Pharmacol 2017 Oct 21;83(10):2214-2224. Epub 2017 Jun 21.

Clinical Pharmacology & Pharmacometrics, Teva Pharmaceutical Industries Ltd, Netanya, Israel.

Aims: Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed.

Methods: The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady-state pridopidine 45 mg twice daily. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study.

Results: Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin-containing monooxygenase heat inactivation of liver microsomes did not affect pridopidine metabolism-dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN . Exposure to metoprolol was markedly increased when coadministered with pridopidine; the ratio of the geometric means (90% confidence interval) for maximum observed plasma concentration, and area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration and extrapolated to infinity were 3.5 (2.9, 4.22), 6.64 (5.27, 8.38) and 6.55 (5.18, 8.28), respectively. Systemic exposure to pridopidine was unaffected by food conditions.

Conclusions: As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food.
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http://dx.doi.org/10.1111/bcp.13317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595947PMC
October 2017

Genetics of schizophrenia: A consensus paper of the WFSBP Task Force on Genetics.

World J Biol Psychiatry 2017 10 23;18(7):492-505. Epub 2017 Jan 23.

a Department of Psychiatry, Psychotherapy, and Psychosomatics , Martin Luther University of Halle-Wittenberg , Halle , Germany.

Objectives: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes.

Methods: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing.

Results: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases.

Conclusions: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.
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http://dx.doi.org/10.1080/15622975.2016.1268715DOI Listing
October 2017

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response.

World J Biol Psychiatry 2017 02 7;18(1):5-28. Epub 2016 Sep 7.

d Department of Psychiatry, Psychotherapy and Psychosomatics , Martin Luther University of Halle-Wittenberg , Halle , Germany.

Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.
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http://dx.doi.org/10.1080/15622975.2016.1208843DOI Listing
February 2017

NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects.

J Psychopharmacol 2016 Mar 10;30(3):253-62. Epub 2015 Dec 10.

Centre for Human Drug Research (CHDR), Leiden, the Netherlands.

NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled. The eight subjects of each cohort received NS11821 (10 mg, 30 mg, 75 mg, 150 mg, 300 mg or 600 mg) or placebo in a 6:2 ratio. At low dose levels, NS11821 had a relatively low exposure and a more-than-proportional increase of the area under the curve and maximum plasma concentrations, probably due to poor solubility. Saccadic peak velocity decreased in a dose-related manner while limited impairments were seen on body sway and the visual analogue scale for alertness. The most common adverse events were somnolence and dizziness, which were more prominent with the higher doses. Although no positive control was used in this study, the results were compared post hoc with a Centre for Human Drug Research dataset for lorazepam 2 mg. The maximum saccadic peak velocity effects seemed comparable to the typical effects of lorazepam, whereas the other central nervous system effects were smaller. These results support the pharmacological selectivity of NS11821 and show that pharmacodynamic effective doses of NS11821 were safe and well tolerated in healthy subjects.
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http://dx.doi.org/10.1177/0269881115620435DOI Listing
March 2016

No association between NRG1 and ErbB4 genes and psychopathological symptoms of schizophrenia.

Neuromolecular Med 2014 Dec 21;16(4):742-51. Epub 2014 Aug 21.

Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Policlinico G.B. Rossi, P.le L.A. Scuro 10, 37134, Verona, Italy,

Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.
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http://dx.doi.org/10.1007/s12017-014-8323-9DOI Listing
December 2014

Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes.

Am J Med Genet B Neuropsychiatr Genet 2014 Jun 3;165B(4):303-13. Epub 2014 Apr 3.

Molecular Neuropsychiatry & Development Lab, Campbell Family Mental Health Research Institute, The Centre for Addiction & Mental Health, Toronto, Ontario, Canada.

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.
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http://dx.doi.org/10.1002/ajmg.b.32232DOI Listing
June 2014

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1.

BMC Med Genet 2014 Jan 4;15. Epub 2014 Jan 4.

Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), R-32, 250 College Street, Toronto, ON M5T 1R8, Canada.

Background: Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).

Methods: Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.

Results: Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.

Conclusions: The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.
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http://dx.doi.org/10.1186/1471-2350-15-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901032PMC
January 2014

Investigating the genetic variation underlying episodicity in major depressive disorder: suggestive evidence for a bipolar contribution.

J Affect Disord 2014 Feb 29;155:81-9. Epub 2013 Oct 29.

MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.

Background: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD.

Methods: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies.

Results: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly.

Limitations: Episode count was self-reported and, therefore, subject to recall bias.

Conclusions: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.
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http://dx.doi.org/10.1016/j.jad.2013.10.027DOI Listing
February 2014

Identification of altered dipeptidyl-peptidase activities as potential biomarkers for unipolar depression.

J Affect Disord 2013 Nov 31;151(2):667-672. Epub 2013 Jul 31.

Clinical Pharmacology Unit, GlaxoSmithKline, Addenbrooke's Hospital, Cambridge CB2 2GG, UK; Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, Cambridge University, Tennis Court Road, Cambridge CB2 1QT, UK. Electronic address:

Background: Changes in circulatory aminopeptidases [dipeptidyl-peptidase-IV (DPP-IV), Prolyl-oligopeptidase (POP) and Leucine aminopeptidase (LAP)] activities have been found to be associated with psychiatric illnesses and inflammatory diseases.

Methods: The discriminatory indices of aminopeptidases activities were assessed by enzymatic assays in plasma samples from 240 unipolar depression (UD) patients and 264 matched controls. In addition the relationship between soluble and cellular DPP-IV activity was determined in plasma and blood cells from healthy subjects.

Results: Greater than 95% of the plasma DPP-IV activity could be blocked by inhibitors, demonstrating the specificity of the assay. Also, DPP-IV protein and activity levels were strongly correlated. In contrast, only 50% of the membrane-bound activity in blood cells was inhibited, which suggested that other similar peptidases may be present in these cells. UD patients had decreased plasma levels of DPP-IV and POP activities compared to healthy controls with a concomitant increase in LAP activity. Finally, testing of the LAP/DPP-IV ratio resulted in good discrimination of UD patients from controls with an area under the curve-receiver operating characteristic of 0.70.

Limitations: Further biological validation studies using different cohorts are warranted.

Conclusions: The finding that plasma DPP-IV activity was decreased and LAP activity was increased in UD patients suggests the potential value for testing the levels of these enzymes for improved classification of patients. In addition, the changes in these enzymes, suggests that the proteolytic maturation of their proneuropeptide and prohormone subtrates may also be affected in UD, resulting in altered production of the associated bioactive peptides.
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http://dx.doi.org/10.1016/j.jad.2013.07.015DOI Listing
November 2013

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Nat Genet 2013 Sep 11;45(9):984-94. Epub 2013 Aug 11.

The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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http://dx.doi.org/10.1038/ng.2711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800159PMC
September 2013

Genome-wide association analysis accounting for environmental factors through propensity-score matching: application to stressful live events in major depressive disorder.

Am J Med Genet B Neuropsychiatr Genet 2013 Sep 15;162B(6):521-9. Epub 2013 Jul 15.

MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.

Stressful life events are an established trigger for depression and may contribute to the heterogeneity within genome-wide association analyses. With depression cases showing an excess of exposure to stressful events compared to controls, there is difficulty in distinguishing between "true" cases and a "normal" response to a stressful environment. This potential contamination of cases, and that from genetically at risk controls that have not yet experienced environmental triggers for onset, may reduce the power of studies to detect causal variants. In the RADIANT sample of 3,690 European individuals, we used propensity score matching to pair cases and controls on exposure to stressful life events. In 805 case-control pairs matched on stressful life event, we tested the influence of 457,670 common genetic variants on the propensity to depression under comparable level of adversity with a sign test. While this analysis produced no significant findings after genome-wide correction for multiple testing, we outline a novel methodology and perspective for providing environmental context in genetic studies. We recommend contextualizing depression by incorporating environmental exposure into genome-wide analyses as a complementary approach to testing gene-environment interactions. Possible explanations for negative findings include a lack of statistical power due to small sample size and conditional effects, resulting from the low rate of adequate matching. Our findings underscore the importance of collecting information on environmental risk factors in studies of depression and other complex phenotypes, so that sufficient sample sizes are available to investigate their effect in genome-wide association analysis.
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http://dx.doi.org/10.1002/ajmg.b.32180DOI Listing
September 2013

Dissecting the genetic heterogeneity of depression through age at onset.

Am J Med Genet B Neuropsychiatr Genet 2012 Oct 22;159B(7):859-68. Epub 2012 Aug 22.

MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.
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http://dx.doi.org/10.1002/ajmg.b.32093DOI Listing
October 2012

The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families.

Psychiatr Genet 2012 Aug;22(4):177-81

Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.

Objective: The objective of this study was to replicate an association study on a newly collected Italian autism spectrum disorder (ASD) cohort by studying the genetic markers associated with ASDs from recent genome-wide and candidate gene association studies.

Methods: We have genotyped 746 individuals from 227 families of the Italian Autism Network using allelic discrimination TaqMan assays for seven common single-nucleotide polymorphisms: rs2292813 (SLC25A12 gene), rs35678 (ATP2B2 gene), rs4307059 (between CDH9 and CDH10 genes), rs10513025 (between SEMA5A and TAS2R1 genes), rs6872664 (PITX1 gene), rs1861972 (EN2 gene), and rs4141463 (MACROD2 gene). A family-based association study was conducted.

Results: A significant association was found for two of seven markers: rs4307059 T allele (odds ratio: 1.758, SE=0.236; P-value=0.017) and rs35678 TC genotype (odds ratio: 0.528, SE=0.199; P-value=0.0013).

Conclusion: A preferential allele transmission of two markers located at loci previously associated with social and verbal communication skill has been confirmed in patients of a new ASD family sample.
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http://dx.doi.org/10.1097/YPG.0b013e32835185c9DOI Listing
August 2012

A mega-analysis of genome-wide association studies for major depressive disorder.

Mol Psychiatry 2013 Apr 3;18(4):497-511. Epub 2012 Apr 3.

Harvard University/Broad Institute, USA.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.
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http://dx.doi.org/10.1038/mp.2012.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837431PMC
April 2013
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