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Background Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD. Methods MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions. Results MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC. Limitations Cross-sectional design, modest sample size. Conclusions There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.

The interindividual variability in opioid response is an issue that contributes to the ongoing opioid crisis. Current evidence suggests this variability can be attributed to genetic factors. The pharmacogenetics of Opioid Treatment for acute post-operative Pain (OTP) project was a prospective study that aimed to identify genetic markers associated with opioid treatment outcomes. Healthy patients undergoing third-molar extractions were recruited from dental offices located within the Greater Toronto Area. Participants were evaluated using the Brief Pain Inventory Short Form, the Opioid Related Symptom Distress Scale, and the Leeds Dependence Questionnaire. Seventy-two participants had an active opioid prescription. Participants were prescribed one of the following opioids: codeine, morphine, hydromorphone, tramadol, or oxycodone. The majority of participants were female (57%), ranging from 16 to 44 years of age. Pain severity, pain interference, and side effects declined over the seven-day post-operative period. Additionally, 4% of participants displayed medium to high risk of dependence. It is anticipated that OTP will enable the development of a genetic test for opioid use and facilitate the introduction of this test into routine healthcare practice. The OTP study represents a novel approach to opioid treatment and has significant implications for future interventions targeting the ongoing opioid crisis. Employing a pharmacogenomic-guided strategy for prescribing opioids may improve patients' response to this treatment and, in so doing, increase adherence to the target treatment plan. Optimized prescriptions may also provide public healthcare systems with beneficial savings and reduce the risks associated with opioid use.

Osteopathic manipulative treatment (OMT) is used in both inpatient and outpatient settings. Evidence suggests that OMT can reduce both patients’ recovery time and the financial cost of their acute medical treatment and rehabilitation. Multiple studies from neonatal intensive care units (NICUs) are presented in this article that demonstrate infants treated with OMT recover faster, are discharged earlier, and have lower healthcare costs than their non-OMT-treated counterparts. Data clearly show that adjunctive OMT facilitates feeding coordination in newborns, such as latching, suckling, swallowing, and breathing, and increases long-term weight gain and maintenance, which reduces hospital length of stay (LOS). Osteopathic techniques, such as soft tissue manipulation, balanced ligamentous tension, myofascial release, and osteopathic cranial manipulation (OCM), can reduce regurgitation, vomiting, milky bilious, or bloody discharge and decrease the need for constipation treatment. OMT can also be effective in reducing the complications of pneumonia in premature babies. Studies show the use of OCM and lymphatic pump technique (LPT) reduces the occurrence of both aspiration and environmentally acquired pneumonia, resulting in significantly lower morbidity and mortality in infants. Based on published findings, it is determined that OMT is clinically effective, cost efficient, a less invasive alternative to surgery, and a less toxic choice to pharmacologic drugs. Therefore, routine incorporation of OMT in the NICU can be of great benefit in infants with multiple disorders. Future OMT research should aim to initiate clinical trial designs that include randomized controlled trials with larger cohorts of infants admitted to the NICU. Furthermore, a streamlined and concerted effort to elucidate the underlying molecular mechanisms associated with the beneficial effects of OMT will aid in understanding the significant value of incorporating OMT into optimal patient care.

Background: Clozapine has heterogenous efficacy in enhancing working memory in schizophrenia. We have previously hypothesized that this is due to opposing effects of clozapine and its metabolite, N-desmethylclozapine, at the muscarinic M1 receptor and demonstrated that a lower clozapine/ N-desmethylclozapine ratio is associated with better working memory than clozapine or N-desmethylclozapine levels alone. Aims: In this study, we expanded the above hypothesis to explore whether genetic variation in the cholinergic receptor muscarinic 1 gene, encoding the M1 receptor, affects the relationship between clozapine/ N-desmethylclozapine and working memory. Further, we explored whether CYP1A2 gene variants affect the ratio of clozapine/ N-desmethylclozapine and by this, working memory performance. Methods: We evaluated two functionally significant single nucleotide polymorphisms, rs1942499 and rs2075748, in cholinergic receptor muscarinic 1, with the haplotype T-A associated with lower transcriptional activity than the haplotype C-G. Further, we examined CYP1A2 *1F, with *1F/*1F conferring high inducibility in the presence of smoking. Results: In a sample of 30 patients with schizophrenia on clozapine monotherapy, clozapine/ N-desmethylclozapine was correlated with working memory only in non-carriers of the haplotype T-A of the cholinergic receptor muscarinic 1 gene. Interaction of CYP1A2 genotype and smoking status significantly affected clozapine concentrations, but there were no significant effects of CYP1A2 genotype and smoking status on the relationship between clozapine/ N-desmethylclozapine on working memory. Conclusions: Our finding that the relationship between clozapine/ N-desmethylclozapine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of cholinergic receptor muscarinic 1) supports a cholinergic mechanism underlying this relationship.

Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long-term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin-1, encoded by the dystrobrevin-binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three-marker haplotypes to be associated with TD occurrence and TD severity (p

Background Bipolar disorder (BD), among the most heritable psychiatric conditions, is associated with increased pro-inflammatory blood markers and pro-inflammatory gene expression in post-mortem brain. We therefore examined the effects of pro-inflammatory single nucleotide polymorphism interleukin-1β (IL-1β) rs16944 on brain structure in adolescents with BD and healthy control (HC) adolescents. Methods T1-weighted 3-T magnetic resonance imaging data were acquired for 38 adolescents with BD and 32 HC adolescents (14–20 years). Using FreeSurfer, a priori regions of interest analyses, examining hippocampus, amygdala, dorsolateral prefrontal cortex (DLPFC), and caudal anterior cingulate cortex, were complemented by exploratory whole-brain vertex-wise analyses. General linear models assessed the association between IL-1β rs16944 and the ROIs, controlling for sex, age, and intracranial volume. Results There was an IL-1β rs16944 polymorphism-by-diagnosis interaction effect on the DLPFC; T-carriers with BD had greater surface area compared to non-carriers with BD. Whereas, HC T-carriers had smaller DLPFC volume compared to HC non-carriers. In vertex-wise analyses, similar interactions were evident in a pars triangularis surface area cluster and a lateral occipital cortex volume cluster. Whole-brain analyses also yielded a main effect of IL-1β rs16944 polymorphism, whereby T-carriers had greater lateral occipital cortex surface area and volume. Conclusions The IL-1β rs16944 polymorphism is associated with neurostructural phenotypes in cognitive and visual regions that subserve functions, including facial recognition and response inhibition, which are known to be aberrant in BD. Future studies are warranted to evaluate whether the observed rs16944-related structural differences are relevant to neurocognitive function, functional neuroimaging phenotypes and IL-1β protein levels.

Individuals carrying genetic variants that result in non-extensive CYP2D6 and CYP2C19 enzyme activity seem to be more prone to non-response and side-effects of psychotropic medications. Therefore, tailoring prescriptions using genetic information may improve patient outcomes. This study examined treatment outcome in psychiatric care after CYP2D6 and CYP2C19 genetic information was provided to patients and physicians. CYP2D6 and CYP2C19 genotyping, assessment of side effects and medical histories were obtained from 80 subjects who were prescribed either antidepressant or antipsychotic medications. Our measure of outcome was mainly physicians' opinions however UKU side effects scores were also used. For CYP2D6, we calculated an activity score based on genotype and psychiatric medications. Correlation analysis was performed for CYP2D6 activity scores and UKU scores. Overall, we received supportive responses from physicians who enrolled patients in our study. Notably, while almost every fourth physician reported improvement in patient outcome, not a single physician indicated that their patient's symptoms worsened after they had used a pharmacogenetic report to guide treatment. We did not observe statistically significant differences in side effects. Overall, our results suggest improved patient outcome following pharmacogenetic testing; nonetheless, more research is required to assess the exact benefit of pharmacogenetics in clinical practice.

Suicide claims over 800,000 lives each year worldwide. Suicide rates in indigenous populations in Canada are about double that of the national average, making it a serious public health issue. Numerous factors are involved in suicide risk, including genetic factors, as well as various psychosocial stressors, such as historical experience with the Indian Residential School system for Indigenous populations, as well as protective variables such as social support. Here, we report the first genetic study of suicidal behaviors that includes multiple measures of stress and social supports. We investigated the role of the functional Val66Met marker (rs6265) in the Brain-Derived Neurotropic Factor (BDNF) gene in suicidal ideation and suicide attempt in a First Nations community sample (N = 278). We did not find a significant association between the BDNF rs6265 marker and suicidal behaviors. We found childhood adversities, recent life stress, chronic stress, perceived stress, difficulties, and hazardous alcohol use to be associated with both suicidal ideation and suicide attempt. Thus, while additional studies with larger samples are required to elucidate the genetic component of suicide, addressing environmental stressors may be important for suicide prevention.

BackgroundIn a push for universal health coverage, Ethiopia introduced two insurance schemes in 2010. Yet coverage rates remain very low. To encourage greater adoption, policymakers require a better understanding of who chooses to enroll and which promotional efforts are most effective in encouraging enrollment.ObjectiveUsing nationally representative Demographic and Health Surveys, this research assessed the social determinants of health insurance coverage, including media exposure, in Ethiopia from 2011-2016.MethodsThis research analyzed health insurance coverage and other sociodemographic and media exposure variables using multivariable logistic regression model.ResultsHealth insurance coverage increased 3.30 times from 1.48% in 2011 to 4.89% in 2016. In both years, coverage was associated with higher education, older age, higher wealth levels, and exposure to newspaper and television. Compared to those with no exposure to newspaper, those with newspaper exposure at least once a week were 1.80 times (2011) and 1.86 times (2016) more likely to be insured. Similar results were obtained for television exposure.ConclusionInitiatives that target the poor and less educated will be necessary if Ethiopia is to achieve universal health coverage. This research suggests that, to date, newspaper and television mediums have been effective promotion mechanisms for growing enrollment.

Objective Brain-derived neurotrophic factor (BDNF) rs6265 single-nucleotide polymorphism has been associated with bipolar disorder (BD), and with brain structure among adults with BD. We set out to investigate the association of the BDNF rs6265 Met allele with neurostructural phenotypes in youth BD. Methods Caucasian youth (N = 99; 13-20 years; n = 56 BD, n = 43 age and sex-matched healthy controls) underwent 3-Tesla Magnetic Resonance Imaging and genotyping for BDNF rs6265. Region of interest (ROI) analyses of the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and hippocampus were complemented by vertex-wise analyses examining cortical thickness, surface area (SA) and volume. Multivariable models included the main effects of diagnosis and gene, and a diagnosis-by-genotype interaction term, controlling for age, sex, and intracranial volume. Results There were no significant gene main effects or diagnosis-by-gene interaction effects in ROI analyses. The vertex-wise analysis yielded a significant gene main effect whereby Met allele carriers had greater middle temporal gyrus SA (p = 0.001) and supramarginal gyrus volume (p = 0.03) than Val/Val individuals. Significant interaction effects were found on lateral occipital lobe SA (p = 0.03), whereby the Met allele was associated with increased SA in BD only. Interaction effects were also found on postcentral gyrus SA (p = 0.049) and supramarginal gyrus SA (p = 0.04), with smaller SA in BD Met carriers versus healthy control Met carriers. Conclusion These findings suggest that BDNF rs6265 is differentially associated with regional SA in youth BD. Further investigation is warranted to evaluate whether BDNF protein levels mediate the observed effects, and to evaluate rs6265-related developmental changes.

Background Oxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD. Methods SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD = 75; healthy controls = 72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (prefrontal cortex [PFC], caudal anterior cingulate cortex, hippocampus) and for vertex-wise whole-brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume, area, and thickness analyses. Result Regions of interest analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for caudal anterior cingulate cortex volume and surface area as well as PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs the healthy controls GG genotype group. There was a significant BD diagnosis × GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group. Conclusion We found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structures in youth with BD in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.

BACKGROUND: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. MATERIALS & METHODS: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). RESULTS: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. CONCLUSION: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Given the limited effectiveness of treatments for pathological anxiety, there is a pressing need to identify genetic markers that can aid the precise selection of treatments and optimize treatment response. Anxiety and startle response levels demonstrate a direct relationship, and previous literature suggests that exaggerated startle reactivity may serve as an endophenotype of pathological anxiety. In addition, genetic variants related to startle reactivity may play a role in the etiology of pathological anxiety. In the current study, we selected 22 single nucleotide polymorphisms (SNPs) related to startle reactivity in the literature, and examined their association with anxiety symptom severity across psychiatric disorders (n = 508), and in a subset of patients with an anxiety disorder (n = 298). Overall, none of the SNPs pass correction for multiple independent tests. However, across psychiatric patients, rs6323 from the monoamine oxidase A (MAOA) gene and rs324981 from the neuropeptide S receptor 1 (NPSR1) gene were nominally associated with baseline anxiety symptom severity (p = 0.017, 0.023). These preliminary findings provide support for investigating startle-related genetic variants to identify biomarkers of anxiety symptom severity.

Sleep disturbance affects about 75% of depressed individuals and is associated with poorer patient outcomes. The genetics in this field is an emerging area of research. Thus far, only core circadian genes have been examined in this context. We expanded on this by performing a genome-wide association study (GWAS) followed by a preplanned hypothesis-driven analysis with 27 genes associated with the biology of sleep. All participants were diagnosed by their referring physician, completed the Beck Depression Inventory (BDI), and the Udvalg for Kliniske Undersogelser Side Effect Rating Scale at baseline. Our phenotype consisted of replies to 3 questions from these questionnaires. From standard GWAS chip data, imputations were performed. Baseline total BDI scores (n = 364) differed significantly between those with and those without sleep problems. We were unable to find any significant GWAS hits although our top hit was for changes in sleep and an intergenic marker near SNX18 (p = 1.06 × 10–6). None of the markers in our hypothesis-driven analysis remained significant after applying Bonferroni corrections. Our top finding among these genes was for rs13019460 of Neuronal PAS Domain Protein 2 with changes in sleep (p = 0.0009). Overall, both analyses were unable to detect any significant associations in our modest sample though we did find some interesting preliminary associations worth further exploration.

Tardive dyskinesia (TD) is a movement disorder that may develop in schizophrenia patients being treated long-term with antipsychotic medication. TD interferes with voluntary movements and leads to stigma, and can be associated with treatment non-adherence. The etiology of TD is unclear, but it appears to have a genetic component. There is emerging evidence of immune dysregulation in TD. In the current study, we set out to investigate the complex schizophrenia-associated complement component 4 (C4) gene for possible association with TD occurrence and TD severity as assessed by the Abnormal Involuntary Movement Scale (AIMS) in a sample of 129 schizophrenia patients of European ancestry. We have genotyped the copy numbers of long and short forms of C4A and C4B gene variants in 129 European ancestry patients with schizophrenia or schizoaffective disorder. We did not find predicted C4A or C4B expression to be nominally associated with TD risk or severity. However, we found the number of copies of C4BL to be nominally associated with TD severity (p = 0.020).

Melanocortin-4-receptor (MC4R) gene codes for a G-protein-coupled receptor that is highly expressed in the hypothalamus and involved in the regulation of appetite. Single-nucleotide polymorphisms (SNPs) in the MC4R gene region have been associated with obesity, type 2-diabetes (T2D) and with antipsychotic-induced weight gain. Of these, rs17066842 (G>A) in the MC4R promoter region is the top variant associated with obesity and diabetes. In this study, we investigated the effect of rs17066842 on MC4R expression at various glucose concentrations using reporter gene expression in the SH-SY5Y cell line and regulation of MC4R expression in human cerebral organoids. We observed that higher glucose concentrations significantly reduced MC4R mRNA expression in SH-SY5Y cells. In addition, at high glucose concentrations, the luciferase reporter plasmid containing the MC4R promoter insert with the G-allele of rs170066842 showed significantly reduced activity compared to the A-allele carrying plasmid. The immediate early gene product, early growth-response 1 (EGR-1), was identified to bind to the sequence containing the G-allele at rs17066842 but not to the A-allele-containing sequence. Interestingly, in human induced pluripotent stem cell (hiPSC)-derived cerebral organoids, we observed increased MC4R expression in response to high glucose exposure. These opposite observations might suggest that glucose regulation is complex and may be cell-specific. This study provides evidence that rs17066842 regulates MC4R gene expression through binding of EGR-1 and that this process is influenced by glucose concentration.

Background Few studies have examined multiple genetic variants concurrently for the purpose of classifying bipolar disorder (BD); the literature among youth is particularly sparse. We selected 35 genetic variants, previously implicated in BD or associated characteristics, from which to identify the most robustly predictive group of genes. Methods 215 Caucasian adolescents (114 BD and 101 healthy controls (HC), ages 13–20 years) were included. Psychiatric diagnoses were determined based on semi-structured diagnostic interviews. Genomic DNA was extracted from saliva for genotyping. Two models were used to calculate a multi-gene risk score (MGRS). Model 1 used forward and backward regressions, and model 2 used a PLINK generated method. Results In model 1, GPX3 rs3792797 was significant in the forward regression, DRD4 exonIII was significant in the backward regression; IL1β rs16944 and DISC1 rs821577 were significant in both the forward and backward regressions. These variants are involved in dopamine neurotransmission; inflammation and oxidative stress; and neuronal development. Model 1 MGRS did not significantly discriminate between BD and HC. In model 2, ZNF804A rs1344706 was significantly associated with BD; however, this association did not predict diagnosis when entered into the weighted model. Limitations This study was limited by the number of genetic variants examined and the modest sample size. Conclusions Whereas regression approaches identified four genetic variants that significantly discriminated between BD and HC, those same variants no longer discriminated between BD and HC when computed as a MGRS. Future larger studies are needed evaluating intermediate phenotypes such as neuroimaging and blood-based biomarkers.

Tardive dyskinesia (TD) is an adverse movement disorder induced by chronic treatment with antipsychotics drugs. The contribution of common genetic variants to TD susceptibility has been investigated in recent years, but with limited success. The aim of the current study was to investigate the potential contribution of rare variants to TD vulnerability. In order to identify TD risk genes, we performed whole-exome sequencing (WES) and gene-based collapsing analysis focusing on rare (allele frequency

A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG.We analysed 40 tagSNPs in HRH1 (n = 34) and HRH3 (n = 6) in schizophrenia/schizoaffective disorder patients (n = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates.In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine (PThe current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.

The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinson's disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system.media-1vid110.1093/brain/aww109_video_abstractaww109_video_abstract.

Objective Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents. Methods Seventy-one adolescents (14–20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume. Results Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions. Conclusions The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.

Schizophrenia is a severe, debilitating disorder with a lifetime prevalence of 1% irrespective of gender or ethnicity and is typically treated with antipsychotic drugs. Antipsychotic-induced weight gain (AIWG) is a leading factor of patient non-compliance and has previously been shown to increase the risk of type 2 diabetes, metabolic syndrome, and cardiovascular events. The current study intends to replicate findings from a recent genome-wide association study in Han-Chinese patients implicating two gene variants (rs10977144 and rs10977154) of the protein tyrosine phosphatase receptor type D (PTPRD) in antipsychotic-induced weight gain (AIWG). We investigated a sample of European and African American ancestry (n = 201) and calculated percentage of weight change using linear regression corrected for type of antipsychotics, duration of treatment and principal components from ancestry checks. As secondary goal, we investigated additional gene variants of PTPRD previously not associated with AIWG. We found no association with rs10977144 and rs10977154. However, we found nominally significant results between PTPRD and AIWG with rs73398242 in Europeans (BETA = − 0.267, p = 0.002) and rs13294608 in African Americans (BETA = 0.423, p = 0.003). According to Haploreg, both SNPs are histone marks for enhancers and promoters across various brain regions including the cingulate gyrus and dorsolateral prefrontal cortex. In summary, our results tentatively suggest that PTPRD might be associated with AIWG although different SNPS might be involved in different ethnic groups.

Background The current process used to prescribe antidepressant medication is markedly inefficient, as more than 50% of treated patients fail to reach remission. Antidepressant treatment success has been associated with genetic variation, but studies are not well replicated and epigenetic mechanisms remain under investigated. DNA methylation may provide more information regarding antidepressant response and guide physicians in choosing the most effective medication for each patient. We investigated the influence of SLC6A4 methylation and 5-HTTLPR genotypes on antidepressant response in our sample. Methods A subset of depression patients with complete clinical data (European Caucasian, n=166), were selected from our discovery sample (IMPACT; N=8,000). Saliva samples were collected at enrollment and genetic testing was done of cytochrome P450 liver enzyme, 5HTTLPR and 5HT2A variants to guide clinical choice and dosage of psychotropic medications. As such, a significant component of our sample includes treatment refractory, as well as medication intolerant patients. DNA was bisulfite converted and methylation profiles were interrogated using the Infinium HumanMethylation450 Beadchip array. Nine CpG probes located across the SLC6A4 promoter region were selected, based on previous studies, to quantify methylation levels. Change in Beck Depression Inventory II (BDI-II) score was used to measure antidepressant response over eight weeks. The relationship among genotype, methylation levels, and antidepressant response was analysed using linear regression modeling. Results Increased methylation in the promoter region of the SLC6A4 gene was nominally associated with impaired response to antidepressants in our sample. The effect was driven by methylation site cg05016953, located in exon 1 A. Increased methylation level as measured by CpG cg05016953 was associated with less improvement in BDI-II score over eight weeks of antidepressant treatment (F(3,163)=6.14, puncorr=0.012). 5-HTTLPR genotype was not associated with SLC6A4 DNA methylation or antidepressant treatment response. Discussion An increase in SLC6A4 DNA methylation at cg05016953 may be associated impaired response to antidepressant medications in our sample. The SLC6A4 transcriptional control region contains a CpG island, previously shown to functionally influence mRNA levels depending on 5-HTTLPR genotypes. Typically, hypermethylation in promoter regions is associated with decreased gene expression. Theoretically, hypermethylation of the 5-HTT promoter would reduce the number of serotonin transporters, and reduce serotonin re-uptake, which in simple terms should improve response to SSRI treatment. Further pharmaco-epigenetic studies are required to elucidate the effect of DNA methylation changes on antidepressant response.

Background Suicidal behaviour can be a serious symptom of psychiatric disorder and may change during the course of psychotropic medication treatment. There have been a number of published Genome-Wide Association Studies (GWASs) of treatment-emergent suicidal ideation, but there has not been GWAS of resolution of suicidal ideation during drug treatment. Here we report on two such GWASs. Methods From the STEP-BD study, we have 450 patients with bipolar disorder assessed on the MADRS. We analyzed the change in suicidality from baseline to six months. From the IMPACT study (Individualized Medicine: Pharmacogenetic Assessment & Clinical Treatment), we have 118 participants suffering from anxiety, depression, bipolar disorder, and/or attention-deficit hyperactivity disorder. They were genotyped on the Illumina Omni 2.5 M chip and were followed for eight weeks on the Beck Depression Inventory. Of these participants, 69 experienced suicidal ideation at baseline, and 23 of them did not experience suicidal ideation at their eight-week study visit. Conversely, 49 participants did not have suicidal ideation at baseline, of which six reported suicidal ideation at the eight-week visit. We analyzed the change in suicidal ideation during these studies, including baseline suicidality scores, age, and sex as covariates. Results We did not observe genome-wide significant findings from either GWAS. We observed a possible genetic overlap between suicidal ideation in the STEP-BD bipolar disorder sample and suicidal ideation in the IMPACT sample (p=0.047). Discussion Suicide is a clinically important phenotype in clinical studies. Investigating the increases as well as decreases in suicidal ideation during psychotropic medication may be an interesting avenue for further genetic investigations.

OBJECTIVE: Antipsychotics are effective in treating schizophrenia symptoms. However, the use of clozapine and olanzapine in particular are associated with significant weight gain. Mouse and human studies suggest that the protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene may be involved in energy metabolism, and there is evidence that it is associated with clozapine's effects on triglyceride levels. We aimed at assessing PRKAR2B's role in antipsychotic-induced weight gain in schizophrenia patients. METHODS: DNA samples from adult schizophrenia or schizoaffective disorder patients of mixed ancestry were genotyped, and weight gain was assessed. We analyzed 16 tag single-nucleotide polymorphisms across the PRKAR2B gene in a Caucasian subset treated either with clozapine or olanzapine (N = 99). Linear regression based on an additive model was performed with the inclusion of relevant covariates. RESULTS: Normalized per cent weight change was analyzed, revealing that patients with the minor allele at rs9656135 had a mean weight increase of 4.1%, whereas patients without this allele had an increase of 3.4%. This association is not significant after correcting for multiple testing. CONCLUSIONS: Because of limited power, PRKAR2B's role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved. Further research in larger sample sizes is warranted.

Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.

Emotionally enhanced memory and susceptibility to intrusive memories after trauma have been linked to a deletion variant (i.e., a form of a gene in which certain amino acids are missing) of ADRA2B, the gene encoding subtype B of the α2-adrenergic receptor, which influences norepinephrine activity. We examined in 207 participants whether variations in this gene are responsible for individual differences in affective influences on initial encoding that alter perceptual awareness. We examined the attentional blink, an attentional impairment during rapid serial visual presentation, for negatively arousing, positively arousing, and neutral target words. Overall, the attentional blink was reduced for emotional targets for ADRA2B-deletion carriers and noncarriers alike, which reveals emotional sparing (i.e., reduction of the attentional impairment for words that are emotionally significant). However, deletion carriers demonstrated a further, more pronounced emotional sparing for negative targets. This finding demonstrates a contribution of genetics to individual differences in the emotional subjectivity of perception, which in turn may be linked to biases in later memory.

We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18–75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery–Asberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (β=0.69, P=1.25 × 10−8) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ2=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; β=−0.46, P=1.55 × 10−5), NCAM1 (rs2303377; β=0.45, P=1.76 × 10−5) and MLL5 (rs117986340; β=0.91, P=3.04 × 10−5). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.

OBJECTIVES A recent genome-wide association study (GWAS) in obsessive-compulsive disorder (OCD) reported a significant marker in the dispatched homolog 1 (Drosophila) gene (DISP1 gene) associated with serotonin reuptake inhibitor (SRI) antidepressant response (Qin et al., ). DISP1 has never been examined before in terms of association with SRI response until this GWAS. We attempt to replicate the GWAS finding by investigating the association of the DISP1 rs17162912 polymorphism with SRI response in our sample of 112 European Caucasian OCD patients. METHODS Patients were previously treated naturalistically with up to 6 different SRIs sequentially, including 5 selective SRIs (fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram) and 1 SRI (clomipramine). Each medication trial was evaluated retrospectively for response and was rated categorically as either responder or nonresponder using the Clinical Global Impression-Improvement scale. Fisher's exact test was used to investigate the relationship between the DISP1 rs17162912 genotype distribution and SRI response. RESULTS We did not observe a significant association between rs17162912 and SRI response (p = .32). CONCLUSION This replication study did not support the role of DISP1 in predicting SRI response in OCD; however, methodological differences between the original GWAS and our study, as well as limited power and low minor allele frequency, may have hindered replication.

For scientific data visualizations, real-time data streams present many interesting challenges when compared to static data. Real-time data are dynamic, transient, high-volume and temporal. Effective visualizations need to be able to accommodate dynamic data behavior as well as Abstract and present the data in ways that make sense to and are usable by humans. The Visual Content Analysis of Real-Time Data Streams project at the Pacific Northwest National Laboratory is researching and prototyping dynamic visualization techniques and tools to help facilitate human understanding and comprehension of high-volume, real-time data. The general strategy of the project is to develop and evolve visual contexts that will organize and orient high-volume dynamic data in conceptual and perceptive views. The goal is to allow users to quickly grasp dynamic data in forms that are intuitive and natural without requiring intensive training in the use of specific visualization or analysis tools and methods. Thus far, the project has prototyped five different visualization prototypes that represent and convey dynamic data through human-recognizable contexts and paradigms such as hierarchies, relationships, time and geography. We describe the design considerations and unique features of these dynamic visualization prototypes as well as our findings in the exploration and evaluation of their use.

We map the weekly position of the Antarctic Polar Front (PF) in the Southern Ocean over a 12-year period (2002–2014) using satellite sea surface temperature (SST) estimated from cloud-penetrating microwave radiometers. Our study advances previous efforts to map the PF using hydrographic and satellite data and provides a unique realization of the PF at weekly resolution across all longitudes (doi:10.1594/PANGAEA.855640). The mean path of the PF is asymmetric; its latitudinal position spans from 44 to 64° S along its circumpolar path. SST at the PF ranges from 0.6 to 6.9 °C, reflecting the large spread in latitudinal position. The average intensity of the front is 1.7 °C per 100 km, with intensity ranging from 1.4 to 2.3 °C per 100 km. Front intensity is significantly correlated with the depth of bottom topography, suggesting that the front intensifies over shallow bathymetry. Realizations of the PF are consistent with the corresponding surface expressions of the PF estimated using expendable bathythermograph data in the Drake Passage and Australian and African sectors. The climatological mean position of the PF is similar, though not identical, to previously published estimates. As the PF is a key indicator of physical circulation, surface nutrient concentration, and biogeography in the Southern Ocean, future studies of physical and biogeochemical oceanography in this region will benefit from the provided data set.

Aim: This study investigated polymorphisms of five inflammatory-related genes for association with duloxetine and placebo response in patients with major depression. Patients & methods: Twenty SNPs in IL-1β, IL-2, IL-6, TSPO and BDNF were genotyped in major depressive disorder patients treated with either duloxetine (n = 215) or placebo (n = 235) for up to 8 weeks. Treatment response was measured with the Montgomery–Åsberg Depression Rating Scale. Results: IL-6 variants rs2066992 and rs10242595 were nominally associated with response to duloxetine (p = 0.047 and p = 0.028, respectively). Notably, the variant rs2066992 was also associated with placebo response (p = 0.026). However, none of our results remained significant after correction for multiple testing. Conclusion: Our findings tentatively suggest that IL-6 variants play a role in duloxetine and placebo response, which warrants further investigation.

Objectives: Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG. Methods: Schizophrenia or schizoaffective disorder subjects (n = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates. Results: Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (PP = 0.043) and rs12662510 (P = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG. Conclusion: This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.

Background A recent genome-wide association study (GWAS) of antidepressant response in obsessive-compulsive disorder (OCD) reported a genome-wide significant marker in the dispatched homolog 1 (Drosophila) gene (DISP1). This gene encodes for a protein that is important for spinal cord development. Methods In this study, we attempted to replicate this finding by investigating the DISP1 rs17162912 polymorphism in 359 OCD patients with serotonin reuptake inhibitor (SRI: fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, and clomipramine) antidepressant response data. SRI response was defined categorically as responder ("very much" and "much" improved) and non-responder ("minimal" improvment, "no change", or "worse") using the Clinical Global Impression – Improvement (CGI-I) scale and Pearson chi-squared test was performed between the genotype distribution and SRI response status. Results We did not observe significant association between the DISP1 rs17162912 (P=0. 470) with SRI response. Discussion This study did not provide support for a role of the DISP1 rs17162912 in predicting SRI response in OCD patients. Future investigation of the region of DISP1 may provide further insight into whether it contributes to SRI response in patients with OCD. Financial Relationships I (or my spouse/partner) do have potential conflicts of interest to disclose.

CYP2D6 contributes to the metabolism of many clinically used drugs and is increasingly tested to individualize drug therapy. The CYP2D6 gene is challenging to genotype due to the highly complex nature of its gene locus. TaqMan® technology is widely used in the clinical and research settings for genotype analysis due to assay reliability, low cost and the availability of commercially available assays. The assay identifying 1023C>T (rs28371706) defining a reduced function (CYP2D6*17) and several nonfunctional alleles, produced a small number of unexpected diplotype calls in three independent sets of samples, i.e. calls suggested the presence of a CYP2D6*4 subvariant containing 1023C>T. Gene resequencing did not reveal any unknown SNPs in the primer or probe binding sites in any of the samples, but all affected samples featured a trio of SNPs on their CYP2D6*4 allele between one of the PCR primer and probe binding sites. While the phenomenon was ultimately overcome by an alternate assay utilizing a PCR primer excluding the SNP trio, the mechanism causing this phenomenon remains elusive. This rare and unexpected event underscores the importance of assay validation in samples representing a variety of genotypes, but also vigilance of assay performance in highly polymorphic genes such as CYP2D6.