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1.
Mol Psychiatry ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591465

RESUMO

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

2.
J Psychiatr Res ; 119: 33-47, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563039

RESUMO

Generalized anxiety disorder (GAD) is a prevalent and chronic mental disorder that elicits widespread functional impairment. Given the high degree of non-response/partial response among patients with GAD to available pharmacological treatments, there is a strong need for novel approaches that can optimize outcomes, and lead to medications that are safer and more effective. Although investigations have identified interesting targets predicting treatment response through pharmacogenetics (PGx), pharmaco-epigenetics, and neuroimaging methods, these studies are often solitary, not replicated, and carry several limitations. This review provides an overview of the current status of GAD genetics and PGx and presents potential strategies to improve treatment response by combining better phenotyping with PGx and improved analytical methods. These strategies carry the dual benefit of delivering data on biomarkers of treatment response as well as pointing to disease mechanisms through the biology of the markers associated with response. Overall, these efforts can serve to identify clinical, genetic, and epigenetic factors that can be incorporated into a pharmaco(epi)genetic test that may ultimately improve treatment response and reduce the socioeconomic burden of GAD.

3.
J Vet Intern Med ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31557361

RESUMO

BACKGROUND: Advanced machine learning methods combined with large sets of health screening data provide opportunities for diagnostic value in human and veterinary medicine. HYPOTHESIS/OBJECTIVES: To derive a model to predict the risk of cats developing chronic kidney disease (CKD) using data from electronic health records (EHRs) collected during routine veterinary practice. ANIMALS: A total of 106 251 cats that attended Banfield Pet Hospitals between January 1, 1995, and December 31, 2017. METHODS: Longitudinal EHRs from Banfield Pet Hospitals were extracted and randomly split into 2 parts. The first 67% of the data were used to build a prediction model, which included feature selection and identification of the optimal neural network type and architecture. The remaining unseen EHRs were used to evaluate the model performance. RESULTS: The final model was a recurrent neural network (RNN) with 4 features (creatinine, blood urea nitrogen, urine specific gravity, and age). When predicting CKD near the point of diagnosis, the model displayed a sensitivity of 90.7% and a specificity of 98.9%. Model sensitivity decreased when predicting the risk of CKD with a longer horizon, having 63.0% sensitivity 1 year before diagnosis and 44.2% 2 years before diagnosis, but with specificity remaining around 99%. CONCLUSIONS AND CLINICAL IMPORTANCE: The use of models based on machine learning can support veterinary decision making by improving early identification of CKD.

4.
Schizophr Res ; 212: 204-212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31447353

RESUMO

BACKGROUND: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. METHODS: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. RESULTS: When examining Europeans (n = 147), we noticed an association between rs62097526 (ß = 0.39, p = 3.59 × 10-6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (ß = 0.411, p = 3.15 × 10-9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (ß = 0.271, p = 0.002) and African Americans (ß = 0.579, p = 5.73 × 10-5) with the same risk allele. Our top genes (p < 5 × 10-5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. CONCLUSIONS: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

5.
Environ Toxicol Chem ; 38(11): 2503-2508, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31441959

RESUMO

Terrestrial organisms such as shoreline spiders that consume prey from aquatic food webs can be contaminated with methylmercury (MeHg). However, no studies have examined the relationship between MeHg contamination of shoreline spider taxa and the proportion of aquatic and terrestrial prey in their diets. The present study had 2 objectives: 1) determine concentrations of MeHg in 7 taxa of shoreline spiders, and 2) assess the relationship between concentrations of MeHg in spiders and the proportion of aquatic and terrestrial prey in spider diets. We collected shoreline spiders, emergent aquatic insects, and terrestrial insects from in and around 10 experimental ponds. Methylmercury concentrations were greatest in spiders, intermediate in aquatic insects, and lowest in terrestrial insects. The elevated MeHg concentrations in spiders indicate that they were feeding, at least in part, on emergent aquatic insects. However, variability in MeHg concentration observed among spider taxa suggested that the proportion of aquatic and terrestrial prey in spider diets likely varied among taxa. We estimated the proportion of aquatic and terrestrial prey in the diet of each spider taxon from the nitrogen (δ15 N) and carbon (δ13 C) isotope values of spiders and their potential aquatic and terrestrial prey items. The median proportion of aquatic prey in spider diets varied by almost 2-fold, and MeHg concentrations in shoreline spiders were strongly correlated with the proportion of aquatic prey in their diet. In the present study, we demonstrate for the first time that the degree of connectivity to aquatic food webs determines MeHg contamination of shoreline spiders. Environ Toxicol Chem 2019;38:2503-2508. © 2019 SETAC.

6.
Mol Psychiatry ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439935

RESUMO

The complement system is a set of immune proteins involved in first-line defense against pathogens and removal of waste materials. Recent evidence has implicated the complement cascade in diseases involving the central nervous system, including schizophrenia. Here, we provide an up-to-date narrative review and critique of the literature on the relationship between schizophrenia and complement gene polymorphisms, gene expression, protein concentration, and pathway activity. A literature search identified 23 new studies since the first review on this topic in 2008. Overall complement pathway activity appears to be elevated in schizophrenia. Recent studies have identified complement component 4 (C4) and CUB and Sushi Multiple Domains 1 (CSMD1) as potential genetic markers of schizophrenia. In particular, there is some evidence of higher rates of C4B/C4S deficiency, reduced peripheral C4B concentration, and elevated brain C4A mRNA expression in schizophrenia patients compared to controls. To better elucidate the additive effects of multiple complement genotypes, we also conducted gene- and gene-set analysis through MAGMA which supported the role of Human Leukocyte Antigen class (HLA) III genes and, to a lesser extent, CSMD1 in schizophrenia; however, the HLA-schizophrenia association was likely driven by the C4 gene. Lastly, we identified several limitations of the literature on the complement system and schizophrenia, including: small sample sizes, inconsistent methodologies, limited measurements of neural concentrations of complement proteins, little exploration of the link between complement and schizophrenia phenotype, and lack of studies exploring schizophrenia treatment response. Overall, recent findings highlight complement components-in particular, C4 and CSMD1-as potential novel drug targets in schizophrenia. Given the growing availability of complement-targeted therapies, future clinical studies evaluating their efficacy in schizophrenia hold the potential to accelerate treatment advances.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31153890

RESUMO

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 < 1%) and putatively deleterious variants (qualifying variants). 82 Jewish schizophrenia patients chronically treated with antipsychotics were included and classified as having severe TD or lack of any abnormal movements based on a rigorous definition of the TD phenotype. First, we performed a case-control, exome-wide collapsing analysis comparing 39 schizophrenia patients with severe TD to 3118 unrelated population controls. Then, we checked the potential top candidate genes among 43 patients without any TD manifestations. All the genes that were found to harbor one or more qualifying variants in patients without any TD features were excluded from the final list of candidate genes. Only one gene, regulating synaptic membrane exocytosis 2 (RIMS2), showed significant enrichment of qualifying variants in TD patients compared with unrelated population controls after correcting for multiple testing (Fisher's exact test p = 5.32E-08, logistic regression p = 2.50E-08). Enrichment was caused by a single variant (rs567070433) due to a frameshift in an alternative transcript of RIMS2. None of the TD negative patients had qualifying variants in this gene. In a validation cohort of 140 schizophrenia patients assessed for TD, the variant was also not detected in any individual. Some potentially suggestive TD genes were detected in the TD cohort and warrant follow-up in future studies. No significant enrichment in previously reported TD candidate genes was identified. To the best of our knowledge, this is the first WES study of TD, demonstrating the potential role of rare loss-of-function variant enrichment in this pharmacogenetic phenotype.

8.
J Psychopharmacol ; 33(8): 1015-1029, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31219367

RESUMO

BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.

9.
Sci Rep ; 9(1): 8181, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160620

RESUMO

Collateral perfusion is important for sustaining tissue viability in acute ischemic stroke. Conventional techniques for its visualization are invasive, require contrast agents and demonstrate collateral vessels, rather than measuring perfusion directly. In this study we utilize a non-invasive, non-contrast magnetic resonance imaging (MRI)-based method to directly quantify collateral perfusion in acute stroke patients. Vessel-encoded multi-postlabeling delay arterial spin labeling (ASL) was used to separately quantify the blood flow and blood arrival time from four arteries supplying the brain in patients presenting within 18 hours of stroke onset. Twenty-nine acute ischemic stroke patients were scanned with a median time of onset to first MRI of 3 hours. Collateral perfusion at presentation was associated with tissue fate at 1-week. It sustained tissue prior to reperfusion, but was less effective than direct blood flow at maintaining tissue viability in patients who did not reperfuse. Delay in the blood arrival around the ischemic region was found at presentation and reduced over time but was not consistently associated with collateral perfusion. Vessel-encoded multi-postlabeling delay ASL provides a non-invasive tool for direct measurement of collateral perfusion and delayed blood arrival in acute stroke patients.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31209540

RESUMO

PURPOSE: Unicompartmental knee replacement (UKR) has substantial benefits over total knee replacement (TKR) but has higher revision rates. The cementless Oxford UKR was introduced to address this but there are concerns about fixation and tibial plateau fractures. The first long-term study of the device with clinical and radiographic outcomes is reported. METHODS: The first 1000 medial cementless Oxford UKR were prospectively identified and followed up by independent physiotherapists. Survival was calculated using the endpoints reoperation, revision, revision to TKR, major revision requiring revision TKR components and patient mortality. The Oxford Knee Score (OKS), Tegner Activity Score and American Knee Society Score (AKSS) were recorded and radiographs analysed. RESULTS: The ten year survival was 96.6% (CI 94.8-97.8), 97.5% (CI 95.7-98.5), 98.9% (CI 97.7-99.4) and 99.6% (CI 98.8-99.9) using reoperation, revision, revision to TKR and major revision as the endpoint, respectively. Commonest causes for revision were bearing dislocation (n = 7, 0.7%), disease progression (n = 4, 0.4%) and pain (n = 2, 0.2%). There was one lateral tibial plateau fracture and one femoral component loosening. At 10 years, the mean OKS was 41.2 (SD 9.8), Tegner 2.8 (SD 1.3), AKSS-O 89.1 (SD 13.0) and AKSS-F 80.4 (SD 14.6). There were no pathological radiolucencies or complete radiolucent lines. There were no implant-related deaths. CONCLUSIONS: The cementless Oxford UKR is a safe procedure with excellent long-term clinical results. Our results suggest that reliable fixation was achieved with only one (0.1%) revision for loosening (femoral), no radiographic evidence of loosening in the remaining cases and no fractures related to implantation. LEVEL OF EVIDENCE: III.

11.
Neuroimage ; 199: 261-272, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163268

RESUMO

BACKGROUND: Previous research has demonstrated significant relationships between obesity and brain structure. Both phenotypes are heritable, but it is not known whether they are influenced by common genetic factors. We investigated the genetic etiology of the relationship between individual variability in brain morphology and BMIz using structural MRI in adolescent twins. METHOD: The sample (n = 258) consisted of 54 monozygotic and 75 dizygotic twin pairs (mean(SD) age = 13.61(0.505), BMIz = 0.608(1.013). Brain structure (volume and density of gray and white matter) was assessed using VBM. Significant voxelwise heritability of brain structure was established using the Accelerated Permutation inference for ACE models (APACE) program, with structural heritability varying from 15 to 97%, depending on region. Bivariate heritability analyses were carried out comparing additive genetic and unique environment models with and without shared genetics on BMIz and the voxels showing significant heritability in the APACE analyses. RESULTS: BMIz was positively related to gray matter volume in the brainstem and thalamus and negatively related to gray matter volume in the bilateral uncus and medial orbitofrontal cortex, gray matter density in the cerebellum, prefrontal lobe, temporal lobe, and limbic system, and white matter density in the brainstem. Bivariate heritability analyses showed that BMIz and brain structure share ∼1/3 of their genes and that ∼95% of the phenotypic correlation between BMIz and brain structure is due to shared additive genetic influences. These regions included areas related to decision-making, motivation, liking vs. wanting, taste, interoception, reward processing/learning, caloric evaluation, and inhibition. CONCLUSION: These results suggested genetic factors are responsible for the relationship between BMIz and heritable BMIz related brain structure in areas related to eating behavior.

13.
Acta Biomater ; 94: 145-159, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125729

RESUMO

Silver and silver nanoparticles (AgNPs) exhibit antimicrobial properties against some bacteria, fungi and viruses, however, the ever-increasing application of nanosilver in consumer products, water disinfection and healthcare settings, have raised concerns over the public health/environmental safety of this nanomaterial. The current ubiquity of nanosilver may result in repeated exposure through various routes (skin, inhalation, or ingestion) which may lead to health complications. While there are a number of review articles and case studies published to date on the subject, an updated coherent review that clearly delineates thresholds and safe doses is lacking. Thus, it is plausible to have an overview of the most recent findings on the threshold limits, safe doses of silver and its related nanoscale forms, and the needed actions to ensure the safety and health of human, terrestrial and aquatic lives. This review provides an account of the effects of nanosilver in our daily lives. STATEMENT OF SIGNIFICANCE: This manuscripts is a review of the toxicity of nanosized silver. With respect to the existing literature, it goes beyond stating that there is a knowledge gap, drawing the attention of a wider readership to the ever-growing evidence of nanosilver toxicity to human and nature, and outlining the dose thresholds based on comprehensive data mining and visualisation. There are nearly 500 consumer products that claim to contain nanosilver. Thus, we trust a review of recent conclusive findings is timely. This manuscript is in line with the scope of the Journal, enabling a better understanding of the biological response to a widely-used bionanomaterial. Moreover, it provides a bigger picture of the link between surface properties and biocompatibility of nanosilver in different forms.

14.
Schizophr Res ; 209: 171-178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31080157

RESUMO

The genetic underpinnings of schizophrenia (SCZ) remain unclear. SCZ genetic studies thus far have only identified numerous single nucleotide polymorphisms with small effect sizes and a handful of copy number variants (CNVs). This study investigates the prevalence of well-characterized CNV syndromes and candidate CNVs within a cohort of 348 SCZ patients, and explores correlations to their phenotypic findings. There was an enrichment of syndromic CNVs in the cohort, as well as brain-related and immune pathway genes within the detected CNVs. SCZ patients with brain-related CNVs had increased CNV burden, neurodevelopmental features, and types of hallucinations. Based on these results, we propose a CNV-SCZ model wherein specific phenotypic profiles should be prioritized for CNV screening within the SCZ patient population.

15.
Psychiatry Res ; 275: 247-252, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30933702

RESUMO

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.

17.
Hum Brain Mapp ; 40(10): 2853-2866, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30860660

RESUMO

Metabolic markers of baseline brain oxygenation and tissue perfusion have an important role to play in the early identification of ischaemic tissue in acute stroke. Although well established MRI techniques exist for mapping brain perfusion, quantitative imaging of brain oxygenation is poorly served. Streamlined-qBOLD (sqBOLD) is a recently developed technique for mapping oxygenation that is well suited to the challenge of investigating acute stroke. In this study a noninvasive serial imaging protocol was implemented, incorporating sqBOLD and arterial spin labelling to map blood oxygenation and perfusion, respectively. The utility of these parameters was investigated using imaging based definitions of tissue outcome (ischaemic core, infarct growth and contralateral tissue). Voxel wise analysis revealed significant differences between all tissue outcomes using pairwise comparisons for the transverse reversible relaxation rate (R 2 '), deoxygenated blood volume (DBV) and deoxyghaemoglobin concentration ([dHb]; p < 0.01 in all cases). At the patient level (n = 9), a significant difference was observed for [dHb] between ischaemic core and contralateral tissue. Furthermore, serial analysis at the patient level (n = 6) revealed significant changes in R 2 ' between the presentation and 1 week scans for both ischaemic core (p < 0.01) and infarct growth (p < 0.05). In conclusion, this study presents evidence supporting the potential of sqBOLD for imaging oxygenation in stroke.

18.
Phys Med Biol ; 64(9): 095016, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-30921782

RESUMO

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T 2 relaxation time changes in ischaemic brain such that T 2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T 2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T 2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T 2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T 1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T 2 images, respectively. T 2 changes measured by the spherical reference method were 1.94 ± 0.61, 1.50 ± 0.52 and 1.40 ± 0.54 ms h-1 in the whole, GM, and WM lesions, respectively. Thus, T 2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T 2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T 2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.

19.
Am J Med Genet B Neuropsychiatr Genet ; 180(1): 46-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30556376

RESUMO

Many genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with standard psychotropic medications. This study tests the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected inborn errors of metabolism (IEMs). Using next-generation sequencing, 2046 psychiatric patients were screened for pathogenic variants in genes associated with four IEMs, Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM), and acute intermittent porphyria (AIP). Among the 2046 cases, carrier rates of 0.83, 0.98, and 0.20%, for NPC, WD and HOM, and affected rates of 0.10 and 0.24% for NPC and AIP were seen, respectively. An enrichment of known and predicted pathogenic variants in the genes associated with NPC and AIP was found in the psychiatric cohort and especially in schizophrenia patients. The results of this study support that pathogenic variants in genes associated with IEMs are enriched in psychiatric populations. Underlying undiagnosed IEMs could account for the psychiatric symptomatology in a subset of psychiatric patients. Further studies are warranted to investigate the possibility that carriers for IEMs may have an increased risk for psychiatric disorders, particularly in the context of poor treatment response.

20.
Int J Neuropsychopharmacol ; 22(3): 186-193, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576541

RESUMO

BACKGROUND: Schizophrenia is a severe psychiatric disorder with a complex pathophysiology. Given its prevalence, high risk of mortality, early onset, and high levels of disability, researchers have attempted to develop early detection strategies for facilitating timely pharmacological and/or nonpharmacological interventions. Here, we performed a meta-analysis of publicly available gene expression datasets in peripheral tissues in schizophrenia and healthy controls to detect consistent patterns of illness-associated gene expression. We also tested whether our earlier finding of a downregulation of NPTX2 expression in the brain of schizophrenia patients replicated in peripheral tissues. METHODS: We conducted a systematic search in the Gene Expression Omnibus repository (https://www.ncbi.nlm.nih.gov/gds/) and identified 3 datasets matching our inclusion criteria: GSE62333, GSE18312, and GSE27383. After quality controls, the total sample size was: schizophrenia (n = 71) and healthy controls (n = 57) (schizophrenia range: n = 12-40; healthy controls range: n = 8-29). RESULTS: The results of the meta-analysis conducted with the GeneMeta package revealed 2 genes with a false discovery rate < 0.05: atlastin GTPase 3 (ATL3) (upregulated) and arachidonate 15-lipoxygenase, type B (ALOX15B) (downregulated). The result for ATL3 was confirmed using the weighted Z test method, whereas we found a suggestive signal for ALOX15B (false discovery rate < 0.10). CONCLUSIONS: These data point to alterations of peripheral expression of ATL3 in schizophrenia, but did not confirm the significant association signal found for NPTX2 in postmortem brain samples. These findings await replication in newly recruited schizophrenia samples as well as complementary analysis of their encoded peptides in blood.

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