Brain-derived neurotrophic factor (BDNF) has extensive effects on the nervous system including cell survival, differentiation, neuronal growth and maintenance, as well as cell death. Moreover, it ...promotes synaptic plasticity and interacts with dopaminergic and serotonergic neurons, suggesting an important role on the alteration of brain function with antipsychotic medications and induced weight gain in schizophrenia patients. The differential effects of BDNF gene variants could lead to changes in brain circuitry that would in turn cause variable response to antipsychotic medication. Therefore, we hypothesized that genetic variation in this candidate gene helps in explaining the inter-individual variation observed in antipsychotic drug treatment with respect to response and induced weight gain.
We examined four single-nucleotide polymorphisms across the BDNF gene, including Val66Met (rs6265). Prospective BPRS change scores and weight change after six weeks were obtained from a total of 257 schizophrenia patients of European ancestry.
The markers rs11030104 and Val66Met were associated with antipsychotic response (P=0.04; 0.007, respectively). On the other hand, marker rs1519480 was associated with weight gain (P=0.04). Moreover, a two-marker haplotype across rs6265 and rs1519480 was associated with weight change (P=0.001). Results with Val66Met in response, and results with rs6265-rs1519480 haplotypes remained significant at the modified Bonferroni corrected alpha of 0.017.
BDNF genetic variants might play an important role in predicting antipsychotic response and antipsychotic-induced weight gain. However, replication in larger and independent samples is required.
►We analyzed markers across the Brain-derived neurotrophic factor gene. ►We examined antipsychotic response and antipsychotic-induced weight gain. ►We found markers and haplotypes including Val66Met associated with response. ►We found the Val66Met-rs1519480 G-A haplotype associated with weight gain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Canada exhibits one of highest lifetime prevalence for post-traumatic stress disorder (PTSD), but the etiology of this debilitating mental health condition still remains largely unknown. This study ...aims to examine the genetics of PTSD in the Canadian Longitudinal Study on Aging (CLSA) to identify potential genetic factors involved in the development of PTSD.
The CLSA sample was screened for primary (PTSD status) and secondary outcomes (avoidance, detachment, guardedness, and nightmares) based on the Primary Care PTSD Screen Scale (PC-PTSD). After GWAS quality control and whole-genome imputation, single-marker, gene-based, and polygenic risk score (PRS) analyses were performed.
Based on available genotype and phenotype data, N = 16,535 individuals were selected for the analyses. While genome-wide analyses did not show significant findings for our primary and secondary outcomes, PRS analyses showed variable levels of association between PC-PTSD items with trauma, major depressive disorder, schizophrenia, bipolar disorder, educational attainment, and insomnia (p < 5e-4).
This is the first GWAS of PTSD status and individual PC-PTSD items in a population sample of older adults from Canada. This study was also able to replicate findings from previous studies. Genetic investigations into individual symptom components of PTSD may help untangle the complex genetic architecture of PTSD.
•Our GWAS of post-traumatic stress disorder in the Canadian Longitudinal Study on Aging sample replicated recent findings.•We found associations of a number of polygenic risk scores with PTSD symptoms.•Our study encourages examining the genetics of individual post-traumatic stress disorder symptoms across psychiatric disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tardive dyskinesia (TD) is a potentially irreversible and often debilitating movement disorder secondary to chronic use of dopamine receptor blocking medications. Genetic factors have been implicated ...in the etiology of TD. We therefore have reviewed the most promising genes associated with TD, including DRD2, DRD3, VMAT2, HSPG2, HTR2A, HTR2C, and SOD2. In addition, we present evidence supporting a role for these genes from preclinical models of TD. The current understanding of the etiogenesis of TD is discussed in the light of the recent approvals of valbenazine and deutetrabenazine, VMAT2 inhibitors, for treating TD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PURPOSE OF REVIEWThis review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects.
RECENT FINDINGSAntipsychotics prescribed to treat ...psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications.
SUMMARYThe findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings.
Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a cross-disorder ...GWAS meta-analysis of 3495 AN cases, 2688 OCD cases, and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (r
= 0.49 ± 0.13, p = 9.07 × 10
) and a sizable SNP heritability (SNP h
= 0.21 ± 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., r
= 0.36 with bipolar disorder and 0.34 with neuroticism) and negative genetic correlations with metabolic phenotypes (e.g., r
= -0.25 with body mass index and -0.20 with triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN-OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Precision medicine utilizing genetic testing has recently received much attention given that the variability of response and tolerability to psychotropic medications are partly due to an individual's ...genetic variations. This has led to increasing research to investigate the role of specific genetic factors on psychotropic medication response and utility of testing in the clinical realm. Antidepressant medications are the first-line pharmacological treatment for anxiety disorders and obsessive-compulsive disorder (OCD). However, 20-50% of patients show poor or minimal response to these medications. We will review the current literature on pharmacogenetics in psychiatry, specifically in anxiety disorders and OCD. Genetic variants may be clinically useful in predicting antidepressant resistance versus response in patients with anxiety disorders and/or OCD, thereby, reducing their duration of suffering via the traditional trial-and-error method of prescribing and improving clinical outcome. Limited studies have been published in pharmacogenetics of anxiety disorders and OCD with inconsistent findings at this time. Future directions should focus more effort into examining pharmacogenetics of these disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Research demonstrates the important role of genetic factors in attention-deficit/hyperactivity disorder (ADHD). DNA sequencing of families provides a powerful approach for identifying de ...novo (spontaneous) variants, leading to the discovery of hundreds of clinically informative risk genes for other childhood neurodevelopmental disorders. This approach has yet to be extensively leveraged in ADHD. We conduct whole-exome DNA sequencing in 152 families, comprising a child with ADHD and both biological parents, and demonstrate a significant enrichment of rare and ultra-rare de novo gene-damaging mutations in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3206 ADHD cases and 5002 controls), we identify lysine demethylase 5B ( KDM5B) as a high-confidence risk gene for ADHD and estimate that 1057 genes contribute to ADHD risk. Using our list of genes harboring ultra-rare de novo damaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions and are enriched in several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. This work provides insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.
•We examined the DRD3 and BDNF genes in alcohol use disorders in schizophrenia patients.•We found BDNF Val66Met and haplotypes to be associated with alcohol dependence.
Alcohol use disorder (AUD) is ...a leading risk factor of disease burden in the world. It is also commonly comorbid with over 20% of schizophrenia patients. The brain-derived neurotrophic factor (BDNF) and dopamine D3 receptor (DRD3) have been implicated in alcohol drinking behaviour. Previous genetic studies of the BDNF and DRD3 genes produced mixed findings; however, only one study investigated two BDNF genetic markers with alcohol dependence in schizophrenia patients. We investigated 15 single-nucleotide polymorphisms (SNPs) in DRD3 and four SNPs in BDNF for possible association with alcohol abuse or dependence in schizophrenia patients of European ancestry (N = 195). The patients were assessed for the occurrence of alcohol abuse or alcohol dependence using the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-I/P). We found the BDNF Val66Met to be associated with alcohol dependence (p = 0.004). We also found haplotypes across BDNF to be nominally associated with alcohol dependence. Analyses of DRD3 markers and haplotypes yielded mostly negative findings. Our findings support a role of the BDNF gene in alcohol dependence in schizophrenia patients. Larger samples are required to confirm our findings, particularly those of BDNF haplotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objectives: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current ...knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).
Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.
Results: The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition.
Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
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IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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