Showing papers in "Psychiatric Genetics in 2018"
TL;DR: The PRS for schizophrenia varied significantly between ancestral groups (P<2×10−16) and was much higher in African than European HapMap subjects, and clearly contains a strong ancestry component.
Abstract: BackgroundThe polygenic risk score (PRS) for schizophrenia, derived from very large numbers of weakly associated genetic markers, has been repeatedly shown to be robustly associated with schizophrenia in independent samples and also with other diseases and traits.AimThis study aims to explore the di
108 citations
TL;DR: Genetic evidence supporting associations between hippocampal volume and MDD, which may reflect underlying cellular stress responses is provided, and biological mechanisms that should be further explored in the search for disease-modifying therapeutic targets for depression are provided.
Abstract: Objective
Glycogen synthase kinase 3β (GSK3β) has been implicated in mood disorders. We previously reported associations between a GSK3β polymorphism and hippocampal volume in major depressive disorder (MDD). We then reported similar associations for a subset of GSK3β-regulated genes. We now investigate a comprehensive list of genes encoding proteins that directly interact with GSK3β to identify a genotypic network influencing hippocampal volume in MDD.
Participants and methods
We used discovery (N=141) and replication (N=77) recurrent MDD samples. Our gene list was generated from the NetworKIN database. Hippocampal measures were derived using an optimized Freesurfer protocol. We identified interacting single nucleotide polymorphisms using the machine learning algorithm Random Forest and verified interactions using likelihood ratio tests between nested linear regression models.
Results
The discovery sample showed multiple two-single nucleotide polymorphism interactions with hippocampal volume. The replication sample showed a replicable interaction (likelihood ratio test: P=0.0088, replication sample; P=0.017, discovery sample; Stouffer’s combined P=0.0007) between genes associated previously with endoplasmic reticulum stress, calcium regulation and histone modifications.
Conclusion
Our results provide genetic evidence supporting associations between hippocampal volume and MDD, which may reflect underlying cellular stress responses. Our study provides evidence of biological mechanisms that should be further explored in the search for disease-modifying therapeutic targets for depression.
23 citations
TL;DR: The findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors.
Abstract: The clinical comorbidity of alcohol dependence (AD) and major depressive disorder (MDD) is well established, whereas genetic factors influencing co-occurrence remain unclear. A recent study using polygenic risk scores (PRS) calculated based on the first-wave Psychiatric Genomics Consortium MDD meta-analysis (PGC-MDD1) suggests a modest shared genetic contribution to MDD and AD. Using a (~10 fold) larger discovery sample, we calculated PRS based on the second wave (PGC-MDD2) of results, in a severe AD case–control target sample. We found significant associations between AD disease status and MDD-PRS derived from both PGC-MDD2 (most informative P-threshold=1.0, P=0.00063, R2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R2=0.663%) meta-analyses; the larger discovery sample did not yield additional predictive power. In contrast, calculating PRS in a MDD target sample yielded increased power when using PGC-MDD2 (P-threshold=1.0, P=0.000038, R2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R2=0.81%). Furthermore, when calculating PGC-MDD2 PRS in a subsample of patients with AD recruited explicitly excluding comorbid MDD, significant associations were still found (n=331; P-threshold=1.0, P=0.042, R2=0.398%). Meanwhile, in the subset of patients in which MDD was not the explicit exclusion criteria, PRS predicted more variance (n=999; P-threshold=1.0, P=0.0003, R2=0.693%). Our findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors. Larger target samples are needed to reduce noise and take advantage of increasing discovery sample size.
18 citations
TL;DR: The suicide-associated gene coexpression network was found, finding that suicide genes are significantly concentrated within chromosomes 11 and 6, and it turned out that genetically, suicidal behavior is more likely in patients with mood and affective disorders.
Abstract: OBJECTIVE In recent decades, the role of genetic factors in the predisposition to suicidal behavior has attracted considerable attention. Although each genetic investigation appears to be valuable, no one study on its own can comprehensively explain the etiology of suicidal behavior. METHODS In this study, using a broad literature review, we found the suicide-associated gene coexpression network. In addition, cytoband, molecular function, biological process, cellular component, tissue-based expression, and disease/disorder enrichment analyses were carried out to determine the most central cellular and molecular infrastructures involved in suicidal behavior. RESULTS The reconstructed network consisted of 104 genes, including 91 previously known genes and 13 novel genes, and 354 interactions. Topological analysis showed that in total, CCK, INPP1, DDC, and NPY genes are the most fundamental hubs in the network. We found that suicide genes are significantly concentrated within chromosomes 11 and 6. Further analysis showed that monoaminergic signal transduction, especially through GPCRs, in the cingulate gyrus, superior prefrontal gyrus, dorsal striatum, and the cerebellum are the main, deficient routes in suicide. Moreover, it turned out that genetically, suicidal behavior is more likely in patients with mood and affective disorders. CONCLUSION Like other behavioral disorders, suicide has a complex and multifactorial basis and at present, the only approaches to the integrated study of such disorders are computer-based methods. The results of such studies, although subject to a degree of uncertainty, however, can pave the way for future basic and clinical studies.
12 citations
TL;DR: Evidence is provided of association between the DRD4 exon III VNTR polymorphism and novelty-seeking, which is inconsistent with the results of previous meta-analysis, and several direct and indirect moderators are identified to explain contradictory results.
Abstract: Objective Two widely studied genetic polymorphisms in the dopaminergic system [DRD4 exon III variable number of tandem repeat (VNTR) and COMT Val158Met] have been reported to be associated with novelty-seeking, but the results have been highly inconsistent. Therefore, a meta-analysis of the associations between these two polymorphisms and novelty-seeking was conducted. Participants and methods For DRD4, 24 studies comprising 27 samples and including 4933 participants were selected. Genotype grouping, sex, mean age, ethnicity, and sample characteristics were examined as moderators. For COMT, nine studies comprising 13 samples and including 2633 participants were selected. Sex, mean age, ethnicity, and sample characteristics were included as moderators. We also tested for possible publication bias. Results The significant association between the DRD4 polymorphism and novelty-seeking was supported, but no association was found between the COMT polymorphism and novelty-seeking. In addition, our findings revealed that sex and age both directly moderate the relationship between DRD4 and novelty-seeking. Meanwhile, ethnicity can interact with age, sex, and genotype grouping, and age and sex can interact with each other, to moderate the association between the DRD4 exon III VNTR polymorphism and novelty-seeking. Conclusion Our results provide evidence of association between the DRD4 exon III VNTR polymorphism and novelty-seeking, which is inconsistent with the results of previous meta-analysis. Furthermore, several direct and indirect moderators are also identified to explain contradictory results in the existing literature. However, our results regarding COMT are consistent with those of previous meta-analysis.
11 citations
TL;DR: The results did not support the association between FOXP2 rs10447760 and schizophrenia in a Chinese Han population, and large-scale genetic replication studies with different racial and geographic origins are required in the future.
Abstract: BACKGROUND Schizophrenia (SCZ) is a severe and heritable psychiatric disorder, and previous studies have shown that regulation of the forkhead-box P2 gene (FOXP2) may play a role in schizophrenia. Moreover, just a few studies have identified a single nucleotide polymorphism (SNP) rs10447760 within the gene that was a risk variant for SCZ in the Chinese Han population. METHODS To examine whether the variant in the FOXP2 gene contributes toward SCZ susceptibility, we carried out an association analysis of the SNP rs10447760 of the FOXP2 gene in a case-control study (1405 cases, 1137 controls) from China. RESULTS We identified no association of rs10447760 in the FOXP2 gene with SCZ (all P>0.05). In addition, a meta-analysis indicated that the SNP rs10447760 was not associated with susceptibility to SCZ in Han Chinese populations (pooled odds ratio=1.44, 95% confidence interval: 0.63-3.31, P=0.39). CONCLUSION Thus, our results did not support the association between FOXP2 rs10447760 and schizophrenia in a Chinese Han population, and large-scale genetic replication studies with different racial and geographic origins are required in the future.
10 citations
TL;DR: The findings suggest that the COMT gene polymorphisms may influence the response to antipsychotic treatment in Han Chinese patients with schizophrenia.
Abstract: AIM Catechol-O-methyltransferase (COMT) gene variants may be involved in the pathogenesis of psychotic symptoms, and associated especially with negative symptom in schizophrenia, but their roles in cognitive function and treatment response remain unclear. The aim of this study was to explore the association between COMT gene polymorphisms, clinical symptoms (including cognitive function), and treatment response to antipsychotic medications in patients with schizophrenia. PATIENTS AND METHODS A total of 200 Han Chinese inpatients with schizophrenia were recruited in accordance with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). In total, 96 of them completed assessments at baseline and after 8 weeks of antipsychotic treatment. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale (PANSS), and cognitive function was evaluated using the Verbal Fluency Test, Trail Making Test A-B, Stroop Color-Word Test, and Wisconsin Card Sorting Test. Two single nucleotide polymorphisms, rs4680 and rs165599, on the COMT gene were genotyped. RESULTS At baseline, we found no significant genotypic association between rs4680 and clinical symptoms or cognitive function. After 8 weeks of antipsychotic treatment, compared with patients with GG genotype, patients with AA/AG genotypes at rs4680 showed significantly higher scores on PANSS total, both at baseline and at the end of 8 weeks, especially in negative and general psychopathology symptoms. Patients with GG at rs165599 scored significantly higher on the Stroop test, suggesting better cognitive performance after 8 weeks of treatment. No significant association was found between rs165599 genotype and psychiatric symptoms as assessed by the PANSS and cognitive function tests at baseline. CONCLUSION Our findings suggest that the COMT gene polymorphisms may influence the response to antipsychotic treatment in Han Chinese patients with schizophrenia.
10 citations
TL;DR: This analysis failed to show that the PRS captures a cumulative effect of multiple variants impacting the expression of a small number of genes and it failed to focus attention on a smallNumber of genes of biological relevance.
Abstract: BACKGROUND The polygenic risk score (PRS) is derived from single nucleotide polymorphisms (SNPs) including those that are genome-wide significant and also including a large number of others more weakly associated with schizophrenia. Such variants are widely dispersed, though concentrated near genes expressed in the brain, and it has been proposed that these SNP associations result from impacts on cell regulatory networks that ultimately affect the expression or function of a modest number of 'core' genes. A previous study showed association of some genome-wide association study-significant variants with expression of a number of genes, by examining pairwise correlations of gene expression with SNP genotypes. METHODS The present study used data downloaded from the CommonMind Consortium site, consisting of SNP genotypes and RNAseq expression data from the dorsolateral prefrontal cortex, to examine whether the expression of individual genes or sets of genes correlated with PRS in 207 controls and 209 schizophrenia cases. RESULTS Although the PRS was significantly associated with phenotype, the correlations with genes and gene sets followed distributions expected by chance. Thus, this analysis failed to show that the PRS captures a cumulative effect of multiple variants impacting the expression of a small number of genes and it failed to focus attention on a small number of genes of biological relevance. CONCLUSION The multiple SNP associations observed in schizophrenia may result from other mechanisms, including effects mediated indirectly through environmental risk factors.
7 citations
TL;DR: This is the first study that reports an association between perceived stress and MTHFR methylation levels, and adds evidence to the emerging role of epigenetic changes in endophenotypes related to affective disorders.
Abstract: Background Epigenetic factors have been identified in the past years as interesting candidates for psychiatric disorders and related endophenotypes. It has been found that the methylenetetrahydrofolate reductase (MTHFR) gene is associated with major depressive disorder, and the aim of the current study was to examine the possible association between perceived stress and MTHFR methylation, taking into account depressive symptoms as a covariate. Participants and methods Seventy-eight healthy Colombian participants (mean age=20.9 years; SD=3.0) were evaluated with the Perceived Stress Scale and with the Patient Health Questionnaire-9 for depressive symptomatology. MTHFR methylation levels were measured with a methylation-sensitive high-resolution melting method. A multiple regression analysis (adjusting for age, sex, and depressive symptoms) was carried out to assess the association between MTHFR methylation and perceived stress scores. Results We found a significant inverse correlation between MTHFR methylation levels and perceived stress scores (r=-0.502; P=5.9×10(-5)), which remained significant after being adjusted for age, sex, and depressive symptomatology. Conclusion To our knowledge, this is the first study that reports an association between perceived stress and MTHFR methylation levels. This report adds evidence to the emerging role of epigenetic changes in endophenotypes related to affective disorders.
6 citations
TL;DR: This research presents a novel probabilistic approach that allows us to assess the importance of knowing the carrier and removal status of canine coronavirus, as a source of infection for other animals.
Abstract: Supplemental Digital Content is available in the text.
5 citations
TL;DR: This meta-analysis indicated that rs3737597 of DISC1 was significantly associated with schizophrenia in Europeans, and it can be suggested as an ethnic-specific risk genetic factor.
Abstract: INTRODUCTION In recent years, various studies have accumulated evidence of the involvement of single nucleotide polymorphisms (SNPs) in introns and exons in schizophrenia. The association of functional SNPs in the 3'-untranslated regions with schizophrenia has been explored in a number of studies, but the results are inconclusive because of limited meta-analyses. To systematically analyze the association between SNPs in 3'-untranslated regions and schizophrenia, we conducted a meta-analysis by combining all available studies on schizophrenia candidate genes. MATERIALS AND METHODS We searched candidate genes from the schizophrenia database and performed a comprehensive meta-analysis using all the available data up to August 2017. The association between susceptible SNPs and schizophrenia was assessed by the pooled odds ratio with 95% confidence interval using fixed-effect and random-effect models. RESULTS A total of 21 studies including 8291 cases and 9638 controls were used for meta-analysis. Three investigated SNPs were rs165599, rs3737597, and rs1047631 of COMT, DISC1, and DTNBP1, respectively. Our results suggested that rs3737597 showed a significant association with schizophrenia in Europeans (odds ratio: 1.584, P: 0.002, 95% confidence interval: 1.176-2.134) under a random-effect framework. CONCLUSION This meta-analysis indicated that rs3737597 of DISC1 was significantly associated with schizophrenia in Europeans, and it can be suggested as an ethnic-specific risk genetic factor.
TL;DR: Department of Research Planning, Mental Health Research Institute, National Center for Mental Health, Asan Institute for Life Sciences, and Department of Psychiatry, Yale University School of Medicine.
Abstract: Department of Research Planning, Mental Health Research Institute, National Center for Mental Health, Asan Institute for Life Sciences, Department of Psychiatry, Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Department of Psychiatry, School of Medicine, Sungkyunkwan University, Samsung Medical Center, Department of Health Screening and Promotion Center, Asan Medical Center, Seoul, Republic of Korea and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA Correspondence to Jin Pyo Hong, MD, Department of Psychiatry, School of Medicine, Sungkyunkwan University, Samsung Medical Center, 81 Irwon-ro Gangnam-gu, Seoul 06351, Republic of Korea Tel: + 82 234 103 585; fax: + 82 234 100 050; e-mail: suhurhong@gmail.com
TL;DR: This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.
Abstract: Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.
TL;DR: It is concluded that BRD1 and ZBED4 might be population specific in schizophrenia and may not account for a substantial proportion of genetic risk for schizophrenia in the Asian population.
Abstract: The distal long arm of chromosome 22 (22q13.3) may harbor genes implicated in schizophrenia. This is evidenced by various genetic mapping studies. BRD1 and its neighboring gene ZBED4, both located within this region, have repeatedly been found to be associated with schizophrenia in the Caucasian population. In this study, we chose seven SNPs (two BRD1 SNPs, five ZBED4 SNPs) to carry out an association study between these two genes and schizophrenia in the Chinese population. However, no significant result was obtained, which was consistent with the Japanese population. Taken together, we could conclude that BRD1 and ZBED4 might be population specific in schizophrenia and may not account for a substantial proportion of genetic risk for schizophrenia in the Asian population.
TL;DR: In veterans with military-related PTSD, a familial vulnerability for bipolar disorder and anxiety disorders was associated with an increased risk of developing PTSD with psychotic features.
Abstract: Aims/objectives/background Post-traumatic stress disorder (PTSD) is a leading cause of morbidity among military veterans, with up to one-in-five individuals with PTSD also having psychotic symptoms. The current study was designed to determine the association between a known family history of psychiatric illness and risk of developing psychosis in patients with PTSD. Methods Retrospective medical record review was performed on a cohort study of 414 consecutive individuals admitted to the Veteran Administration in 2014 with a diagnosis of military-related PTSD, but without a prior diagnosis of a psychotic disorder. PTSD with psychotic features was defined as the presence of hallucinations, paranoia, other delusions, thought insertion, withdrawal, broadcasting, and/or dissociative episodes. Results Overall, 22.9% of individuals with PTSD had psychotic symptoms. Having a first-degree relative with bipolar affective and with anxiety disorders was associated with an increased risk of PTSD with psychosis (odds ratio=2.01, 95% confidence interval: 1.01-4.45 and odds ratio=2.72, 95% confidence interval: 1.16-6.41, respectively). A family history of schizophrenia or depression was not associated with risk of developing psychotic features in patients with PTSD. In veterans with military-related PTSD, a familial vulnerability for bipolar disorder and anxiety disorders was associated with an increased risk of developing PTSD with psychotic features. These are preliminary data, given the limitations of a retrospective record review design. These results await replication in future prospective direct family interview studies.
TL;DR: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center and Institutes of Biomedical Sciences.
Abstract: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, People’s Republic of China Correspondence to Guang He, PhD, Bio-X Institutes, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, People’s Republic of China Tel/fax: + 86 216 282 2491; e-mail: heguang@sjtu.edu.cn
TL;DR: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Institutes, Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center and Shanghai Key laboratory of Reproductive Medicine are disclosed.
Abstract: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Institutes, Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center and Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China Correspondence to Guang He, PhD, Bio-X Institutes, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, People’s Republic of China Tel/fax: + 86 216 282 2491; e-mail: heguang@sjtu.edu.cn
Journal Article•
TL;DR: A 28-year-old Sri Lankan male with Langer-Giedion syndrome and high-functioning autism is described, with a karyotype found a microdeletion of the long arm of chromosome 8 with mosaicism.
Abstract: The trichorhinophalangeal syndrome is a rare genetic disorder with a classical clinical triad of sparse hair, bulbous nose, and short digits. There are three known phenotypes, and the type II with exostoses in long bones is known as Langer-Giedion syndrome. Here, we describe a 28-year-old Sri Lankan male with Langer-Giedion syndrome and high-functioning autism. The karyotype found a microdeletion of the long arm of chromosome 8 with mosaicism [46,XY/46,XY,del(8)(q24.1q24.3)]. This is probably the first report of Langer-Giedion Syndrome with autism and the first report of the genetic syndrome from Sri Lanka. Furthermore, we could only access one previous report of the same microdeletion, which was from an autopsy of a 36-week-old infant.
TL;DR: A case of Nablus mask-like facial syndrome accompanied by a diagnosis of ASD is reported, which is a rare condition with a characteristic facial appearance.
Abstract: Nablus mask-like facial syndrome is a rare condition with a characteristic facial appearance. Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by impaired social interaction and linguistic skills, limited spheres of interest and repetitive or stereotyped behaviors. We report a case of Nablus mask-like facial syndrome accompanied by a diagnosis of ASD. The parents gave their written consent for the publication of this report.