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Degenhardt states that there are no conflicts of interest. ...doi:10.1515/medgen-2020-2009 fatcat:ieg6ftiahffalo3v7hqcnqlwrq
Degenhardt · M. M. NöthenDie Rolle seltener Varianten bei häufigen Krankheiten Zusammenfassung Häufige Krankheiten, die sog. ... Degenhardt und M.M. Nöthen geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. ...doi:10.1007/s11825-019-0246-2 fatcat:oquewg27zff6tmhyur6uw5it7u
After a short summary on Fragile-X-Syndrome and fmr1-premutation, we present a case report on a patient pre diagnosed with fmr1-premutation undergoing a series of 14 ECTs because of a treatment resistant major depressive episode. In the course of the series, several unexpected adverse incidents occurred. According to a literature research we did on PubMed, we concluded that these adverse incidents may be related to fmr1-premutation and associated abnormities in cerebral and other physical features.doi:10.33425/2639-9474.1187 fatcat:fumxdduxorhdhfxovwzsxkljyu
doi:10.1007/s00787-021-01761-2 pmid:33772393 fatcat:po7pk6ubnzf2fjhca6qs765acq
Degenhardt · A. J. ... Degenhardt und A.J. Forstner geben an, dass kein Interessenkonflikt besteht. Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren. Access. ...doi:10.1007/s00115-018-0670-6 pmid:30758637 fatcat:awbrgrzckbdhjdolsefcfojnvm
Alcohol Use Disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n=53) and controls (n=58) using a brain region-specific approach. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatumdoi:10.1101/2021.08.01.21261118 fatcat:mdtwf3jwz5asffjwzk5w3hizuu
more »... ), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted Correlation Network Analysis (WGCNA), gene-set and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < .05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < .05) were found in the CN (n=6), VS (n=18) and ACC (n=1). These findings were mapped to several genes including IREB2, SLC30A8, and DDAH2. In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD
It has been shown previously that homozygous and compound-heterozygous variants affecting protein function in the human NLRP genes impact reproduction and/or fetal imprinting patterns. These variants represent so-called 'maternal effect mutations', that is, although female variant carriers are healthy, they are at risk of reproductive failure, and their offspring may develop aberrant methylation and imprinting disorders. In contrast, the relevance to reproductive failure of maternaldoi:10.1038/ejhg.2017.94 pmid:28561018 pmcid:PMC5567160 fatcat:wvynfufcdvacrehhicjt54xhwq
more »... NLRP7 variants remains unclear. The present report describes the identification of a heterozygous NLRP7 variant in a healthy 28-yearold woman with a history of recurrent reproductive failure, and the molecular findings in two of the deceased offspring. Nextgeneration sequencing (NGS) for NLRP variants was performed. In the tissues of two offspring (one fetus; one deceased premature neonate) methylation of imprinted loci was tested using methylation-specific assays. Both pregnancies had been characterized by the presence of elevated human chorionic gonadotropin (hCG) levels and ovarian cysts. In the mother, a heterozygous nonsense 2-bp deletion in exon 5 of the NLRP7 gene was identified (NM_001127255.1:c.2010_2011del, p. (Phe671Glnfs*18) ). In the two investigated offspring, heterogeneous aberrant methylation patterns were detected at imprinted loci. The present data support the hypothesis that heterozygous NLRP7 variants contribute to reproductive wastage, and that these variants represent autosomal dominant maternal effect variants which lead to aberrant imprinting marks in the offspring. Specific screening and close prenatal monitoring of NLRP7 variant carriers is proposed. Egg donation might facilitate successful pregnancy in heterozygous NLRP7 variant carriers.
The 22q11.2 deletion is the strongest known genetic risk factor for schizophrenia. Research has implicated microRNA-mediated dysregulation in 22q11.2 deletion syndrome (22q11.2DS) schizophrenia-risk. Primary candidate genes are DGCR8 (DiGeorge syndrome critical region gene 8), which encodes a component of the microprocessor complex essential for microRNA biogenesis, and MIR185, which encodes microRNA 185. Mouse models of 22q11.2DS have demonstrated alterations in brain microRNA biogenesis, anddoi:10.3389/fnmol.2013.00047 pmid:24367288 pmcid:PMC3851736 fatcat:36veb6jtvrgkbe2sige3l7j27m
more »... hat DGCR8 haploinsufficiency may contribute to these alterations, e.g., via downregulation of a specific microRNA subset. miR-185 was the top-scoring down-regulated microRNA in both the prefrontal cortex and the hippocampus, brain areas which are the key foci of schizophrenia research. This reduction in miR-185 expression contributed to dendritic and spine development deficits in hippocampal neurons. In addition, miR-185 has two validated targets (RhoA, Cdc42), both of which have been associated with altered expression levels in schizophrenia. These combined data support the involvement of miR-185 and its down-stream pathways in schizophrenia. This review summarizes evidence implicating microRNA-mediated dysregulation in schizophrenia in both 22q11.2DS-related and idiopathic cases.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany.doi:10.18154/rwth-conv-243309 fatcat:kmm42aed3baptdpmwbkkrgnzle
more »... ES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (p adj < 0.006) and schizophrenia (p adj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.
Linkage and fine mapping studies have established that the neuregulin 3 gene (NRG3) is a susceptibility locus for schizophrenia. Association studies of this disorder have implicated NRG3 variants in both psychotic symptoms and attention performance. Psychotic symptoms and cognitive deficits are also frequent features of bipolar disorder. The aims of the present study were to extend analysis of the association between NRG3 and psychotic symptoms and attention in schizophrenia and to determinedoi:10.1017/s1461145712000697 pmid:22831755 fatcat:t2rtjqcknrd7hm4p6k2ckcnyxy
more »... ther these associations also apply to bipolar disorder. A total of 358 patients with schizophrenia and 111 patients with bipolar disorder were included. Psychotic symptoms were evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and attention performance was assessed using the Trail Making Test (TMT). Symptoms and performance scores were then tested for association with the NRG3 variant rs6584400. A significant association was found between the number of rs6584400 minor alleles and the total OPCRIT score for psychotic symptoms in patients with schizophrenia. Moreover, in both schizophrenia and bipolar disorder patients, minor allele carriers of rs6584400 outperformed homozygous major allele carriers in the TMT. The results suggest that rs6584400 is associated with psychotic symptoms and attention performance in schizophrenia. The finding of a significant association between rs6584400 and attention performance in bipolar disorder supports the hypothesis that this NRG3 variant confers genetic susceptibility to cognitive deficits in both schizophrenia and bipolar disorder.
Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencingdoi:10.1101/116624 fatcat:k3dhigbodnftnmyjvsoh2m2gra
more »... aches. Here we advocate a complementary approach making use of already existing GWAS data: applying a data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research,to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2,835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. Two of these - one associated with eating disorder and the other with anxiety - remained significant in an independent dataset after robust correction for multiple testing, showing considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively). Our approach may help detect novel specific genotype-phenotype relationships in BD typically not explored by analyses like GWAS. While we adapted the data mining tool within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.
Aims Phosphatase inhibitor-1 (I-1) is a conditional amplifier of b-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to b-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. Methods and results We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiacdoi:10.1093/cvr/cvn208 pmid:18689792 fatcat:mv2ekmfcl5amhhtbndzc2mhz2a
more »... function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to badrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the b-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute badrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca 2þ release channel and the sarcoplasmic reticulum (SR) Ca 2þ -ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca 2þ release and Ca 2þ uptake and thus stabilize the SR and account for the protection. Conclusion Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.
AbstractAlcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevantdoi:10.1101/2021.10.04.21264523 fatcat:uv7xmpacazeydizt2kus4pnfiy
more »... r mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. In the dorsal striatum, we discovered differential expression (FDR<0.05) for a total of 50 genes. In the VS, DE genes at FDR<0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.
Motivation: Complex neuropsychiatric conditions including autism spectrum disorders are among the most heritable neurodevelopmental disorders with distinct profiles of neuropsychological traits. A variety of genetic factors modulate these traits (phenotypes) underlying clinical diagnoses. To explore the associations between genetic factors and phenotypes, genome-wide association studies are broadly applied. Stringent quality checks and thorough downstream analyses for in-depth interpretation ofdoi:10.1101/336776 fatcat:hoe5mkff7rf7hd57nvz57uallq
more »... the associations are an indispensable prerequisite. However, in the area of neuropsychology there is no framework existing, which besides performing association studies also affiliates genetic variants at the brain and gene network level within a single framework. Results: We present a novel bioinformatics approach in the field of neuropsychology that integrates current state-of-the-art tools, algorithms and brain transcriptome data to elaborate the association of phenotype and genotype data. The integration of transcriptome data gives an advantage over the existing pipelines by directly translating genetic associations to brain regions and developmental patterns. Based on our data integrative approach, we identify genetic variants associated with Intelligence Quotient (IQ) in an autism cohort and found their respective genes to be expressed in specific brain areas. Conclusion: Our data integrative approach revealed that IQ is related to early down-regulated and late up-regulated gene modules implicated in frontal cortex and striatum, respectively. Besides identifying new gene associations with IQ we also provide a proof of concept, as several of the identified genes in our analysis are candidate genes related to intelligence in autism, intellectual disability, and Alzheimer's disease. The framework provides a complete extensive analysis starting from a phenotypic trait data to its association at specific brain areas at vulnerable time points within a timespan of four days.
To avoid technical artifacts in CNV calling, stringent quality control criteria were applied prior to computational CNV prediction, as described in Degenhardt et al.  . ...doi:10.1371/journal.pone.0064035 pmid:23843933 pmcid:PMC3699619 fatcat:m3rl4lzypfazxcucwjpjzvqb3e
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